The Optispan Podcast with Matt Kaeberlein PhD

In this episode of the Optispan Podcast, our host sits down with Peter to explore a range of topics related to healthspan, lifespan, and longevity interventions. The conversation kicks off with a discussion on the definition of healthspan, covering aspects of physical performance, cognitive function, and emotional well-being. Peter emphasizes the importance of both subjective and objective measures in assessing healthspan, noting that while physical and cognitive functions can be tracked quantitatively, emotional health is more challenging to define but equally crucial. The discussion also touches on the widening gap between healthspan and lifespan, with Peter arguing that prioritizing healthspan naturally extends lifespan.

The conversation shifts to the role of exercise in optimizing long-term health. Peter outlines the distinction between general exercise and targeted training, advocating for specificity in movement to maintain functionality as one ages. He cautions against the common mistake of exercising without a clear purpose, emphasizing that while any physical activity is beneficial, a strategic approach yields the best results. The discussion also tackles common fitness misconceptions, such as the trade-off between endurance activities like running and resistance training, and the necessity of incorporating both for optimal aging outcomes.

Nutrition emerges as a central theme, with Peter addressing the ongoing debate around diet composition, caloric intake, and meal timing. He argues that energy balance is the most critical factor in diet, though the quality of food choices significantly impacts one's ability to maintain that balance. The conversation touches on processed foods, with Peter acknowledging their utility in a modern lifestyle while emphasizing the importance of ingredient quality. He also weighs in on time-restricted eating, stating that while it can be a useful tool for caloric control, the direct longevity benefits remain unproven.

Alcohol consumption is another contested topic, with Peter dissecting the claims around its potential benefits and risks. He explains that while there is no clear evidence that moderate alcohol intake improves longevity, the associated lifestyle and social benefits might outweigh negligible risks for many individuals. The discussion also explores the effects of alcohol on sleep and metabolic health, reinforcing the notion that timing and quantity play critical roles in its impact on overall well-being.

Finally, the episode wraps up with a deep dive into the validity and clinical utility of biological aging clocks, particularly epigenetic tests. Peter expresses skepticism about their accuracy and actionability, emphasizing that while many biomarkers correlate with aging, aggregating them into a single score lacks scientific rigor. The conversation then expands to experimental therapies, including rapamycin, stem cells, and peptides, with Peter advocating for cautious, evidence-based approaches rather than speculative interventions. The discussion concludes with a lively rapid-fire ranking of various longevity-related interventions, providing listeners with a practical framework for assessing current trends in the field.

In this episode of the Optispan Podcast, the hosts discuss the emerging market of longevity supplements for companion animals, focusing on a specific product called Pure Pet. They analyze the composition of this supplement, which includes NMN (nicotinamide mononucleotide), a SIRT6 activator derived from seaweed, and hyaluronic acid. While acknowledging the growing interest in extending healthspan beyond humans, they critically assess the scientific validity of these ingredients and question whether sufficient evidence supports their use in pets. The conversation raises concerns about the marketing of such products, emphasizing the need for rigorous scientific validation before claims are made.

The discussion highlights the broader challenges in the supplement industry, particularly regarding transparency, efficacy, and potential risks. The hosts express skepticism about the benefits of NMN in pets, citing mixed results from mouse studies and the absence of concrete data in dogs or cats. They also question the impact of the SIRT6 activator, noting that while some studies suggest a role in DNA repair and cellular health, there is no established evidence of lifespan extension in animals. Additionally, the potential for negative effects, such as kidney damage in aged animals, is addressed as a critical risk factor.

Expanding the conversation, the hosts explore the ethical responsibility of companies marketing longevity supplements for pets. They argue that if a product claims to enhance health and longevity, it should be backed by robust research. The discussion touches on the influence of academic scientists endorsing such products, questioning whether researchers should align their names with commercial ventures that lack conclusive evidence. The need for third-party, unbiased testing is emphasized as a crucial step toward accountability in the industry.

The episode also delves into broader regulatory and financial implications of longevity supplements, discussing how current incentive structures may discourage rigorous testing. The hosts express frustration with the lack of oversight and call for better mechanisms to ensure product efficacy and safety. They point out that many supplements on the market contain either ineffective dosages or do not even include the claimed active ingredients, further complicating consumer trust in the industry.

Wrapping up, the hosts reflect on the potential of longevity science and the necessity for higher standards in both human and pet supplements. They encourage listeners to remain skeptical of bold health claims, seek out well-researched interventions, and advocate for more stringent scientific scrutiny in the field. The episode closes with a preview of an upcoming discussion on human longevity supplements endorsed by celebrities, highlighting the intersection of science, marketing, and consumer awareness in the longevity space.

In this episode of the Optispan Podcast, the hosts discuss two fascinating topics: the impact of hypochondriasis on mortality and a recent study on aging-related changes in the brain. The episode begins with an exploration of a JAMA Psychiatry paper analyzing all-cause mortality among individuals with hypochondriasis. The discussion centers around the potential psychological risks associated with an obsession over biological age testing and other health diagnostics. While some individuals may use such data to improve their health behaviors, excessive fixation can lead to anxiety, stress, and possibly even negative health outcomes. The hosts reflect on whether health trackers and diagnostics might be harmful for certain individuals, particularly those prone to excessive worry about their health.

The conversation expands into the role of chronic stress and anxiety in biological aging. The hosts acknowledge that while stress has been linked to negative health effects, it remains unclear whether an obsession with health monitoring accelerates aging. They consider the fine line between health optimization and excessive concern, questioning how influencers and the biohacker community contribute to anxiety about aging. They emphasize the importance of self-awareness and encourage listeners to assess whether their use of health tracking tools is benefiting or harming their well-being.

The second half of the episode dives into a recent study from the Allen Institute, published in Nature, which maps aging-related changes in the brain at a high resolution. The study used single-cell transcriptomics to analyze gene expression across various brain regions in young and middle-aged mice. A key finding was that different brain regions age at different rates, with the hypothalamus showing significant changes in gene expression, particularly related to inflammation. While the study provides valuable data, the hosts discuss whether it offers fundamentally new insights or simply reinforces existing knowledge about inflammation and neurovascular changes in aging.

The discussion also touches on the role of glial cells in brain aging, emphasizing their importance in supporting neuronal function and contributing to neuroinflammation. While the study does not suggest any immediate clinical applications, it highlights the potential for targeting neurovascular interactions in future aging interventions. The hosts discuss how maintaining cardiovascular health, through exercise and lifestyle interventions, may support brain health by reducing inflammation and improving neurovascular stability.

The episode concludes with practical takeaways for listeners interested in brain health and longevity. The hosts suggest that engaging in regular exercise, managing stress, and maintaining an intellectually stimulating environment may help slow brain aging. They emphasize the importance of maintaining a balanced approach to health monitoring—leveraging technology and data when useful, but avoiding excessive concern that may lead to anxiety. Looking ahead, they hint at future discussions on neurodegenerative diseases and interventions that may target aging at a cellular level.

In this special New Year’s episode of the Optispan Podcast, Matt and Nick reflect on their goals for 2025, the direction of the podcast, and take the opportunity to clarify or correct statements from past episodes. The discussion begins with a candid look at personal and professional resolutions, including an increased focus on cardiovascular fitness, reconnecting with past colleagues, and upcoming book projects related to aging and longevity. The hosts also share their excitement for upcoming collaborations with Peter Attia and Thomas DeLauer, which promise fresh insights and dynamic discussions in the field of healthspan and longevity.

A major segment of the episode is dedicated to revisiting past discussions where clarification or correction is needed. First, they re-examine the costs and benefits of the Ezra whole-body MRI bundle, acknowledging an initial oversight regarding the inclusion of two MRIs in the package. They still express skepticism about the value proposition and the need to prepay for multiple scans without clear long-term benefits. Next, they revisit the DrugAge database, correcting a misinterpretation about its scope. The database primarily includes drugs that have demonstrated at least one positive effect on lifespan, rather than cataloging all tested compounds, including those with neutral or negative effects.

The conversation also dives into biological age testing, a topic that generated significant audience feedback. Matt and Nick discuss Matt’s recent self-experiment comparing different epigenetic tests and the variation in results. They clarify concerns raised by True Diagnostic regarding their methodology and reinforce their stance that current direct-to-consumer biological age tests lack precision and reliability. They caution listeners about over-reliance on these tests for health decisions and emphasize the importance of considering multiple health markers instead of a single biological age score.

Another key topic is the balance of conversation between hosts and guests. Matt responds to audience feedback about the dialogue format, explaining his preference for engaging, back-and-forth discussions rather than traditional structured interviews. He affirms his commitment to maintaining an interactive and exploratory format while also ensuring guests have ample opportunity to share their expertise. Additionally, they address criticisms regarding the inclusion of health influencers and non-scientist guests, defending their approach to featuring a diverse range of perspectives while maintaining scientific rigor.

Finally, the episode touches on reaction videos and the role they play in public discussions around longevity science. They acknowledge critiques of the format but argue that when done responsibly, reaction videos serve as a valuable tool for providing context, correcting misinformation, and fostering meaningful dialogue. Wrapping up, Matt and Nick express their commitment to transparency, ongoing learning, and keeping the podcast a valuable resource for those interested in optimizing health and longevity.

In this episode, Matt and Brian Kennedy delve into the potential benefits and side effects of interventions like Rapamycin, the role of biomarkers, and optimal approaches to enhancing healthspan and cognitive function. Together they highlight the challenges of supplement use, aging research methodologies, and regulatory hurdles like the FDA’s stance on aging. They address emerging ideas such as leveraging AI for aging research, the importance of lifestyle factors like diet and sleep, and the need for actionable biomarkers. The session is a candid exchange of expert opinions, tackling scientific controversies and practical strategies for healthy aging.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

mTOR inhibition improves immune function in the elderly - PubMed

Matt addresses the question about optimal clinical study design for evaluating the efficacy of a putative gerotherapeutic intervention with the example of Joan Mannick’s everolimus trial on immune health and functioning. Joan’s trial was a randomized, double-blind, placebo-controlled trial involving generally healthy, elderly individuals taking various doses of rapamycin (0.5 mg/day and 20 mg/week) and evaluated antibody response to the influenza vaccine four weeks post-vaccination, a marker of immune function that typically declines with age. Participants demonstrated a statistically significant improvement in antibody response compared to placebo.

Nonlinear dynamics of multi-omics profiles during human aging | Nature Aging

Does the rate of aging change across an individual’s life course ? Matt and Brian discuss the limitations in interpreting the study evaluating multi-omic biological aging signatures suggesting individuals go through two accelerated phases of aging in their life, one in their 40’s and the other in their 60’s. Researchers conducted a comprehensive analysis of over 135,000 molecular profiles across 108 adults aged 25 to 75. They examined a wide array of molecules, including metabolites, lipids, proteins, and transcripts, to identify patterns of change associated with aging. Their findings suggest that the human body undergoes dramatic molecular shifts in the 5th and 7th decades of life, challenging the traditional view of a steady age-related decline over time. Further, authors suggest that timing longevity interventions according to these anticipated changes may improve healthy aging outcomes. Matt and Brian conclude that the study has too many limitations to conclude anything about an individual’s rate of aging based on how the clock was developed (cross-sectional, retrospective study on a small and specific population), the limitations of proteomic data used as a surrogate for aging, and the lack of supporting data of external factors that may have influenced these changes.

Evaluation of off-label rapamycin use to promote healthspan in 333 adults - PubMed

Matt addresses the question of optimal dose and regimen of rapamycin for healthy aging by highlighting that the existing clinical literature in normative aging individuals is limited, but there is a growing body of real world data in which most individuals are taking 6 mg per week based on initial studies by Joan Mannick demonstrating improvements in immune health with a similar regimen. This study evaluated off-label rapamycin use in 333 adults taking rapamycin from anywhere between 1 month and several years. The findings suggested that rapamycin can be used safely in normative aging adults over extended periods, with over one-third of users self-reporting positive health outcomes and preliminary signals of decreased severity of COVID-19 symptoms for individuals taking rapamycin. Randomized controlled trials are needed to provide more clarity on optimal dose and regimen for improving various healthspan metrics.

Rapamycin and Alzheimer’s disease: Time for a clinical trial? - PMC

This perspective article coauthored by Matt discusses the potential of rapamycin as a therapeutic intervention for Alzheimer's disease (AD). The authors highlight rapamycin’s promise in various animal models of neurodegeneration and aging, including mouse models of Alzheimer's disease and cognitive decline through its effects on enhancing autophagy, reducing protein aggregation, and modulating inflammatory responses. Clinical trials focused on individuals with neurodegenerative disease and cognitive decline are overdue as promising preclinical data and rapamycin's established safety profile in humans justifies its evaluation in a clinical setting.

Attenuation of age-elevated blood factors by repositioning plasmapheresis: A novel perspective and approach - ScienceDirect

The biological aging process is associated with increased levels of certain plasma factors that impair tissue function, drive inflammation and alter inter-organ communication. These factors contribute to the decline in regenerative capacity and overall health. TPE, commonly known as plasmapheresis, involves the removal and replacement of plasma. This perspective piece reviews existing literature and presents a novel perspective on using therapeutic plasma exchange (TPE) to dilute and reduce the concentration of systemic, age-elevated deleterious factors in the bloodstream. Within preclinical studies, attenuating these harmful factors with TPE restores youthful signaling pathways, enhances tissue function, and promotes systemic rejuvenation.

In this Part 1 episode, Matt and Brian Kennedy cover various aspects of aging research, including the connection between the immune system and aging, the role of inflammation, the potential of supplements and wearables in healthspan, and insights on longevity interventions. They also discuss the challenges in the field regarding clinical practices, the influence of AI on aging research, and personal experiences with health optimization.

This is Part 1 of a two-part series—stay tuned for even more in the next episode.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

https://pubmed.ncbi.nlm.nih.gov/38151871/

Matt and Brian talk about supplementing vitamin D as a healthy aging intervention, specifically when supplementing deficiencies. The RESORT study was a prospective, observational, and longitudinal analysis of 1,328 geriatric rehabilitation inpatients highlighting the importance of supplementing vitamin D in individuals that are deficient and associations with improved age-related outcomes. Researchers measured vitamin D levels near the time of rehabilitation admission, categorizing them as sufficient, insufficient, and deficient. The study examined associations between vitamin D levels and adverse health outcomes, including institutionalization at three months post-discharge, in-hospital mortality, and post-discharge mortality. Patients not using vitamin D supplements and having insufficient or deficient 25(OH)D levels exhibited significantly higher in-hospital mortality compared to those on supplementation. This study highlights the importance of vitamin D in physiological resilience and suggests that monitoring and addressing vitamin D status is crucial to potentially mitigate adverse health outcomes 

Age Reversal & Thymus Rejuvenation TRIIM-X 2024 Update | Dr Greg Fahy Full Interview

Matt discusses his thoughts on the promise and relative safety of the putative gerotherapeutic cocktail including growth hormone, metformin and DHEA, especially considering the preliminary results from the Thymus Regeneration, Immunorestoration, and Insulin Mitigation (TRIIM) trial demonstrating partial thymus regeneration, improvements in immune markers, glucoregulatory improvements, and reversal of epigenetic biological age clock score. This Modern Healthspan podcast is an interview with Dr Greg Fahy, principal investigator of the TRIIM-X trial (12 month follow up to TRIIM), going through the latest updates from the study which assesses the effects of personalized doses of the above interventions on biomarkers for epigenetic aging and immunosenescence, as well as clinical measures and risk factors for conditions such as physical frailty, cancer, cardiovascular disease, diabetes, dementia, and infectious diseases, including flu and COVID-19. 

https://pmc.ncbi.nlm.nih.gov/articles/PMC9810745/

Matt and Brian discuss the significant role of post-menopause on accelerating the biological aging process and contributing to age-related diseases. This review coauthored by Brian highlights progress in understanding the biology of ovarian aging and the potential of manipulating aging-related pathways in animal models for prolonging female reproductive lifespan and healthspan. Further, slow aging of the reproductive system could delay menopause, thereby reducing the incidence of age-related diseases like osteoporosis, cardiovascular disease, and Alzheimer’s while improving overall health in aging women. The review also highlights the personal and social impacts of addressing reproductive decline as it influences women's life choices, often forcing a balance between career aspirations and family planning. Advancements in reproductive longevity research could provide women with greater autonomy over their reproductive health, aligning biological and health outcomes with personal and professional goals. 

https://www.biorxiv.org/content/10.1101/2022.02.06.479300v1

Brian discusses Peter Fedichev’s theory of aging when explaining his perspective on why addressing each hallmark of aging is an insufficient strategy for significantly improving healthy longevity due to the substantial number of permutations and random nature of age-related damage accumulation. This paper highlights Peters’ theory of aging and introduces the novel concept of "thermodynamic biological aging" (tBA), which quantifies the accumulation of random variations in physiological state variables over time. Specifically, this model measures changes in entropy through tracking changes in various biological processes associated with energy usage and heat production (a function of increasing entropy). The study found that tBA increases with chronological age and leads to a linear and irreversible drift in variables associated with physiological health, contributing to the gradual decline in bodily functions associated with aging. The researchers also found that the accumulation of tBA correlates with an exponential rise in the risk of chronic diseases and mortality, aligning with observed patterns in aging populations. The study suggests that the entropic nature of aging imposes fundamental constraints on the potential for age reversal. Despite limitations in reversing aging, the research highlights universal features in the transition between different physiological health states that could be targeted to modulate the rate of aging. This suggests that interventions may be developed to slow down aging processes, thereby extending healthspan and lifespan.

Epigenetic age oscillates during the day - Koncevičius - 2024 - Aging Cell - Wiley Online Library

Matt and Brian discuss the complexities of interpreting epigenetic aging clock results given research suggesting epigenetic readouts fluctuate within a 24 hour cycle. This study highlights how epigenetic age fluctuates throughout the day, suggesting a circadian rhythm influence on biological aging. Using DNA methylation data, the study tracks epigenetic age variations across different times. The findings indicate a rhythmic pattern, with epigenetic age fluctuating by several years over a 24-hour cycle. This highlights the potential importance of daily biological rhythms in understanding the epigenetic aging processes and the impact of time-of-day on the collection, interpretation, and standardization of biological age clocks within both research and the commercial space. Brian highlights an interesting concept that the fluctuating nature of epigenetic biological age natures may even reflect the underlying, malleable nature of the biological aging process.

In this Q&A, Matt and Brian Kennedy cover a range of topics on caloric restriction, lifespan studies, interventions like rapamycin, and the importance of control groups in research. They critique the validity of certain longevity claims, discuss the complexities of aging mechanisms, and question the effectiveness of supplements. The conversation also touches on dietary impacts, the role of exercise, and the significance of personalized medicine in aging research, emphasizing the need for careful interpretation of scientific data.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

The impact of short-lived controls on the interpretation of lifespan experiments and progress in geroscience – Through the lens of the “900-day rule” - ScienceDirect

Matt and Brian talk about being cautious about interpreting the results from mouse lifespan studies when evaluating the potential effectiveness of a putative longevity intervention. This research study performed a comprehensive reanalysis of mouse  lifespan studies to assess how the lifespan of control groups influences the perceived efficacy of longevity interventions. The analysis revealed that interventions appeared more effective in studies where control groups had shorter lifespans. This suggests that the relative efficacy of longevity treatments may be overstated when control animals are inherently short-lived. The researchers (including Matt and Brian) propose that individuals apply the “900 day rule” as one important criteria to safeguard against over-interpreting the results of lifespan studies, as this is the average lifespan of control mice.

A mechanistic perspective on the health promoting effects of alcohol – A focus on epigenetics modification - ScienceDirect

 Matt and Brian discuss the data suggesting chronic alcohol consumption is detrimental to longevity but also the body of preclinical literature demonstrating low dose alcohol consumption improves lifespan in multiple preclinical studies across different model organisms. This perspective piece coauthored by Brian explores how low-dose alcohol consumption may confer health benefits through epigenetic mechanisms, particularly histone acetylation. The authors discuss how alcohol is metabolized into acetate, which is then converted to acetyl-CoA, a key substrate in the histone acetylation process which can lead to changes in gene expression that may have health-promoting effects. They suggest that this mechanism could underlie some of the observed benefits associated with low to moderate alcohol consumption, such as improved cardiovascular health. This perspective highlights the complex role of alcohol in health and disease, emphasizing the importance of dosage and likely also physiological context.

The effect of glycine administration on the characteristics of physiological systems in human adults: A systematic review | GeroScience

This systematic review evaluated 52 studies involving glycine administered over periods ranging from up to 14 days in healthy individuals to up to 4 months in diseased populations to elucidate effects on various physiological systems and healthspan metrics. Glycine's effects on cognitive health were most robust, with marked improvements in emotional health and sleep in normative aging individuals.The authors highlight that dietary glycine has been associated with increased healthy lifespan in model organisms and may decrease inflammation in humans, suggesting its potential as a geroprotective agent. The authors highlight the necessity for larger, long-term studies with robust designs in healthy populations to examine glycine's effects on preventing, delaying, or reversing aspects of the aging process.

https://link.springer.com/article/10.1007/s11357-023-01011-0

Brian discusses his enthusiasm for the compound astaxanthin as a putative geroprotective intervention, in large part based on positive feedback he’s received from several different clinicians on its positive effects on the health of their patients. While Matt is encouraged by the preclinical data and clinical anecdotes, he emphasizes caution as astaxanthin is still relatively understudied. This research paper from the Intervention Testing Program highlights the differential effectiveness of several different gerotherapeutic candidates for extending lifespan, the popular senolytic fisetin had no effect on lifespan while the anti-nausea medication meclizine extended median lifespan by 8% and astaxanthin extended median lifespan by 12%, both in male mice. This highlights the modest gains in lifespan and sex-specificity observed in preclinical studies.

Mice Producing Reduced Levels of Insulin-Like Growth Factor Type 1 Display an Increase in Maximum, but not Mean, Life Span - PMC

Matt discusses how the pro-longevity benefits of reduced IGF-1 signaling seen in small dogs may not be entirely due to effects on body size and energetic efficiency. This research study authored by Derek Huffman demonstrates that mice genetically modified for reduced IGF-1 signaling slightly extends lifespan, regardless of body size. Further, age-specific mortality rates were reduced in IGF-1-deficient mice, particularly in late life, indicating an improvement in the typical exponential increase in mortality observed in aging populations.

In this episode, Matt shares his thoughts on Peter Attia's AMA , exploring areas of agreement and differing perspectives on health and longevity. Topics include the significance of grip strength, biomarkers for health assessment, exercise strategies while traveling, and advancements in longevity research like Klotho and GLP-1 agonists. Matt also discusses the role of AI in healthcare and addresses concerns about direct-to-consumer biological age tests. The episode concludes with a discussion of foundational exercises and the interconnected nature of aging and health.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

ChatGPT With GPT-4 Outperforms Emergency Department Physicians in Diagnostic 

Accuracy: Retrospective Analysis - PMC

One of the advancements that both Matt and Peter are most excited about within the geroscience field is the evolution and increasing relevance of artificial intelligence (AI) and machine learning, not just in research but also clinical care. The successful implementation of generative AI in the clinical space opens the opportunity for making clinical care more accessible and caring for underserved populations. This study demonstrates the promise of  generative AI in the clinical space by retrospectively analyzing 100 adult patients admitted to the internal medicine emergency department and comparing how the ChatGPT-4 models’ diagnostic output compared to initial diagnosis made by resident physicians and evaluated both against final hospital discharge diagnosis.  A point-based system was utilized to grade diagnostic accuracy, with 2 points for accurate, 1 point for partially correct, and 0 for incorrect diagnoses. Across various disease subgroups—cardiovascular, endocrine, gastrointestinal, and infectious diseases—GPT-4 consistently outperformed resident physicians, with statistical significance noted in several comparisons. This underscores the potential of AI to enhance clinical decision-making and potentially streamline clinical care in the future.

Hand grip strength as a proposed new vital sign of health: a narrative review of evidences - PMC

Matt discusses his thoughts on hand grip strength (HGS) as a robust functional marker of biological aging and emphasizes the difference between its correlation with longevity from any causative role it may play. This study conducted a narrative review to evaluate HGS as a potential “vital sign” for systemic health and age-related decline. A correlation was identified between low HGS and several diseases, including Type 2 diabetes, cardiovascular disease, stroke, chronic kidney and liver disease, certain cancers, sarcopenia, and fragility fractures. Additionally, low HGS was associated with increased hospitalization, poorer nutritional status, higher overall mortality, and reduced quality of life. One of the major limitations of HGS is that while it may be a marker of declining health and accelerate biological age, it does not inform interventional care decisions. It is unlikely that improving HGS alone is enough to mitigate the risks of adverse age-related outcomes it is strongly associated with. On the other hand, it may be a strong indicator for an individual that investing in improving functional fitness (e.g. through exercise) could significantly improve healthspan. 

Glucagon‐like peptide‐1 receptor agonists to expand the healthy lifespan: Current and future potentials - PMC

Matt and Peter both converge on glucagon-like peptide-1 receptor agonists (GLP-1 RAs) as one of the interventions they are most enthusiastic about in regards to improving healthy longevity. This narrative review examines the potential of GLP-1RAs to enhance healthy lifespan by addressing several age-related diseases. The review evaluates findings from clinical trials and studies to evaluate the therapeutic benefits and future applications of GLP-1 RAs. The review highlights that beyond significant benefits in managing type 2 diabetes and obesity, GLP-1 RAs have been associated with cardiovascular risk reduction and possess anti-inflammatory properties. Ongoing clinical developments suggest potential therapeutic roles for GLP-1 RAs in treating chronic kidney disease, metabolic liver diseases, and Alzheimer's disease.Their pleiotropic effects, including metabolic regulation and anti-inflammatory actions, position them as promising candidates for address multi-organ function and mitigating multi-morbidity. The review underscores the need for further research to fully elucidate the potential of GLP-1 RAs in promoting healthy aging in normative aging individuals without unmanaged disease or frailty.

https://www.nature.com/articles/s43587-023-00441-x

The peptide alpha-klothos (klotho) has been in the spotlight as a potential longevity intervention for years due to promising findings of improved lifespan in C. elegans, mice, and humans (within genetic association studies). In this study, researchers investigated the effects of klotho on cognitive function in aged nonhuman primates.The study found that a single administration of low-dose klotho enhanced memory and learning in aged nonhuman primates (sustained at least 2 weeks after administration), while the high-dose did not produce the same effect. This suggests a dose-dependent response, with low-dose klotho improving cognitive function in these primates. This positions klotho as a promising therapeutic agent for mitigating cognitive decline associated with aging in humans.

https://www.nature.com/articles/s41586-024-07701-9

In this study, researchers investigated the role of interleukin-11 (IL-11), a pro-inflammatory cytokine, in aging and age-related diseases using mouse models. They showed that both pharmacological inhibition (with an anti-IL-11 antibody) and mice genetically engineered to lack the IL-11 gene demonstrated improved lifespan (greater than 20% in males and females) and several healthspan metrics including reduced frailty, improved physical function, and a lower incidence of fibrosis and cancer compared to control mice. Mechanistic studies suggest that IL-11 may exert its effects through inhibition of mTOR, similar to rapamycin, prompting Matt to hypothesize that, while effective, this intervention may not show substantially improved longevity benefits compared to rapamycin. Further research is needed to elucidate other benefits of IL-11 on various healthspan metrics (e.g. cognition) as well as mTOR independent mechanisms through which it may be enhancing longevity. 

In this episode of the Optispan Podcast, Matt Kaeberlein shares his experience of undergoing a whole body MRI, discussing its potential as a screening and preventative tool for health optimization. He covers the benefits and drawbacks of whole body MRIs, shares specific details about his experience with the provider Ezra, and reflects on his results, emphasizing the importance of having quality follow-up care. Kaeberlein concludes with advice on avoiding overpriced MRI packages marketed by influencers.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Clinical Applications and Controversies of Whole-Body MRI: AJR Expert Panel Narrative Review

This study evaluates the clinical applications and major challenges with whole-body MRI assessment. The authors conclude that this technology is most suitable for cancer detection and prevention of malignancies, especially in individuals with several risk factors. Further, MRI’s offer further value for screening for osteomyelitis, myopathies, inflammatory arthritis, and degenerative disk conditions. Overall there are several disease risks whole body MRI could be used to distinguish it from other screening technologies, but detection of these conditions have limited value without follow up consultation to address abnormalities. Further MRI’s are sensitive to incidentalomas (benign clinical findings that incur further anxiety, money, and follow up time), accessibility and cost, and lack of standardized imaging protocols and reporting criteria, which can lead to variability in interpretation and diagnostic accuracy.

Will a Full-Body MRI Scan Help You or Hurt You? | The New Yorker

This New Yorker article discusses the potential use cases for routine full body MRI’s as a screening technology that can be utilized to support healthy aging. Many of the challenges include distinguishing between harmless and potentially harmful findings, which can lead to overdiagnosis, unnecessary anxiety and potentially overtreatment associated with risk of side effects. The authors suggest that currently, there is insufficient evidence to support the routine use of full-body MRI scans in asymptomatic individuals without specific risk factors. Full-body MRI scans have demonstrated utility in certain high-risk groups, such as individuals who have a significantly increased risk of developing various cancers. In these cases, the benefits of early detection may justify the use of comprehensive imaging. As Matt discusses in the podcast, advances in AI and machine learning may make data from full body MRI scans more actionable, accessible, and impactful in regards to detecting aspects of age-related decline that can be detected years before disease arises and corresponding treatment regimens to mitigate risk and optimize health.

Comprehensive full body MRI scan for preventative care | Prenuvo

Prenuvo is one of the full body MRI services that Matt discusses in the podcast which is popularly considered the “gold standard” of full body MRI providers

Full-Body MRI Screening Service by ezra

Ezra is another full body MRI service that Matt discusses in the podcast. This is the service that Matt utilized (due to convenience) and evaluates his experience and datat. The positive aspects of Ezra is that it was easy to schedule an appointment as a DTC service and the visualization platform was high quality. The challenges are that scheduling was difficult and there was no follow up care based on results. Matt recommends making sure to have some follow up service (physician or expert) that can help contextualize and interpret the full body MRI results.

neuroagetx.com

Matt mentions he is the advisor for the company NeuroAge therapeutics which has developed and offers several cutting-edge early diagnostic tests for evaluating cognitive decline and detecting risk for neurodegenerative disease decades before disease is formally diagnosed. Diagnostic tests include an RNA-based blood test and brain MRI scans.

In the final installment of this three-part series, Matt and Kim Celmer explore the essential topic of hormonal health for women, highlighting its impact on both overt and silent symptoms of hormonal changes. Celmer offers practical advice for initiating meaningful conversations with healthcare providers about hormone levels with both diving into the intricacies of hormone replacement therapy (HRT)—what it is, how it works, and its potential benefits and risks. Addressing public concerns, they discuss the relationship between HRT and breast cancer, dosing considerations, and what care might look like for women seeking treatment. The episode concludes with thought-provoking questions and potential directions for future clinical research on hormones and health outcomes. For more information On Kim’s practice you can go to ICmedicine.com

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

https://pmc.ncbi.nlm.nih.gov/articles/PMC9178928/

Matt and Kim discuss the flaws with the interpretation of the women's health initiative study that suggested that hormone replacement therapy (HRT) predisposes women to cardiovascular and cancer disease risk. Namely, the misleading statistical analysis and the use of premerin (a synthetic progesterone analogue).

In contrast, Kim highlights the evidence suggesting HRT use prevents the incidence of disease in post menopausal women. This review presents the clinical trials highlighting the benefits of early administration of HRT for the prevention of cardiovascular disease, osteoporosis, and all-cause mortality in post-menopausal women.

https://pubmed.ncbi.nlm.nih.gov/24082040/

Matt and Kim discuss the importance of maintaining healthy testosterone levels in women, especially in regards to bone health and preventing osteoporotic fractures. This meta analysis demonstrates that oral contraceptive use is associated with a substantial reduction in total and free testosterone levels in several clinical trials in healthy women. Further, the lower free testosterone levels were accompanied by a higher level of sex hormone binding globulin (SHBG), which bind to testosterone and reduce its bioavailability. As osteoporosis is a major cause of morbidity in women, this data suggests that women using oral contraceptives should talk to their doctors about having their testosterone levels measured at baseline and post-contraceptive as a precaution.

Incidence of invasive breast cancer in women treated with testosterone implants: a prospective 10-year cohort study - PubMed

Kim discusses data from Rebecca Glazer suggesting that testosterone does not increase cancer incidence and in fact may reduce the incidence/recurrence of breast cancer in certain contexts. Based on the physiology, it is likely that if testosterone plays any role in cancer progression, it’s when present at supra-physiological levels and it may fuel existing cancer cells rather than playing a causative role. This prospective cohort study was conducted on 1,268 women between the ages of 25-87 treated for symptoms of hormone deficiency and followed up for over 10 years. The participants were treated with subcutaneous testosterone prescribed on an individualized level. Breast cancer incidence was found to be 165 cases per 100,000 person years, significantly lower than the expected 271 cases per 100,000 person years, suggesting a protective effect from testosterone replacement therapy. These findings support the safety of subcutaneous testosterone therapy which can make a significant difference on the mental health, body composition, and quality of life of aging women.

A critique of the Women’s Health Initiative hormone therapy study - Fertility and Sterility

This study presents the flaws of the influential WHI hormone therapy study suggesting estrogen replacement therapy (including premarin) leads to increased risk of breast cancer. Criticisms include:

The study included women with an average age of 63, indicating treatment was conducted in older postmenopausal women. Earlier HRT administration following menopause has been demonstrated to be more effective

The study used premarin, a synthetic progesterone analogue, which has been demonstrated to exert cross-interactions with testosterone receptors, potentially influencing any adverse outcomes

Within the statistical analysis, the absolute incidence of breast cancer in treated and untreated cohorts was very small and results were not statistically significant.

These flaws with the WHI HRT study, combined with the data suggesting that estrogen replacement is beneficial for cardiovascular health, bone health, cognitive function, and quality of life in postmenopausal women, indicates that HRT may be an extremely important intervention strategy for healthy aging. Especially when dosing is personalized based on boosting estrogen levels to healthy/optimal ranges.

Hormone Replacement Therapy and Risk of Breast Cancer With a Favorable Histology: Results of the Iowa Women's Health Study | Breast Cancer | JAMA | JAMA Network

Kim highlights the complexities inherent within the data associating HRT with breast cancer in postmenopausal women by outlining evidence from a particular study suggesting that post-menopausal who received HRT had a higher incidence of breast cancer, but these tumors were easier to treat leading to better prognosis than women who did not receive HRT but developed breast cancer. This is the study Kim was referring to suggesting that HRT use was most strongly associated with an increased risk of invasive breast cancer presenting with a favorable prognosis. This suggests that while HRT may elevate the likelihood of developing breast cancer in some individuals/contexts, the cancers that do develop tend to be less aggressive and more responsive to treatment. This data further warrants research to understand the biological context and multi-faceted roles that HRT plays on healthy aging to inform better clinical decision making.

Matt Kaeberlein & Nick Arapis discuss the potential of new drugs aimed at extending the lifespan of dogs and cats. The conversation highlights recent advancements, including Loyal’s injection-based treatment targeting the IGF-1 hormone, which may add years to a dog’s life. They also address misconceptions regarding claims about cat lifespan extensions, emphasizing the lack of scientific backing for such assertions. The episode underscores the importance of grounded scientific communication and the excitement surrounding longevity-based advancements.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

https://www.sciencealert.com/a-radical-new-drug-is-poised-to-extend-the-life-of-dogs

Ethan mentions Loyal’s potential lifespan-enhancing intervention (LOY-001) that could extend canine lifespan by up to five years by blocking insulin growth factor signaling. IGF-1 is thought to play a major role in the shorter lives and increased incidence of heart disease and cancer in large dogs compared to their smaller counterparts. While there is data on lifespan extension by blocking IGF-1 signaling in nematode worms, flies, and mice, there is no such data in dogs. This article discusses the conditional approval of LOY-001 which recieved FDA fast track status and may be in the market by 2026, even while evidence is still being collected within clinical trials. If Loyal's clinical trial is successful and LOY-001 extends lifespan by a minimum of one year in large dogs (at least 7 years old), it will be the first gerotherapeutic approved for use. In an observational study of 450 dogs, Loyal has already found that dogs with lower insulin levels experience reduced frailty and a higher quality of life, lending further promise to LOY-001 for enhancing healthy longevity. 

https://www.nature.com/news/2006/061009/full/news061009-12.html

This short but sweet nature article describes how the IGF-1 gene was discovered to be a primary driver of dog size and how this gene may be the most manipulated gene in nature due to humans breeding practices. Little did we know that we were not only breeding dogs for size and look, but also for longevity.

#4810 DIAGNOSTIC AND THERAPEUTIC IMPACTS OF AIM ON END-STAGE KIDNEY DISEASE | Nephrology Dialysis Transplantation | Oxford Academic

Matt discusses the emerging research around the apoptosis inhibitor of macrophages (AIM) protein and claims that it can extend a cat’s life by up to thirty years. AIM is a secreted protein that can help identify and destroy dead cells and other debris in the body. Research has demonstrated that when AIM detaches itself from IgM (immunoglobulin M) antibodies, it proceeds to clean the body of waste and debris. If AIM remains attached to IgM, it no longer preserves its health-promoting functions and this leads to an increased incidence of adverse health outcomes in mouse models of kidney disease.  Since kidney disease is one of the major causes of death in cat’s, it is being studied in clinical trials and offered as a longevity supplement (AIM-30) for pet cats. Based on the data in mice, Matt suggests that if successful, AIM-30 may extend the lifespan of cats by a few years at best. This paper supports the promise of targeting AIM for improving health outcomes in kidney disease patients. The authors evaluate the plasma of hundreds of patients on dialysis and find that those that show low levels of AIM dissociation before initiation of dialysis showed lower levels of inflammatory factors and cellular debris, exhibited lower risk for cardiovascular disease and had better survival than those with high levels of AIM dissociation. Further treatment of cats with kidney disease with an engineered form of AIM that does not bind to IgM prevented aggravation of renal function and inflammation and improved survival dramatically. This study supports the exaggerated claim that AIM supplementation may extend cat lifespan by up to 30 years. 

Impact of feline AIM on the susceptibility of cats to renal disease | Scientific Reports

This is the original nature paper that demonstrated that the feline AIM protein binds IgM 1000x more tightly than the mouse AIM protein, contributing to increased mortality from kidney disease in cats. They support this by demonstrating that replacing mouse AIM protein with feline AIM protein in mouse models of kidney disease leads to impaired recovery from kidney injury. Further, injecting an engineered form of AIM that does not bind to IgM increased survival of mice with kidney injury by 30%.

Substantial Health and Economic Returns From Delayed Aging May Warrant a New Focus for Medical Research - PMC

This paper co-authored by SJ Olshansky makes the case for investing in aging research through highlighting the health and economic benefits of developing interventions that target and slow the biology of aging over the current disease-care model. The study used a model for predicting future health and economic outcomes based on three different scenarios: delaying aging, significant reduction in heart disease, and significant reduction in cancer. The model suggests that delaying aging provides the largest returns with a 2.2 year extension in healthy lifespan and an economic benefit of 7.1 trillion over 50 years.

In this episode, Matt sits down with Thomas Seager, an Associate Professor at Arizona State University (ASU), to explore the challenges and future directions of healthcare. Drawing from his background in environmental engineering and public health, Thomas discusses the pressing health issues affecting longevity in Americans and a potential shift from a reactive healthcare model to one that emphasizes proactive health management. Together, Matt and Thomas examine the complexities of early disease detection, the promise and limitations of AI in analyzing biomarkers, and the difficulties of separating reliable information from misinformation in today’s digital landscape. Thomas shares his personal experiences with biomarkers and resilience practices, such as cold exposure therapy, while he and Matt discuss biases in medical research and differing approaches to health.

Thomas is an Associate Professor at ASU in the School of Sustainable Engineering and the Built Environment. His research focuses on sustainable engineering and resilience, addressing topics such as infrastructure resilience, sustainable energy systems, and environmental ethics. He is also the co-founder of Morozko Forge, a company that promotes cold immersion therapy as a means of supporting metabolic resilience.

Check out the links below for further information and reading about some of the topics we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings but present them as supplementary material to deepen your understanding of the subject. This list is in no way exhaustive but offers a good starting point.

How scaling interventions can improve the lives of those with brain health conditions. | McKinsey

Matt and Thomas discuss the influence of mental health, suicide, and drug overdose as a “hidden mortality risk factor” contributing to the recent decline in life expectancy in the U.S., particularly among young adults. This article by McKinsey Health Institute and Healthy Brains Global Initiative highlights how mental health and substance use disorders account for 15% of the global disease burden, ranking alongside cardiovascular disease as one of the top three most burdensome conditions in society. The authors use interactive graphs to demonstrate that no “silver bullet” exists for mental health disorders. Effective treatment typically requires a personalized and integrated approach combining psychotherapy, behavioral modifications, pharmacotherapy, and social support. Breaking down barriers like stigma and accessibility while strengthening support systems is critical.

From “Sick Care” to Health Care: Reengineering Prevention into the U.S. System - PMC

Matt and Thomas explore the rising incidence of chronic age-related diseases and how the U.S. healthcare system’s “repair shop mentality” often impedes progress. This system addresses diseases and symptoms as they arise rather than adopting a preventative approach. This review article outlines several systemic challenges, including unsustainable healthcare costs, poor outcomes, medical errors, and worsening health disparities.

The authors attribute these issues to:

1. A task-based healthcare model reimbursing for “sick visits” aimed at addressing acute conditions or symptoms of chronic conditions.

2. Economic incentives that prioritize procedures and drugs over lifestyle and behavioral counseling.

3. A preference for specialty care over primary care.

The authors propose that integrating prevention into the healthcare system will require a comprehensive approach emphasizing homeostasis and overall health, rather than focusing solely on disease and diagnosis.

https://www.morozkoforge.com/post/biological-age

Thomas authored this blog post about his experience undergoing a comprehensive health assessment at Optispan HQ. He discusses how this experience changed his perspective on his own health and aging journey. Particularly, Thomas focuses on reviewing the different theories of aging and his intrigue with the metabolic theory of aging and the importance of mitochondrial health for longevity. He concludes by examining evidence for fasting, caloric restriction, exercise, and cold therapy for improving mitochondrial health and how this may translate to improvements in human longevity.

Cold temperature extends longevity and prevents disease-related protein aggregation through PA28γ-induced proteasomes - PMC

This study demonstrates that exposure to cold temperature enhances proteasome function and the clearance of toxic protein aggregates by activating a molecular pathway (PA28y) conserved in nematode worms (C. elegans) and human cells. The authors go on to show that this pathway is required for both cold-induced lifespan benefits and reduction of protein plaques in worm models of neurodegenerative diseases including Huntington’s and amyotrophic lateral sclerosis (ALS). Cold temperature and/or drugs that activate PA28y may hold potential for the treatment of neurodegenerative diseases like Alzheimer’s, but clinical trials are needed to validate these findings in humans.

Do Ice Baths Increase Testosterone? | Morozko Science

Thomas authored this blog post outlining anecdotal evidence from case studies he’s collected over the years suggesting that cold plunge therapy increases testosterone levels, with associated improvements in emotional health, perceived pain, energy and quality of life. Thomas also talks about his own experience boosting his low testosterone levels and reducing his high prostate-specific antigen levels (associated with prostate cancer risk) which he believes is due to his ice bath regimen. Despite the potential promise, well designed clinical trials have not been conducted to validate the effects of cold therapy on testosterone levels. However, such studies are warranted given the favorable risk-to-benefit ratio of cold therapy, preliminary data from aggregate n-of-1 studies, and supporting preclinical evidence.

Grief: one of the most profound emotions humanity shares; a universal experience that transcends time, culture, and place; a phenomenon as ancient as human existence. Grief is as intrinsic to the human experience as joy or hope, and no one escapes it—to grieve is to be human.

In this episode, Matt and Nick discuss their recent personal experiences with grief and loss. Matt lost his German Shepherd Dobby to degenerative myelopathy, while Nick's father succumbed to health issues precipitated by heavy alcohol use. Together they explore how grief affects mental and physical health, including how it affects the four Pillars of Healthspan—Eat, Sleep, Move, and Connect—as well as the hallmarks of aging. They also discuss the tricky emotions that can accompany grief, the different ways people react to change, and the unanticipated positives of negative experiences.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Increased Risk of Acute Cardiovascular Events After Partner Bereavement: A Matched Cohort Study

This study, which compared over 30,000 older individuals who experienced the death of a partner to a control group that didn't experience the death of a partner, found that those who experienced bereavement suffered from myocardial infarction or stroke at twice the rate of those who didn't experience bereavement. The increased risk diminished 30 days after the partner's death. The bereaved also experienced higher rates of rare events such as pulmonary embolism and non-myocardial infarction coronary syndrome.

Risk of Acute Myocardial Infarction After the Death of a Significant Person in One's Life: The Determinants of Myocardial Infarction Onset Study

This study found that myocardial infarction risk increased 21-fold in the 24 hours after the death of a significant person. The study authors hypothesize various factors, including poorer sleep and appetite, higher cortisol levels, lower total cholesterol levels, and higher "negative affect" levels, that may contribute to heightened cardiovascular risk at this time.

Effect of conjugal bereavement on mortality of the bereaved spouse in participants of the Renfrew/Paisley Study

According to this study, participants who suffered the death of a spouse had a higher risk of dying from any cause compared to non-bereaved participants.

The Effect of Widowhood on Mortality by the Causes of Death of Both Spouses

Backing up the previous study, this paper also found that all-cause mortality of people who suffered the death of a spouse was higher for almost all causes, including cancer and cardiovascular disease. Interestingly, all-cause mortality did not significantly increase following the deaths of spouses from Alzheimer's disease or Parkinson's disease, which the authors attribute to a potential effect of "anticipatory grief": an adequate preparation time for caregivers facing a spouse's imminent death.

On the Mortality in Husbands and Wives

Published in 1940, this is one of the earlier studies suggesting a high positive correlation between the lifespan of married partners, even when the partners died of different causes. It also observed a significantly higher tendency for spouses to die of the same cause when the cause is one of cancer, heart disease, tuberculosis, influenza, or pneumonia.

In this episode, Matt sits down with naturopathic doctor and primary care provider Kim Celmer to discuss the distinct approach naturopathic doctors (NDs) bring to patient care, addressing common misconceptions about complementary and alternative treatment modalities and explaining how NDs treat prevalent issues like digestive problems, food sensitivities, and nutrient deficiencies. They dive into the distinctions between food allergies and sensitivities and how NDs manage these through a holistic lens. Celmer provides practical advice on managing heartburn and other digestive concerns, along with insights on nutritional insufficiencies and the impact of common medications on gut health. This episode is a practical guide for anyone interested in a holistic approach to health.

Kim Celmer, ND, is a naturopathic doctor specializing in primary care. After earning her doctorate from Bastyr University, she completed a residency in naturopathic medicine at the Institute of Complementary Medicine in Seattle, focusing on integrative approaches to hormone health, digestive wellness, and chronic disease management.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Effects of vitamin D supplementation on musculoskeletal health: a systematic review, meta-analysis, and trial sequential analysis

Several years ago, this paper made the news for claiming that vitamin D supplementation was ineffective for improving musculoskeletal health. After analyzing 81 randomized controlled trials, the authors argued that vitamin D supplementation did not reduce fractures or falls, nor did it improve bone mineral density.

The health effects of vitamin D supplementation: evidence from human studies

This review summarizes recent randomized control trials on vitamin D supplementation such as the VITAL, ViDA, and DO-HEALTH trials. The authors suggest that vitamin D supplementation beyond normal levels does not present clear benefits, as it does not appear to impact global health, falls or fractures, or the incidence of diseases such as cardiovascular disease, type 2 diabetes, and cancer. They note, however, that vitamin D supplementation does improve conditions such as rickets and could be moderately beneficial for individuals suffering from vitamin D deficiency.

Considerations When Choosing Supplements

Kim notes in this episode that the costliest supplements are the ones that don't actually contain what they say they do and thus don’t work. So how do you figure out which supplements actually do what they say on the tin? This article provides a framework for choosing supplements, which includes assessing safety and efficacy, monitoring dosage, and taking note of a supplement’s chemical form.

Food allergy, intolerance, or sensitivity: What’s the difference, and why does it matter?

Kim discusses the importance of clearly differentiating between food allergies and sensitivities in this episode. This article discusses food intolerances, allergies, and sensitivities and how to distinguish between them. In short, food intolerances refer to an inability to digest specific foods; food allergies typically involve an allergic reaction such as breathing difficulty following consumption of food; and food sensitivities bring about symptoms, possibly as a result of an immune reaction, from eating certain foods.

Efficacy and safety of the probiotic Saccharomyces boulardii for the prevention and therapy of gastrointestinal disorders

Kim often recommends the tropical yeast Saccharomyces boulardii for reducing negative effects of antibiotic consumption on the gut microbiome. This paper reviews potential mechanisms of action as well as the evidence for the efficacy of S. boulardii as a biotherapeutic agent for addressing gastrointestinal issues.

Author and physician Peter Attia popularized the concept of "Medicine 3.0", the third in a series of distinct phases—Medicine 1.0 and Medicine 2.0 included—that describe the evolution of medicine as we know it.

In this episode, Matt takes us through these phases and proposes a "Medicine 4.0" as the best next step beyond Peter's Medicine 3.0. He discusses the reactive disease care approach of Medicine 2.0, noting that while it has done a stellar of job of increasing life expectancy through developments such as widespread antibiotic use, sanitation improvements, and childhood mortality reductions, it has not been quite as useful at improving healthspan. People may stay alive for longer than they used to, but many of them spend this extra time alive suffering from at least one significant chronic disease or disability that significantly impedes their vitality and quality of life. Matt suggests several approaches we should take to kick off Medicine 4.0 and also presents an even longer-range version of the future: Medicine 5.0.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

#231 – AMA #41: Medicine 3.0, developments in the field of aging, healthy habits in times of stress, and more

The concept of Medicine 3.0 comes from author and physician Peter Attia. In this "Ask Me Anything" episode of the Peter Attia Drive podcast, Peter discusses medicine's trajectory through Medicine 1.0, 2.0, and 3.0. He describes each phase thoroughly and argues that while Medicine 2.0 has served us well in some ways, we have reached the limits of its capacity and need to create another fundamental shift to Medicine 3.0 if we want to meaningfully extend human longevity.

What is Medicine 3.0?

If you're pressed for time, here's the CliffsNotes version of Medicine 3.0 from Peter Attia.

How healthy is the healthspan concept?

In 2018, Matt published this article exploring the concept of healthspan and the lack of clarity in the usage of the term. He notes that while a common definition of healthspan is “the period of life spent in good health, free from the chronic diseases and disabilities of aging”, there are many issues with this definition—for example, are all diseases equal in heralding the end of healthspan? If you are simply frail and get sick more often, has your healthspan ended? He discusses the implications of imprecise definitions of healthspan for interpreting new findings in the geroscience field.

In Search of Methuselah: Estimating the Upper Limits to Human Longevity

Published in 1990, this paper argues that major life expectancy gains past 83 years at birth are unlikely to happen absent truly transformative discoveries in modulating biological aging. The paper includes data that highlights the ineffectiveness of a one-by-one approach to curing disease in significantly extending human lifespan: for example, curing all forms of cancer would increase life expectancy at birth by only 3.17 and 3.2 years for females and males respectively, while curing all ischemic heart disease would increase life expectancy at birth by only 3.0 and 3.5 years for females and males respectively.

Articulating the Case for the Longevity Dividend

This paper, whose author S. Jay Olshansky is the lead author on the previous paper in this list, argues that making progress on major individual diseases such as cardiovascular disease and cancer will have diminishing returns on enhancing longevity. As Matt does in this episode, the paper makes the case for tackling the biology of aging as more effective armor against multiple chronic diseases than any intervention currently available.

How much longer might humans live?

This question has fascinated scientists, philosophers, and dreamers for centuries. The average human lifespan has already increased dramatically over the past hundred years thanks to advances in medicine, public health, and technology, and the prospect of radically extending human life remains one of humanity’s most compelling frontiers.

A recent paper published in the scientific journal Nature Aging argues that radical life extension is unlikely to happen in the 21st century. The paper has sparked fascinating conversation in the longevity industry around topics such as realistic deliverables for the field, the predictive value of past technological trajectories, the reasons behind lifespan decreases in the western world, incremental versus bold research goals, and where we should go from here. Matt and Nick discuss the paper and provide their own take on the prospect of radical life extension and what we can realistically expect to see in the coming decades.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Implausibility of radical life extension in humans in the twenty-first century

This paper, which is the focus of this episode, catalyzed some interesting debate in the longevity community. It argues that life expectancy improvements have declined since 1990, we are unlikely to see radical human life extension in the 21st century, and that survival until the age of 100 is unlikely to exceed 15 and 5 percent for females and males respectively. In response to the paper, some in the field argued that previous trajectories are not necessarily predictive of future ones, and that there are in fact developments in the works that may justify cautious optimism about radical life extension.

Living beyond 100: Can humans achieve radical life extension in the 21st Century?

If you don't have time to read the whole paper that the episode discusses, this post provides a useful summary of the paper's core concepts and arguments.

Wealthy nations might be reaching a life expectancy limit, study suggests — at least for now

This article also summarizes the paper, and includes interesting quotes from the study's first author Jay Olshansky and other prominent researchers. Olshansky notes that he focuses on achievable improvements he can make to his lifestyle, such as doing regular exercise and wearing hearing aids to decrease dementia risk, to increase his odds of living in good health for longer.

The slowing pace of life expectancy gains since 1950

Gains in life expectancy at birth have fallen since 1950, according to this paper. The paper, which covers 139 countries, examined increases in life expectancy at birth over the next ten years between 1950 and 2009 and found slowed gains even in countries where starting life expectancy at birth was particularly low (e.g. under 51 years of age). The authors point out that the slowdown is surprising given the scientific breakthroughs that occurred during the analysis period, which include improved treatments for diseases such as AIDS, malaria, and tuberculosis.

Life Expectancy

Here is some useful data on life expectancy over the last two centuries as well as on other interesting longevity topics such as the sex gap in life expectancy, the impact of pandemics such as the Spanish flu, and why life expectancy in the United States is lower than one might expect. The authors note that while many believe that reductions in child mortality are responsible for most of the life expectancy gains, life expectancy increases are actually observable across all age groups.

Here's another Ask Matt Anything episode, with questions from Nick for Matt about topics ranging from the nitty-gritty of bloodwork and workout schedules to bigger-picture questions about upper limits to human lifespan, issues with the US healthcare system, and incentives for food companies to prioritize healthy options.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Is Aging A Disease?

One of the questions Matt addresses in this podcast is whether or not aging is a disease. The question may, at first glance, seem purely philosophical, but some argue that its answer could have implications for the United States Food and Drug Administration (FDA) drug approval process and for how researchers conduct clinical trials. This document presents an analysis of the question by founder and investor Karl Pfleger and covers definitions of disease, the classification of obesity as a disease, the interdependence of different diseases, and more.

Longevity FAQ: A beginner's guide to longevity research

Not exactly an elevator pitch or a description for a 5-year-old, but: this FAQ provides a high-level introduction to the geroscience field. It describes the goals of research into the biology of aging and core areas of interest within the field, along with interventions that scientists have tested in mice for effects on life- and/or healthspan.

Implausibility of radical life extension in humans in the twenty-first century

This paper catalyzed some interesting debate in the longevity community. It argues that life expectancy improvements have declined since 1990, we are unlikely to see radical human life extension in the 21st century, and that survival until the age of 100 is unlikely to exceed 15 and 5 percent for females and males respectively. In response to the paper, some in the field argued that previous trajectories are not necessarily predictive of future ones, and that there are in fact developments in the works that may justify cautious optimism about radical life extension.

From discoveries in ageing research to therapeutics for healthy ageing

This review covers key milestones in longevity research over the last century, beginning with the 1939 finding that caloric restriction increases rodent lifespan. It also discusses some of the difficulties that have impeded progress in the field such as human genetic heterogeneity, the challenges of translating research from model organisms such as mice to humans, and more.

Dear Founders: age1’s 2024 wishlist for new companies to unlock healthy longevity for all

The longevity-focused venture capital fund age1 recently published this wishlist of company ideas they hope to see come to fruition. The authors present several areas that they view as needing more attention from longevity companies, including reproductive longevity, genome stability interventions, and tissue engineering.

Recent articles from outlets such as the BBC and CNN reported that GLP-1 agonists such as Ozempic, a drug used for the treatment of type 2 diabetes and obesity, may help lower risk and death rates from several diseases including COVID-19 and heart failure. Matt and Nick discuss mechanisms by which GLP-1 agonists might slow the biological aging process, the connection between health and biological age, and the potential for future, more effective versions of these drugs. They also touch on the importance of diet quality, protein intake, resistance training, and regular bloodwork and hormone profiling to understand the effects of GLP-1 agonists on the body and to mitigate potential side effects such as muscle and bone loss.

GLP-1 agonists are medications that mimic the action of a hormone called glucagon-like peptide-1 (GLP-1), which is naturally produced in the gut, to manage type 2 diabetes. They regulate blood sugar levels by stimulating insulin release when blood sugar levels are high, slowing down digestion, and reducing the liver’s production of glucose. In recent years, GLP-1 agonists have gained attention for their role in weight management. By affecting appetite control centers in the brain, they help people feel fuller for longer, leading to reduced food intake and weight loss.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Ozempic could delay ageing, researchers suggest

This is one of the mainstream media articles that reported potential age-delaying benefits of taking the GLP-1 agonist Ozempic. The article describes new data published in medical journals suggesting that obese or overweight individuals who took Ozempic had lower all-cause mortality, including from diseases such as COVID-19.

The Effect of Semaglutide on Mortality and COVID-19–Related Deaths: An Analysis From the SELECT Trial

Findings from the Semaglutide Effects on Cardiovascular Outcomes in Patients With Overweight or Obesity (SELECT) trial suggest that patients who received semaglutide, the active ingredient in medications such as Ozempic, experienced lower all-cause mortality compared to patients receiving a placebo. Deaths were caused by both cardiovascular and non-cardiovascular causes such as infections. COVID-19 rates didn't decrease in patients receiving semaglutide, but patients who developed COVID-19 and took semaglutide suffered from lower rates of serious adverse events and death.

Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes

This paper reports SELECT trial findings suggesting that patients with preexisting cardiovascular disease receiving semaglutide experienced reduced death rates from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke compared to patients receiving a placebo. Whether or not semaglutide might have the same effects on patients without preexisting atherosclerotic disease remains to be seen.

Role of Glucagon-Like Peptide-1 Receptor Agonists in Achieving Weight Loss and Improving Cardiovascular Outcomes in People With Overweight and Obesity

This review describes historic approaches to tackling obesity, including lifestyle modifications such as eating healthily and increasing physical activity, bariatric surgery, and anti-obesity medications that were withdrawn from the market. It summarizes trial data to date on the use of GLP-1 agonists such as Ozempic to treat obesity. It also discusses barriers to treating obesity with GLP-1 agonists, including clinician perceptions of obesity as a lifestyle choice rather than a treatable disease and a lack of insurance coverage for anti-obesity medications.

Semaglutide Effects on Cardiovascular Outcomes in People With Overweight or Obesity (SELECT) rationale and design

In this article, researchers outline the design of the SELECT trial methods, rationale, and statistical considerations. The randomized, double-blind trial compares the effects of once weekly semaglutide and a placebo on male or female patients aged 45 years and older with preexisting cardiovascular disease and a ≥27 kg/m² BMI. The trial's primary endpoint is the time from the start of the trial to the first incidence of a composite endpoint that includes cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke.

Matt and Nick discuss a recent New York Times article about rapamycin and its potential as a life-extending and/or anti-aging drug (the article quotes Matt). Matt answers various questions from Nick related to the article about topics including whether one should "feel something" when taking rapamycin, precautions to take when using the drug off-label, and what we know about rapamycin and fertility, cholesterol levels, and neurodegenerative disease. Matt also discusses likely reasons behind the mixed results observed thus far in human clinical trials of rapamycin, and emphasizes the need for well-powered, randomized clinical trials to better profile and understand the true efficacy of rapamycin in humans.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Anti-Aging Enthusiasts Are Taking a Pill to Extend Their Lives. Will It Work?

This New York Times article, which quotes Matt, sparked the discussion in this Longevity This Week episode. The article introduces rapamycin as a drug-of-interest to the longevity community as well as an immunosuppressant for organ transplant patients. It then discusses studies exploring potential benefits of rapamycin supplementation in humans, some of the complexities of conducting such research, and potential risks and side effects of taking rapamycin.

Safety and efficacy of rapamycin on healthspan metrics after one year: PEARL Trial Results

This preprint describes the results of the 12-month double-blinded, randomized, placebo-controlled PEARL trial Matt discusses in this episode. 114 individuals between the ages of 50 and 85 received 5 mg or 10 mg of compounded rapamycin per week, or a placebo. The preprint reports that rapamycin is safe and well-tolerated as well as some intriguing potential benefits of rapamycin, though more work is necessary to more definitively determine rapamycin's effects, if any, on human healthspan.

Case report: Severe asymptomatic hypertriglyceridemia associated with long-term low-dose rapamycin administration in a healthy middle-aged Labrador retriever

In this episode, Matt mentions one dog that developed high triglycerides after receiving rapamycin in a clinical trial. This paper, which Matt coauthored, details that case study: an eight-year-old Labrador retriever developed severe hypertriglyceridemia after six months of rapamycin treatment. While the causal relationship between rapamycin administration and the elevated triglycerides is not conclusive, a causal connection between the two seems likely given that the hypertriglyceridemia resolved 15 days after the dog went off rapamycin.

Sirolimus-induced hyperlipidaemia in liver transplant recipients is not dose-dependent

This study is one of several suggesting that the rapamycin administration causes lipid abnormalities in transplant patients. Six liver transplant recipients experienced hypertriglyceridaemia and moderate total cholesterol increases after receiving rapamycin.

Sirolimus Changes Lipid Concentrations and Lipoprotein Metabolism in Kidney Transplant Recipients

Six kidney transplant recipients in this study experienced increased total plasma cholesterol and triglyceride levels during rapamycin administration. These increases were reversible. The researchers suggest that higher adipose tissue lipase activity or lower lipoprotein lipase activity may be responsible for the lipid changes that accompany rapamycin dosing.

Matt and psychiatrist Jon Berner chat about the potential of lithium, a generic drug typically used as a mood stabilizer in illnesses such as bipolar disorder, as an Alzheimer's disease and/or life extension drug. They discuss the data supporting lithium's potential effectiveness in preventing premature dementia, practical considerations and challenges around lithium dose optimization, and possible biological mechanisms that explain lithium's effectiveness. They also delve into the various challenges of studying lithium's effects on humans as well as useful further directions for lithium research.

Jon has been in solo psychiatric practice at Woodinville Psychiatric in Washington since 1997. He spent several years working at the Monroe Correctional Complex, a Washington State Department of Corrections prison. His specialties include brain disorders, particularly bipolar and psychotic illnesses, complex pain, addiction, and "undiagnosed" neuropsychiatric syndromes, and other general psychiatric disorders such as anxiety and depression. Jon has published multiple scientific papers about various topics in the realm of mood disorders and treatments for them. He holds an M.D and a PhD in neuroscience from the University of California, Los Angeles and a B.A. in psychology from Harvard University.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Lithium treatment extends human lifespan: findings from the biomedical database UK Biobank

According to this study, lithium supplementation correlates with an over threefold decrease in mortality among people suffering from affective disorders such as mania and bipolar depression, compared to those who use other anti-psychotic drugs. The study does not go into the likely molecular mechanisms by which lithium might extend human lifespan.

Disease-modifying properties of long-term lithium treatment for amnestic mild cognitive impairment: randomised controlled trial

In a randomized, double-blind trial, 45 patients suffering from mild cognitive impairment received either lithium or a placebo over the span of a year. The trial found a correlation between lithium use and lower cerebrospinal fluid (CSF) concentrations of phosphorylated tau (p-tau), an Alzheimer's disease biomarker. Researchers speculate that lithium may be more beneficial for individuals suffering from mild, as opposed to severe, cognitive impairment.

A triple drug combination targeting components of the nutrient-sensing network maximizes longevity

This study suggests that the combination of trametinib, rapamycin, and lithium increases longevity in flies by nearly 50 percent. Combining the drugs (combinations: lithium + rapamycin, lithium + trametinib, rapamycin + trametinib) extended lifespan by an average of 30 percent, compared to an average lifespan extension effect of 11 percent for each drug in isolation.

Gene-expression differences in peripheral blood between lithium responders and non-responders in the Lithium Treatment-Moderate dose Use Study (LiTMUS)

There exists considerable variability in the clinical response to lithium. This study identified a specific pattern of gene expression in individuals who responded to one month of lithium treatment, with the gene expression changes being related to mechanisms including autophagy regulation, neurite outgrowth, and mitochondrially-mediated apoptosis. The researchers identified differential regulation of 62 genes in people who responded compared to those who didn't respond to lithium treatment.

Lithium treated mood disorders, paroxysmal rhinorrhea and mesial temporal lobe epilepsy

Jon authored this paper presenting evidence for the effectiveness of lithium in mood stabilization via two case studies of mood disorders. In the first, lithium helped control shoplifting and major discrete cycles in a woman suffering from bipolar II disorder. In the second, lithium contributed to mood stabilization in a prison inmate suffering from chronic depression, though the drug also brought about side effects such as diarrhea and sudden attacks of rhinorrhea.

Amyloid-Tau-Neurodegeneration (ATN) Profile

This is the blood biomarker for Alzheimer's disease pathology that Matt and Jon discuss in the podcast episode.

Coffee: one of the world's most popular beverages, a pick-me-up, a source of comfort and warmth, a symbol of energy and focus, a tool for social interaction. Global consumption adds up to billions of cups per day, and an estimated 75 percent of the United States population drinks the beverage. Its appeal crosses cultures, ages, and lifestyles and has made coffee a central part of many people’s daily routines.

In this episode, Matt and Nick dissect the debate circulating among internet influencers around whether there is an optimal time to consume caffeine in the morning. They discuss individual sensitivity to caffeine, potential negative feedback loops of excessive caffeine consumption, and their own coffee consumption protocols. They also review a 2005 study on how caffeine affects cortisol levels.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Caffeine Stimulation of Cortisol Secretion Across the Waking Hours in Relation to Caffeine Intake Levels

This 2005 study has formed part of the evidence used in the influencer community to discuss certain coffee drinking practices. Researchers investigated the effects of different coffee doses on the cortisol levels of 98 healthy adults. They found that regular coffee consumption blunted the increased cortisol secretion that results from caffeine consumption.

Is Andrew Huberman Ruining Your Morning Coffee?

Nick mentions this video by James Hoffmann, who creates content about coffee, in the podcast episode. James discusses a recommendation by podcaster Andrew Huberman to avoid drinking coffee immediately upon waking up in order to prevent a caffeine crash in the early or late afternoon. He conducts and goes through the results of a 30-day randomized experiment comparing the effects of drinking coffee that contains caffeine versus coffee that doesn't contain caffeine within 30 minutes of waking up.

The Coffee Cortisol Connection...1 Thing Not To Do When Drinking Coffee | Dr. Mandell

This is one of many videos on the internet recommending that people avoid drinking coffee first thing in the morning. Chiropractor Alan Mandell argues that drinking coffee immediately upon waking up further elevates our naturally higher morning cortisol levels and contributes to a drop in energy levels later in the day.

Drink Coffee Right When You Wake Up (why experts have been wrong)

Thomas DeLauer, a nutrition and business performance coach, presents another view of the issue. He argues that cortisol spikes do not actually change based on timing of coffee consumption, and also discusses the potential effects of the naturally-occurring compound adenosine on the effects of timed coffee consumption. He raises a different reason one might want to wait till later in the day to drink coffee.

Coffee Drinking Is Widespread in the United States, but Usual Intake Varies by Key Demographic and Lifestyle Factors

Coffee is popular: around 75 percent of the United States population aged 20 and above drink coffee, and nearly half drink coffee every day. This paper reports demographic and lifestyle differences in coffee consumption. Men, older people, non-Hispanic whites, smokers, and daily alcohol consumers consume more coffee than other demographic groups.

In September 2024, the scientific journal Cell published a paper suggesting that metformin slows the pace of biological aging in male primates. Metformin is an FDA-approved prescription medication commonly used to treat type 2 diabetes by improving insulin sensitivity and decreasing the amount of glucose produced by the liver. After examining the influence of metformin supplementation on a suite of physiological, imaging, histological, transcriptomic, and RNA sequencing parameters, the paper's authors concluded that metformin exerts geroprotective effects on various tissues.

Matt and Nick spend this episode dissecting the paper, highlighting potential improvements to study design and presentation, and discussing the use of metformin as a longevity drug.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Metformin decelerates aging clock in male monkeys

This paper is the focus of the podcast episode. The authors measured the effects of metformin on a large number of parameters in male monkeys aged between 13 and 16 years, which is equivalent to about 40 to 50 human years. They found that metformin administration slowed aging indicators, including "hallmarks of aging" such as inflammation and cellular senescence, across various tissues.

Can people with type 2 diabetes live longer than people without diabetes? A comparison of all-cause mortality in people initiated with metformin monotherapy or sulfonylurea monotherapy and matched controls without diabetes.

Researchers compared survival rates of patients with type 2 diabetes taking metformin to those taking sulfonylurea as well as to people without diabetes, and found that type 2 diabetics on metformin had longer adjusted survival than both other groups. They suggest that, based on these data, type 2 diabetes patients treated with metformin might have survival at least equivalent to that of non-diabetics.

Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: A systematic review and meta-analysis

In this meta-analysis, authors gathered available research examining mortality and diseases of aging in diabetics taking metformin versus non-diabetics or diabetics undergoing other therapeutic interventions. They found that all-cause mortality among diabetics taking metformin was lower than that of non-diabetics as well as diabetics receiving therapies other than metformin. They also noted that metformin supplementation reduced rates of developing any cancer compared to rates observed in the general population.

Metformin Retards Aging in C. elegans by Altering Microbial Folate and Methionine Metabolism

This paper is one of several suggesting a life- and/or healthspan extension in Caenorhabditis elegans, a nematode worm. The study found that metformin brought about dose-dependent lifespan increase of up to 36 percent in C. elegans. The lifespan-extension effects of metformin disappeared when worms received a high-glucose diet. The authors suggest that microbes such as Escherichia coli influence the effects of metformin on worms, and propose mechanisms by which this interaction might occur.

The Targeting Aging with Metformin (TAME) Trial

The TAME trial is a large-scale investigation of whether metformin delays the onset and development of age-related diseases in humans. Currently, the trial aims to enroll 3,000 men and women aged 65 to 79 years at 14 research institutions across the United States. Raising funding for the trial has been a challenge, in part because metformin is an off-patent drug and thus no particular company stands to benefit financially from the potential discovery that metformin exerts geroprotective effects in humans.

We recently came across a study published in the European Journal of Nutrition that examined between the relationship between plant and animal protein intake and measures of biological aging. The study, which uses data from the UK Biobank, a long-term database of biological data from half a million participants in the United Kingdom, found that a higher plant protein intake inversely correlates with biological aging. Matt takes us through the study and gives us his take on the results and potential reasons behind them as well as on the validity of the biological age measures used, the complexities of nutrition research, and core principles of healthy eating.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Association between plant and animal protein and biological aging: findings from the UK Biobank

This is the paper Matt discusses in the episode. Using data from nearly 80,000 UK Biobank participants, researchers investigated the relationship between plant and animal protein intake and various biological aging measurements: higher Klemera-Doubal Method Biological Age (HKDM-BA), higher PhenoAge (HPA), higher allostatic load (HAL), and longer telomere length. They found an inverse association between plant protein and biological age.

The UK Biobank

The UK Biobank is a globally accessible database of genetic and health data from half a million participants in the United Kingdom. Between the years 2006 and 2010, participants aged 40 to 69 provided biological samples such as blood, urine, and saliva and completed questionnaires about their lifestyles. Researchers then conducted long-term follow-ups of participants' health through their medical records.

A new approach to the concept and computation of biological age

Matt references this 2006 paper in the podcast, noting that the following quote remains true today: "The lack of exact definition of the concept of biological age (BA) is a typical feature of works concerning [biological age]. That is why comparison of results of various published methods makes little sense and eventual proof of their optimality is impossible." In the podcast, Matt notes that biological age continues to mean different things in different papers, creating confusion and noise in the field.

Animal and plant protein intake and all-cause and cause-specific mortality: results from two prospective US cohort studies

In this study, researchers found an inverse association and a positive association with mortality in plant and animal protein intake respectively. The association between animal protein intake and mortality was weak, however, and both associations disappeared among participants without unhealthy lifestyle habits such as smoking, high alcohol consumption, and physical inactivity.

Plant Protein and Animal Proteins: Do They Differentially Affect Cardiovascular Disease Risk?

This review emphasizes the inconclusive and nuanced nature of the evidence around the effects of plant and animal protein, and notes the challenges of distinguishing the individual impacts of specific proteins.

We get lots of feedback and questions about the Dog Aging Project (DAP) from viewers, so we wanted to provide an update about how the project is going as well as some context. In this episode, Matt dives into the project's winding 10-year history, which includes navigating the vagaries of government funding, handling skepticism from fellow academics, and managing clinical trial enrollment in the midst of a global pandemic. He provides a candid peek into the logistical coordination, interdisciplinary collaboration, and leadership required to run a large-scale, ambitious scientific project such as the DAP, and the necessity of articulating clear and compelling goals that can rally support from both the scientific community and funding bodies.

The DAP is a study of canine health and longevity aimed at understanding how dogs—and, eventually, humans—age. The project has two broad goals: to help us understand the biology of aging, and to enable us to do something about it. A third goal that often goes unmentioned, but is (to some) no less important, is to give us more time with furry friends who often become part of the family. The DAP has grown to become the world's largest study of aging.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

An open science study of ageing in companion dogs

The Dog Aging Project team published this paper in the scientific journal Nature to lay out the Dog Aging Project's mission, structural design, and data collection methodology.

How man’s best friend could hold the key to anti-ageing

This article in The Guardian "started the snowball" of media interest in Matt's idea to conduct clinical trials in people's pets. It describes how dogs are a "new set of recruits" for longevity research, and the clinical trial that Matt and Daniel Promislow were putting together to test the effects of rapamycin on dogs.

UW scientists seek to extend dogs’ lives with anti-aging drug

The Seattle Times, Matt's local newspaper, was another outlet that profiled the early days of Matt's idea to conduct a rapamycin clinical trial in dogs. In addition to the researchers' plans for the clinical trial, the article describes some of the molecular mechanisms by which rapamycin functions, current uses of rapamycin, and barriers to funding rapamycin clinical trials.

Dogs Test Drug Aimed at Humans’ Biggest Killer: Age

This article, which made the front page of the New York Times, likely catalyzed significant funding for the Dog Aging Project. The article quotes Matt describing previous rapamycin research in mice, as well as why a clinical trial of rapamycin in humans would be a worthwhile endeavor. It also touches on criticisms of the longevity field from various quarters, including Microsoft cofounder Bill Gates.

Reproductive Capability Is Associated with Lifespan and Cause of Death in Companion Dogs

This is one of many examples of research that has benefited from Dog Aging Project data. The study, whose co-authors include Kate Creevy and Daniel Promislow, both of whom Matt mentions in this episode, examines the impact of reproduction on longevity in dogs—a question that researchers are also actively investigating in humans. According to the paper, sterilizing male and female dogs increases their lifespan by 13.8 and 26.3 percent respectively, but also increases cancer risk.

Your health doesn't need to be complicated. With so much conflicting information out there, it's easy to feel overwhelmed and unsure of what truly works. At the Optispan Podcast, we focus on cutting through the noise and providing you with clear, evidence-backed solutions that will make a noticeable difference in your life, rather than creating incremental change or no change at all.

In this episode, Matt goes through the Optispan "Pillars of Healthspan" and explains how these pillars intersect and impact aging and age-related disease prevention. He describes various simple strategies for improving one's weakest pillar, including reducing sugar in coffee, improving sleep hygiene, fostering social connections, and more; and encourages listeners to self-assess, use diagnostics, and seek assistance to enhance their health span trajectory where appropriate.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

How to practically change your behaviors | Peter Attia & James Clear

This snippet of the Peter Attia Drive podcast features New York Times bestselling author James Clear, who wrote the book "Atomic Habits". Clear suggests focusing on displacing bad habits with better ones, and describes how it can sometimes take removing oneself from old environments to do this ("environment is like a form of gravity...it just pulls on you").

Good genes are nice, but joy is better

The Harvard Study of Adult Development is a multi-decade longitudinal effort to track hundreds of Americans in order to gain insight into adult physical and psychological changes. A fascinating finding from the study, which began in 1938, was that close relationships predict life satisfaction and happiness better than do social class, IQ, or genetics. Harvard Medical School Professor of Psychiatry George Vaillant told the Harvard Gazette that "the key to healthy aging is relationships, relationships, relationships.”

Ultra-Processed Diets Cause Excess Calorie Intake and Weight Gain: An Inpatient Randomized Controlled Trial of Ad Libitum Food Intake

Ultra-processed foods such as cereals, breads, and packaged snacks—the foods one often finds in the middle aisles at the grocery store—may be to blame for a lot of the American obesity crisis. This study compared a group of adults receiving ultra-processed foods to a group receiving unprocessed foods. The group on the ultra-processed diet consumed more calories and gained more weight than the group on the unprocessed diet, despite both groups' meals being matched for calories, energy density, macronutrients, sugar, sodium, and fiber.

Ultra-processed foods: what they are and how to identify them

While most of the foods we consume are processed to at least a small degree, some processed foods are worse for you than others. This paper describes pragmatic and simple ways to identify whether a given food is “ultra-processed”—that is, made using specific ingredients and manufacturing processes designed to create low-cost, long shelf-life, convenient, and hyperpalatable foods.

Healthy aging: The ultimate preventative medicine

Matt and colleagues make the case for placing greater emphasis on research into the biology of aging in a review for the journal Science. Traditional biomedical research has created significant advances in medical care by focusing primarily on understanding and treating individual diseases, but has not addressed the accumulation of age-related morbidities in aging populations. The study of aging biology, or geroscience, aims to plug this gap by identifying the mechanisms that underlie aging and developing interventions to extend healthy lifespan. By targeting aging processes themselves rather than individual diseases, researchers hope to delay the onset and progression of various age-related conditions.

The AgelessRx-sponsored Participatory Evaluation of Aging with Rapamycin for Longevity (PEARL) trial was a 48-week randomized, double-blind, placebo-controlled trial investigating the safety and potential efficacy of different intermittent rapamycin doses for mitigating signs of aging. AgelessRx recently published results after one year of data collection, and hosted a webinar with several experts to review the results and answer follow-up questions.

In this episode, Matt tackles questions that the webinar didn't get to about topics including the challenges of determining optimal dosing, the costs of running well-powered longevity trials, the differences between compounded and generic rapamycin, and the potential value of using functional outcome measures as trial endpoints rather than directly measuring aging reversal.

If you have submitted a question that Matt didn't get to, don't worry—we'll be doing more of these. Comment on the Youtube video or email us at optispanpodcast@gmail.com with your questions. We read everything.

Safety and efficacy of rapamycin on healthspan metrics after one year: PEARL Trial Results

This preprint describes the results of the 12-month double-blinded, randomized, placebo-controlled PEARL trial Matt discusses in this episode. 114 individuals between the ages of 50 and 85 received 5 mg or 10 mg of compounded rapamycin per week, or a placebo. The preprint reports that rapamycin is safe and well-tolerated as well as some intriguing potential benefits of rapamycin, though more work is necessary to more definitively determine rapamycin's effects, if any, on human healthspan.

Results of the PEARL Trial: An Expert Analysis

AgelessRx, the company that led the PEARL trial, wrote this blogpost summarizing the background behind the PEARL trial, how the researchers carried the trial out, and the trial's results. The post notes that the PEARL trial results alone are insufficient to determine concrete benefits of rapamycin use in humans.

The bioavailability of compounded and generic rapamycin in normative aging individuals: A retrospective study and review with clinical implications

This preprint, also from AgelessRx and colleagues, discusses the bioavailability of compounded rapamycin. Bioavailability refers to the proportion of a drug that enters the bloodstream when introduced into the body and is available to have an active effect. It is a key measure for understanding how much of the administered drug actually reaches its target site of action, and thus for determining the correct dosage of a medication to ensure it has the intended therapeutic effect.

TORC1 inhibition enhances immune function and reduces infections in the elderly

This paper investigated the effects of rapamycin treatment on elderly humans. It found that six weeks of treatment with a rapamycin derivative improved vaccination response and decreased infection rates in healthy people over 65, with minimal adverse effects.

A novel rapamycin analog is highly selective for mTORC1 in vivo

According to this paper, the rapalog (rapamycin analog) DL001 has 40 times the mTORC1 specificity of rapamycin, and inhibits mTORC1 without significant side effects on glucose homeostasis, lipid metabolism, or the immune system. The paper does not present data on the longevity or healthspan effects of this rapalog.

A recent paper demonstrating that injecting older mice with an anti-IL-11 drug extended their median lifespan made a splash in the geroscience community this summer. IL-11 is a proinflammatory cytokine that plays a role in regulating various biological processes, including hematopoiesis (the production of blood cells), bone health and remodeling, and tissue repair. Meanwhile, cytokines act as messengers between cells, helping to regulate immune responses, inflammation, and the production of blood cells. In excess or when dysregulated, cytokines can contribute to chronic inflammation and autoimmune diseases.

In this episode, Matt discusses the role IL-11 plays in the body, the ERK, AMPK, and mTOR pathways, genetic and pharmacological models of IL-11 reduction, and more. He goes over the paper's claims and evaluates whether this finding is a game-changer in the longevity field as well as what further questions he'd like to see answered in follow-up studies.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Inhibition of IL-11 signalling extends mammalian healthspan and lifespan

This is the paper Matt discusses in the podcast episode. The study's authors examined the effects of IL-11 inhibition on mouse lifespan as well as age-related disease. They demonstrate that IL-11 expression increases with age across various tissue types, and that inhibiting that expression via injection of an anti-IL-11 drug significantly increases both male and female mouse lifespan. They also present some interesting results on the effects of IL-11 on cellular senescence and white adipose tissue beiging.

Prolongation of the yeast life span by the v-Ha-RAS oncogene

As Matt notes in the podcast, this was one of the first papers—or possibly the first paper—to implicate the RAS oncogene in longevity. Published in 1990, the paper demonstrated that altering the expression of the RAS gene lead to a lifespan extension in the budding yeast Saccharomyces cerevisiae.

The Ras-Erk-ETS-Signaling Pathway Is a Drug Target for Longevity

This paper examined the role of Ras-Erk-ETS signaling in flies. The researchers found that inhibiting Ras and Erk activity led to increased lifespan, and that the FDA-approved cancer-targeting drug trametinib could facilitate this inhibition and lifespan extension.

A combination of the geroprotectors trametinib and rapamycin is more effective than either drug alone

Matt discusses this paper in a previous podcast episode. The study compared the effects of administering trametinib, the same drug discussed in the paper above this one, in combination with rapamycin to those of administering both drugs alone. It found that while both treatments had geroprotective effects in isolation, the combination treatment led to a greater lifespan extension, a reduction in liver and spleen tumors, and a lower increase in brain glucose uptake.

The impact of short-lived controls on the interpretation of lifespan experiments and progress in geroscience

This preprint, which Matt coauthored, describes the proposed "900-day rule" in greater detail. The authors describe how using short-lived controls—standards or references that help scientists understand what happens under normal conditions, so they can compare it to the results of their test—in lifespan studies can exaggerate or complicate the apparent effect of a given longevity intervention, describing this reality as "an open secret within the field of geroscience research". They make the case for longer control lifespans using various case studies.

In this episode, Matt discusses two recent mouse lifespan studies: one focused on inhibiting IL-11 signaling, and one focused on combined trametinib and rapamycin treatment. IL-11, or Interleukin-11, is a protein that plays an important role in modulating inflammation and healing, while trametinib is an FDA-approved drug that targets certain cancers, particularly melanoma. You can find extensive discussion of rapamycin in our R-Files series linked above. Matt explains the "900-day rule" for evaluating mouse lifespan studies such as these two, and provides his take on whether these results are game-changers for the geroscience field as well as whether we should consider these interventions for human use at this time.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Inhibition of IL-11 signalling extends mammalian healthspan and lifespan

This is one of the papers Matt discusses in the podcast episode. The study's authors examined the effects of IL-11 inhibition on mouse lifespan as well as age-related disease. They demonstrate that IL-11 expression increases with age across various tissue types, and that inhibiting that expression via injection of an anti-IL-11 drug significantly increases both male and female mouse lifespan. They also present some interesting results on the effects of IL-11 on cellular senescence and white adipose tissue beiging.

A combination of the geroprotectors trametinib and rapamycin is more effective than either drug alone

This is the second paper Matt discusses in the podcast episode. The study compared the effects of administering trametinib in combination with rapamycin to those of administering both drugs alone, and found that while both treatments had geroprotective effects in isolation, the combination treatment led to a greater lifespan extension, a reduction in liver and spleen tumors, and a lower increase in brain glucose uptake.

The impact of short-lived controls on the interpretation of lifespan experiments and progress in geroscience

This preprint, which Matt coauthored, describes the proposed "900-day rule" in greater detail. The authors detail how using short-lived controls—standards or references that help scientists understand what happens under normal conditions, so they can compare it to the results of their test—in lifespan studies can exaggerate or complicate the apparent effect of a given longevity intervention, describing this reality as "an open secret within the field of geroscience research". They make the case for longer control lifespans using various case studies.

Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice

This study found that a single three-month rapamycin regimen increased life expectancy in middle-aged mice without overt detrimental side effects. The paper describes some of the positive effects rapamycin has on various mouth health measures, including cancer prevalence and the microbiome.

Functional conservation in genes and pathways linking ageing and immunity

The authors of the IL-11 paper note that IL-11 ma act on the ERK-mTORC1 and/or JAK/STAT3 pathways. This review describes seven pathways that act on immunity and lifespan, including the JAK/STAT3 and TOR pathways.

In this episode, Matt and Nick react to investigative journalist and author Scott Carney's video describing what he calls "David Sinclair's longevity lie" in the context of David's longevity-focused entrepreneurial ventures. Matt shares his professional history with David, including his early interactions with David in Leonard Guarente's lab at the Massachusetts Institute of Technology (MIT) and scientific differences that emerged after Matt and colleagues were unable to reproduce a key result from David's work pertaining to resveratrol. Their discussion touches on some of David's scientific claims about age reversal, the role of institutions such as Harvard University in regulating scientific integrity, the potential for future interventions in healthspan and longevity, and the importance of separating personal feelings from scientific evaluation.

David, currently a professor in Harvard Medical School's Department of Genetics at the Paul F. Glenn Center for Biology of Aging Research, is a prominent aging researcher whose lab focuses on age-related epigenetic change, cellular reprograming, longevity drug discovery, mitochondrial fitness, reproductive aging, neurodegenerative disease,, and the human secretome. He has received awards including the National Institutes of Health Nathan Shock Award, the Merck Prize, and the Australian Medical Research Medal, and was elected to TIME's 2014 “100 Most Influential People in the World" list. David conducted postdoctoral research at MIT and obtained a PhD in Molecular Genetics at the University of New South Wales.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms

Matt and colleagues coauthored this paper in 1999 demonstrating that the SIR2 gene regulates yeast lifespan. Upregulating SIR2 extended yeast lifespan by about 30 percent.

Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan

This paper really kicked off David's sirtuin story. The paper's authors, which included David, developed an assay—a test or an analysis done to figure out the amount or presence of a specific substance or component in a sample—to identify drugs to activate the SIR2 gene and/or sirtuins, a family of proteins that help regulate important processes like metabolism, DNA repair, and stress response in the body. They found that resveratrol and several other compounds activated sirtuins and made yeast live longer.

Substrate-specific Activation of Sirtuins by Resveratrol

Matt and colleagues examined the effects of resveratrol on yeast SIR2 and found that the resveratrol-induced activation of yeast SIR2 was entirely dependent upon the presence of a particular fluorescent group. Without that group, resveratrol no longer had a significant effect on yeast SIR2 activity.

Mechanism of Human SIRT1 Activation by Resveratrol

This paper independently reproduced the findings of Matt and colleagues that resveratrol did not, in fact, affect sirtuin activation. Researchers tested the effects of resveratrol on three enzymes—yeast SIR2, human SIRT1, and human SIRT2—using the same assay that the authors of the original yeast life-extension-by-resveratrol paper developed and presented. They found that resveratrol activated only one of the enzymes, SIRT1. Crucially, it seemed that removing a particular fluorescent group removed the effect of resveratrol on SIRT1, suggesting that the finding was an artifact. The rather mild title of both this paper and Matt's may have contributed to the resveratrol story's persistence in the public consciousness for many years after these findings should have called the molecule's effectiveness as a lifespan extension tool into question.

A randomized, controlled clinical trial demonstrates improved owner‑assessed cognitive function in senior dogs receiving a senolytic and NAD+ precursor combination

This study describes the results of a clinical trial that Animal Biosciences, a company that David founded, funded. The clinical trial examined the effects of a therapeutic consisting of an NAD+ precursor and senolytic on dogs with mild to moderate cognitive impairment and reported a significant difference in cognitive impairment as measured by the owner-reported Canine Cognitive Dysfunction Rating (CCDR) scale. In a press release, David made claims about the findings of this study that Matt criticized as dishonest.

NAD+ boosters are supplements designed to enhance levels of nicotinamide adenine dinucleotide (NAD+), a central coenzyme found in all living cells and involved in innumerable biochemical reactions that include DNA repair, glycolysis, stress responses, and more. As we age, NAD+ levels naturally decline. Supplements containing NAD+ precursors such as nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN) aim to counteract this decline by providing the body with the building blocks it needs to restore NAD+ levels. Proponents of these supplements suggest that they may support better energy metabolism, improved cognitive function, and even promote longevity. However, while early research is promising, it's important to approach these supplements with caution and consult healthcare professionals to understand their potential benefits and limitations.

For this episode, we examined a 2022 study that looked at the effects of NMN supplementation on VO2 max, or the maximum amount of oxygen a person can use during intense exercise, in amateur runners. Matt and Nick review the study, discuss its limitations, and provide their takes on whether NMN actually improves endurance and aerobic capacity during exercise—and thus whether we should take the claims of NMN supplement sellers seriously.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start

Nicotinamide mononucleotide supplementation enhances aerobic capacity in amateur runners: a randomized, double-blind study

This is the study that Matt and Nick discuss in the episode. Entrepreneurs who sell nicotinamide adenine dinucleotide (NAD+) precursors such as nicotinamide mononucleotide (NMN) sometimes cite this study in making the claim that NMN improves endurance and exercise performance. The study found no statistically significant change in the VO2 max, or the maximum amount of oxygen a person can use during intense exercise, of amateur runners taking NMN. It did find a statistically significant and dose-dependent difference in oxygen uptake at first ventilatory threshold.

Survival of the fittest: VO2max, a key predictor of longevity?

This is an oft-reference review of the impact of VO2 max on longevity. It describes the measurement of VO2 max as well as various studies examining relationships between VO2 max and diseases including chronic obstructive pulmonary disease, heart failure, and cancer. It also discusses the effects of physical activity and training on VO2 max.

Primer on ventilatory thresholds

If you've been wondering what ventilatory thresholds (also called aerobic and anaerobic thresholds) are and why they're important, check this primer out.

Discoveries of Nicotinamide Riboside as a Nutrient and Conserved NRK Genes Establish a Preiss-Handler Independent Route to NAD+ in Fungi and Humans

This 2004 paper is a foundational paper in the NAD+ literature that describes the nicotinamide riboside (NR, another NAD+ precursor) pathway in yeast and humans.

SS-31 and NMN: Two paths to improve metabolism and function in aged hearts

In this paper, researchers administered two mitochondria-targeting drugs, including NMN, to mice and found that treating mice with a combination of both drugs restored various aspects of mitochondrial and heart health.

Metabolite accumulation from oral NMN supplementation drives aging-specific kidney inflammation

Matt and University of Arizona Assistant Professor of Molecular and Cellular Biology George Sutphin discuss this paper in a previous episode. The authors found that, contrary to their expectations that NAD+ boosters would help ameliorate kidney aging in mice, an NAD+ booster actually led to increased levels of potential kidney damage markers. These results do not conclusively demonstrate a negative effect of NAD+ boosters on kidney health, but there's smoke there, as Matt says, and the finding is worth further investigation.

This summer, Matt and Nick visited MYOXCIENCE Nutrition founder and content creator Mike Mutzel in the greater Seattle area to give saunas and cold plunges a try. In this episode, they share their personal experiences with both, noting the mental and physical effects they experienced during and afterward, and emphasize the importance of considering both risks and rewards in healthspan interventions.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Effects of heat and cold on health, with special reference to Finnish sauna bathing

According to this review, sauna use is a common and accessible activity in Finland, with children beginning their introduction to the sauna at 6 months to one year old. Finnish saunas use high temperatures (80–100°C, or 176-212°F), and dry air (humidity 10-20 percent). The review discusses several studies showing positive effects of sauna use on cardiovascular health and neurodegenerative disease, and details potential mechanisms for these health benefits. It also describes potential risks of sauna use,

Cardiovascular and Other Health Benefits of Sauna Bathing: A Review of the Evidence

This is another review of how sauna bathing affects health. It details the impact of sauna use on cardiovascular outcomes such as blood pressure and cardiovascular disease, nonvascular diseases such as obstructive pulmonary disease and the common cold, and pain-related disorders such as headaches and rheumatoid arthritis. The authors also propose several mechanistic pathways by which these effects may occur and describe several contraindications of sauna use.

Association Between Sauna Bathing and Fatal Cardiovascular and All-Cause Mortality Events

Researchers investigated the effects of sauna bathing on 2,315 middle-aged men from Eastern Finland and found that more frequent sauna bathing correlated with a lower risk of sudden cardiac death, fatal coronary heart disease (CHD), fatal cardiovascular disease as well as lower all-cause mortality. They posit that some of the benefit may arise from heart rate increases that occur during sauna bathing that may confer similar benefits to those of regular physical exercise, among other physiological changes.

Acute effects of sauna bathing on cardiovascular function

Based on positive changes in arterial stiffness, blood pressure, and blood biomarkers such as hemoglobin, leucocytes, and thrombocytes after 30 minutes of sauna exposure, researchers provide data supporting the idea of a short-term link between sauna use and better cardiovascular health. The researchers call for more studies to establish how sauna bathing impacts cardiovascular function in the mid- to long-term.

The untapped potential of cold water therapy as part of a lifestyle intervention for promoting healthy aging

This is a review of the relatively sparse data about the effects of cold plunges on human physiology and healthspan. The review is generally positive about the potential for cold plunges to be a longevity intervention, citing potential impacts on cardiovascular, mental, and immune health, but acknowledges the need for further research.

We read every comment you leave on our Youtube channel. For this episode, we pick a few comments that pointed out places where viewers felt we got things wrong and discuss them in order to the record straight and ensure that our channel remains a trustworthy and high-accuracy information source about all things longevity science. Matt and Nick discuss the degradation of rapamycin in the body, how the scientific method really works, allometric scaling, the relevance of facial appearance to biological age, and more.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Complaining About Hype in the Longevity Industry

This blogpost comments on a review by City of Hope Alfred E. Mann Family Foundation Chair of Diabetes and Cancer Metabolism Charles Brenner of the book Lifespan by Harvard genetics professor David Sinclair. Charles' review criticizes David's book using arguments from evolutionary biology, evidence against Sinclair's theories around sirtuin activators and resveratrol, safety data from partial reprogramming experiments on mice, and more.

Plastic Surgery Sees Steady Growth Amidst Economic Uncertainty, American Society of Plastic Surgeons 2023 Procedural Statistics Report Finds

Plastic surgery procedure aimed at improving appearance are on the rise in the United States. These include "minimally invasive" procedures such as microdermabrasion, chemical peels, and Botox, which consumers typically use to look younger. Neuromodulator injections such as Botox, hyaluronic acid fillers, and skin resurfacing procedures such as lasers took the top three spots for the most procedures performed in 2023. The age groups 20-29 and 30-39 both saw increases in Botox use of over 8 percent.

Abdominal fat analyzed by DEXA scan reflects visceral body fat and improves the phenotype description and the assessment of metabolic risk in mice

This study found a high correlation between visceral fat content measured by DEXA scans and the actual excised visceral fat content of mice, suggesting that DEXA scans are accurate tools for noninvasive fat distribution measurement.

DEXA FAQ

This list of FAQs covers many questions people have about DEXA scans, including how much radiation exposure we receive from DEXA scans, height and weight limits, the safety of DEXA scans for pregnant wome, and more.

Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women

How might NAD+ precursors such as NMN affect people? This study reported that overweight or obese prediabetic women who had undergone menopause showed improved muscle insulin sensitivity and insulin signaling with NMN supplementation. They also experienced higher levels of downstream muscle NMN metabolites, or nicotinamide byproducts.

Coach, bodybuilder, and powerlifter Greg Doucette published a video on his Youtube channel discussing what he sees as the shortcomings of DEXA scans and why DEXA scans are not, in fact, the gold standard of body composition measurement. He bases his views on personal experience as well as his interpretation of a 2019 study that examined how closely DEXA and MRI measurements correlate.

In this episode, Matt reacts to Greg's video and presents his own opinion about the validity of DEXA scan measurements. Together with Nick, he discusses what DEXA scans do and don't measure, potential sources of inaccuracy in DEXA scans, honest interpretations of scientific literature, and more.

A DEXA (dual-energy X-ray absorptiometry) scan is an advanced imaging procedure for measuring bone density and composition. DEXA scans utilize two different energy levels of low-dose X-ray beams—one absorbed mostly by soft tissue, and the other absorbed mainly by bone—to differentiate between bone, fat, and lean tissue. In so doing, they provide noninvasive and detailed information about bone health, risk of osteoporosis or fractures, and body composition. While medical practitioners typically perform DEXA scans on the lower spine and hips, they can also perform DEXA scans on the whole body for the purposes of early detection and intervention.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Changes in DXA-derived lean mass and MRI-derived cross-sectional area of the thigh are modestly associated

This is the paper upon which Greg bases his argument that DEXA scans are not necessarily useful tools for body composition measurement (though he does also state his opinion that studies are wrong half the time). This study examines the correlation between magnetic resonance imaging (MRI) and DEXA scans measurements of lean mass, and argues that while the cross-sectional correlation between the measurements is strong, the correlation of percent change over time is modest and thus DEXA scans may not be able to detect lean mass changes over time to a degree of accuracy necessary for use in clinical trials.

What Is a DEXA Scan and How Can It Help You?

This is an introduction to DEXA scans that covers the history of DEXA scans, how DEXA scans work, what happens during a DEXA scan, and how DEXA scans compare to imaging techniques such as CT scans, magnetic resonance imaging (MRI) scans, and x-rays.

Unexpected DEXA Scan Results? Here are Some Potential Causes:

You may have gotten your DEXA scan results back and balked at what you saw. This list addresses some possible reasons for DEXA scan surprises.

Abdominal fat analyzed by DEXA scan reflects visceral body fat and improves the phenotype description and the assessment of metabolic risk in mice

This study found a high correlation between visceral fat content measured by DEXA scans and the actual excised visceral fat content of mice, suggesting that DEXA scans are accurate tools for noninvasive fat distribution measurement.

DEXA FAQ

This list of FAQs covers many questions people have about DEXA scans, including how much radiation exposure we receive from DEXA scans, height and weight limits, the safety of DEXA scans for pregnant wome, and more.

Depending on how you look at them, aging genes are genes whose expression changes in a predictable with age or genes that influence an organism's lifespan by affecting various biological processes associated with aging. Research on aging genes not only deepens our understanding of the biological aging process, but also opens up potential avenues for developing therapies aimed at extending healthy human lifespan. By targeting these genes, scientists hope to delay the onset of age-related diseases such as Alzheimer's disease, cardiovascular disease, and cancer, ultimately promoting a longer and healthier life.

In this episode, Matt discusses several ways we can identify and categorize aging genes. He talks about how genes can serve as predictive signatures of chronological or biological age, potential conserved genetic regulators of longevity, and how unbiased genetic screens can still be biased. He also provides his unique perspective on aging genes in humans and the potential to optimize longevity through genetic modulation.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

A C. elegans mutant that lives twice as long as wild type

Matt calls the daf-2 gene "the classic aging gene". This paper, authored by Cynthia Kenyon in 1993, demonstrated that a single genetic mutation in the daf-2 gene more than doubled the lifespan of C. elegans, a common model organism for geroscience research. This daf-2-mediated lifespan extension requires the activity of a second gene, daf-16.

The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms

This paper, which Matt coauthored with 2 colleagues using work from his PhD thesis, demonstrates that inserting a second copy of the sir2 gene increases lifespan in yeast.

Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production

Matt discusses growth hormone mutants as potential lifespan regulators in this podcast. This paper suggests that mice with genetic mutations in the growth hormone pathway have a lifespan increase of over 40 percent as well as delays in several other biological markers that change with age.

Evidence that conserved essential genes are enriched for pro-longevity factors

In this pilot study, Matt and colleagues overexpressed several essential yeast genes one by one and found that 21 percent of genes increased yeast replicative lifespan. By comparison, only around 3.5 percent of genes have an impact on lifespan when deleted. This is one of the few studies that has examined the impact of turning up essential genes on lifespan.

APOE2 is associated with longevity independent of Alzheimer’s disease

This study presents evidence for an association between the ε2 allele of apolipoprotein E (ApoE), a protein that plays significant roles in lipid metabolism and neurological functions, and longevity. This association holds irrespective of Alzheimer's disease status (researchers have linked variations in ApoE to Alzheimer's disease and other neurological conditions).

Matt and City of Hope Alfred E. Mann Family Foundation Chair of Diabetes and Cancer Metabolism Charles Brenner have had several public disagreements on social media. We love a good conversation between two distinguished scientists whose views may not entirely align, so we were pleased to host Charles on the Optispan Podcast for a discussion of topics in geroscience ranging from whether sirtuins are actually longevity regulators to the clinical utility of epigenetic age tests to the incentive structures around clinical trials. We also spent a chunk of time on NAD+ boosters, one of Charles' areas of expertise, and their relevance to aging and other conditions such as COVID-19.

Prior to his City of Hope appointment, Charles served on the faculties of Thomas Jefferson University, Dartmouth College and University of Iowa, where he was Roy J. Carver Head of Biochemistry for 11 years. He currently serves as the Chief Scientific Advisor of the biotechnology company ChromaDex, which uses his nicotinamide riboside (NR) intellectual property. He is also a cofounder of Alphina and Juvenis, companies in the NAD+ booster space. Charles conducted postdoctoral research at Brandeis University and received a PhD and a B.A. from Stanford University and Wesleyan University respectively.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Discoveries of nicotinamide riboside as a nutrient and conserved NRK genes establish a Preiss-Handler independent route to NAD+ in fungi and humans

This 2004 paper, which Charles coauthored, is a foundational paper in the NAD+ literature that describes the NR pathway in yeast and humans.

Nicotinamide riboside promotes Sir2 silencing and extends lifespan via Nrk and Urh1/Pnp1/Meu1 pathways to NAD+

Charles coauthored this paper describing two NR pathways that boost NAD+ and demonstrating that NR increases yeast sir2 activity and lifespan without caloric restriction.

Targeted, LCMS-based Metabolomics for Quantitative Measurement of NAD(+) Metabolites

This paper describes methods that Charles' group developed as well as technical challenges for quantifying targeted NAD+ metabolites.

Sirtuins are Not Conserved Longevity Genes

Matt and Charles spend some time on a nuanced discussion of sirtuins in this episode, and Charles expresses his grave doubts about claims in the sirtuin literature outside of yeast replicative aging. In 2022, Charles published this paper documenting issues in the animal sirtuin literature as well as providing a working definition of conserved gene function.

RAPAMUNE labeling document

In discussing his concerns with human off-label rapamycin use, Charles cites this RAPAMUNE labeling document along with Blake Rasmussen's randomized clinical trial showing that rapamycin inhibits skeletal muscle protein synthesis after exercise. Charles does consider the premise of the geroscience hypothesis—the idea that the biological processes underlying aging are the root cause of many chronic diseases and conditions commonly associated with aging such as cardiovascular disease, diabetes, Alzheimer's disease, and cancer—to be proven in mice based on the activity of rapamycin.

The papers below discuss the effects of dysregulated NAD+ metabolism on various conditions:

Type II diabetes: Nicotinamide Riboside Opposes Type 2 Diabetes and Neuropathy in Mice

Alcohol-Related Liver Disease: Nicotinamide Adenine Dinucleotide Metabolome Is Functionally Depressed in Patients Undergoing Liver Transplantation for Alcohol-Related Liver Disease

Postpartum conditions: Maternal Nicotinamide Riboside Enhances Postpartum Weight Loss, Juvenile Offspring Development, and Neurogenesis of Adult Offspring

Heart failure: Nicotinamide Riboside Preserves Cardiac Function in a Mouse Model of Dilated Cardiomyopathy

Mitochondrial Myopathy: Niacin Cures Systemic NAD + Deficiency and Improves Muscle Performance in Adult-Onset Mitochondrial Myopathy

Coronavirus infection: Coronavirus infection and PARP expression dysregulate the NAD metabolome: An actionable component of innate immunity

Charles cites a number of positive NR human trials that, in his view, strongly support the use case of NR in healthy aging. We list some of those trials below:

Trials showing anti-inflammatory effects of NR: A Milestone Clinical Study Reveals that Elevating Nicotinamide Adenine Dinucleotide (NAD+) with Nicotinamide Riboside (NR) Supplementation Effectively Reduces Inflammation in Both Healthy Subjects and Immune Cells Derived from Psoriasis Patients (Charles serves as Chief Scientific Advisor of Chromadex)

The NICE trial for peripheral artery disease: Nicotinamide riboside for peripheral artery disease: the NICE randomized clinical trial

The NADPARK trial for Parkinson’s disease: The NADPARK study: A randomized phase I trial of nicotinamide riboside supplementation in Parkinson's disease

In June 2024, the Aspen Ideas Festival held a three-day health-focused event in which speakers discussed new breakthroughs, policy developments, and possible futures in healthcare. "You Can Live Longer!" was a panel discussion during the festival that consisted of Altos Labs founder and chief scientist Rick Klausner, Cradle CEO and cofounder and venture capitalist Laura Deming, BioAge Labs CEO and cofounder Kristen Fortney, and NPR News Food and Health Correspondent Allison Aubrey discussing developments in the longevity field.

In this episode, Matt and Nick react to the panel discussion and discuss the potential of epigenetic reprogramming for improving organ transplants and reversing organ aging, the limitations of current techniques, the relevance of aging models in disease research, and more.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

You Can Live Longer!

The panel discussion that Matt and Nick discuss in this episode took place at the 2024 Aspen Ideas Festival, a gathering of thinkers from different fields in an immersive event exploring new ideas and innovations. The three speakers, each of them leaders in different niches of the longevity space, discuss a wide range of topics, including new drugs in the pipeline that target healthy aging, the manipulability of the cellular aging process, and the functional significance of biological age clocks. They also discuss talent entering the longevity field and difficulties convincing investors to pay attention to aging in years past.

Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors

In 2006, Kazutoshi Takahashi and Shinya Yamanaka published this paper reporting four key transcription factors—Oct3/4, Sox2, c-Myc, and Klf4—whose overexpression induced mouse fibroblasts to return to their pluripotent, or immature, state. We now refer to these four factors as "Yamanaka factors". Transplanting the pluripotent cells that arose from Yamanaka factor introduction gave rise to certain adverse effects such as tumors.

Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors

This paper, which Takahashi and Yamanaka coauthored along with several collaborators, demonstrated that the four Yamanaka factors described in the previous paper also worked to induce a pluripotent cell state in adult human dermal fibroblasts. The Yamanaka-factor-induced pluripotent cells shared many features with human embryonic stem cells. The authors acknowledged the increased risk of tumor formation as a result of Yamanaka factor reprogramming.

Altos Co-founder and Chief Scientist Rick Klausner teases Yamanaka factors success at Aspen Ideas Health Conference

This article covering the Aspen Ideas Festival panel speculates that Altos Labs, a Jeff Bezos-backed company whose founder and chief scientist is panelist Rick Klausner, has achieved positive results with a "reprogramming cocktail" based on the Yamanaka factors.

When are mice considered old?

Mice are some of the most common animal models researchers use for studying human aging. This short article provides a helpful comparison of mouse and human life phases and aging, and shows that the correlation between mouse and human aging is not linear. It proposes an age at which "old mice" best correlate with "old humans", an important metric to consider in studies of mouse aging aimed at eventual translation to human aging.

Matt recently attended the 52nd annual meeting of the American Aging Association in Madison, Wisconsin and met with several people doing fascinating work in or adjacent to the geroscience field.

One of these was Cristal Hill. Cristal is an Assistant Professor of Gerontology at the University of Southern California Leonard Davis School of Gerontology, where she runs a lab focused on how dietary protein might affect adipose tissue (body fat) function, metabolic, and endocrine health during aging. Cristal received postdoctoral training at the Pennington Biomedical Research Center of Louisiana State University, a PhD in molecular biology from Southern Illinois University, and a B.S. in Animal Sciences from Tuskegee University.

In this episode, Matt and Cristal discuss fibroblast growth factor 21 (FGF21), a hormone produced mainly in the liver that helps regulate metabolism and control how the body uses sugar and fat for energy. They also chat about FGF21's influence on food preferences, role in healthy aging and longevity, potential as an obesity treatment, and more, as well as the broader impact of protein restriction on health- and lifespan as we age.

Some definitions: the term "wildtype" refers to the typical form of an organism or gene as it occurs in nature, and represents the standard or normal genetic makeup and phenotype against which mutants or genetically modified organisms are compared. A "knockout" is an organism in which a specific gene has been completely disabled or "knocked out" to study the gene's function by observing the differences between the knockout organism and a wildtype one. Finally, a "transgenic" organism is one that has had a gene or genes introduced into its DNA to give the organism new traits or abilities, such as resistance to diseases, or to study the effects of the introduced gene.

As far as we can tell, FGF21 tests are not yet commercially available.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

The Hill lab

If you're an aspiring undergraduate researcher, PhD or MD student, postdoc, potential collaborator, or even just someone who wants to know more about what Cristal and her team get up to, here's where you can go to learn all about Cristal's lab at the University of Southern California. On this page you'll find a comprehensive list of the Hill lab publications, some of which deal with the topics that Cristal and Matt discuss in this podcast. You can also read a summary of the Hill lab's research interests.

The starvation hormone, fibroblast growth factor-21, extends lifespan in mice

This paper presents data showing a fairly impressive lifespan extension of ~30% and ~40% in male and female mice respectively after overexpression of fibroblast growth factor-21, or FGF21. Caloric restriction brings about a similar lifespan extension. The authors suggest that the mechanism behind this effect could involve the growth hormone/insulin-like growth factor-1 signaling axis. FGF21 administration may produce some adverse effects, such as reduced bone mass.

FGF21 is required for protein restriction to extend lifespan and improve metabolic health in male mice

Cristal and Matt discuss this research in the podcast episode. Cristal is the lead author on this paper demonstrating the effects on protein restriction on male mice, which include lower frailty, functional decline, body weight, and adiposity; improved physical performance and glucose tolerance; altered biomarkers in the liver, adipose tissue, and blood; and longer lifespan. The paper demonstrates the essential role of FGF21 in bringing about the lifespan extension effect of protein restriction in mice: mice without FGF21 do not respond favorably to protein restriction.

FGF21 prevents low-protein diet-induced renal inflammation in aged mice

In this paper, Cristal and colleagues demonstrate how a low-protein diet impacts aging kidneys as well as the degree to which FGF21 mediates those effects. Mice lacking FGF21 had greater kidney damage and inflammation as a result of protein restriction than mice with FGF21, suggesting that FGF21 may help prevent kidney pathology. Interestingly, protein restriction does not seem to have adverse effects on aging kidneys in humans.

FGF21 Signals Protein Status to the Brain and Adaptively Regulates Food Choice and Metabolism

This study, also from the Hill lab, presents data about the role of FGF21 in energy metabolism and nutrient preferences, or feeding behavior, in mice undergoing protein restriction. FGF21 is responsible for changes in protein appetite, growth, glucose intolerance, and more in response to a low-protein diet.

Entrepreneur and competitive bodybuilder Mike Israetel recently released a video discussing Bryan Johnson's anti-aging protocol. Towards the end of the video, he gives us his take on the "big rocks" that account for the bulk of our longevity.

In this episode, Matt reacts in real time to his first watch of this end portion of Mike's video. Together with Nick, he goes over Mike's suggestions about diet, drugs, body composition, and supplements and provides some additional context and nuance to each recommendation where he sees fit.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Renaissance Periodization

Mike Israetel's company, Renaissance Periodization, offers diet and exercise consultations and coaching as well as a hypertrophy app aimed at helping people get bigger muscles. This is the company's Youtube channel. The channel publishes videos featuring diet, exercise, and mindset tips, critiques of workout programs, and more.

Big mice die young: early life body weight predicts longevity in genetically heterogeneous mice

This study found that mice with a smaller body size outlived those with a larger body size. This association was present in both male and female mice and was stronger for weights taken earlier rather than later in life, suggesting that low body weight at earlier ages is particularly advantageous for mouse longevity. The authors hypothesize that body weight is likely a surrogate measure of biological changes that influence weight as well as later life outcomes.

Is height related to longevity?

Good news for short people: according to this study, rates of diet-related chronic disease are lower in people of shorter height, especially after middle age. Shorter people also tend to live longer. Data from centenarians—people who reach 100 years of age—bear this finding out: the study reported that Japanese centenarians were around 10 centimeters shorter than 75 year-olds, and that Hungarian centenarians had an average height of 154cm (about five feet one inch).

Metabolite accumulation from oral NMN supplementation drives aging-specific kidney inflammation

Matt and George Sutphin discussed this preprint in a recent episode. The preprint authors found that, contrary to their expectations that NAD+ boosters would help ameliorate kidney aging in mice, an NAD+ booster actually led to increased levels of potential kidney damage markers. These results do not conclusively demonstrate a negative effect of NAD+ boosters on kidney health, but there's smoke there, as Matt says, and the finding is worth further investigation.

Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women

How might NAD+ precursors such as NMN affect people? This study reported that overweight or obese prediabetic women who had undergone menopause showed improved muscle insulin sensitivity and insulin signaling with NMN supplementation. They also experienced higher levels of downstream muscle NMN metabolites, or nicotinamide byproducts.

Last month, entrepreneur and venture capitalist Bryan Johnson released a Youtube video detailing his trip to Prospera, Honduras to receive follistatin gene therapy from the Minicircle Gene Therapy clinic. Bryan describes Minicircle's gene therapy as "a pioneering technology with the potential to improve muscle and strength, slow the speed of aging, and many more benefits".

In this episode, Matt reacts in real time to his first watch of Bryan's video and responds to Nick's questions about various topics that come up along the way. He provides a primer on gene therapy and its potential as a longevity intervention, discusses the clinical evidence for follistatin's effects on humans and model organisms, and goes through several things one might want to consider when deciding whether to partake in a new therapy. He also gives his honest take on "offshore medicine"—medicine performed in countries that lack the regulatory oversight of the United States Food and Drug Administration—and discusses potential mechanisms for safely offering experimental therapies in the United States.

Follistatin is a glycoprotein that functions as a potent inhibitor of several members of the TGF-beta superfamily, particularly activin and myostatin. It is involved in various physiological processes, including muscle growth and development, reproduction, and inflammation. By binding to these proteins, follistatin prevents them from interacting with their receptors, thereby regulating their activity.
Minicircle Gene Therapy https://minicircle.io

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Minicircle Gene Therapy

Here's Minicircle's website if you'd like to check out the company's claims, follistatin primer, and more for yourself. The website includes the company's answer to "will this turn me into a superhuman?".

What is Gene Therapy?

This is a quick primer on gene therapy that the United States Food & Drug Administration has released. It covers potential mechanisms for manipulating gene expression in humans as well as some of the products currently available to do so.

Plasmid delivery of follistatin gene therapy safely improves body composition and lowers extrinsic epigenetic age in sex- and age-diverse adult human subjects

This paper, sponsored by Minicircle Gene Therapy, presents the results of a clinical trial demonstrating the efficacy of follistatin gene therapy on body composition and extrinsic epigenetic age in humans. Mean lean mass increased by 1.96 lbs, with a maximum increase of 12.15 lbs, and mean body fat reduction was 0.87 percent. The study reported mild trends in inflammatory markers, glucose metabolism, and cholesterol, none of which were significant. Participants did not experience severe adverse effects related to the therapy.

New intranasal and injectable gene therapy for healthy life extension

Matt mentions this paper in the podcast as a piece of research that has received some criticism for several reasons, among them a small sample size of mice in each treatment group. This study tested the efficacy and safety of a viral vector for delivering telomerase reverse transcriptase and follistatin gene therapy, and found lifespan extension effects for both therapies of 41.4 percent and 32.5 percent respectively. The paper also describes other observed effects of one or both gene therapies, including telomere length increases in some tissues, improvements in hair loss and texture, weight loss prevention, improved motor coordination, and preserved mitochondrial integrity.

Senolytic vaccination improves normal and pathological age-related phenotypes and increases lifespan in progeroid mice

A senolytic is an agent that selectively clears senescent cells. This paper describes vaccination as a potential delivery agent for a senolytic, enabling delivery to specific sites and the avoidance of off-target effects. The researchers suggest that a vaccination targeted at glycoprotein nonmetastatic melanoma protein B (GPNMB), a protein that is enriched in senescent cells, increases mouse lifespan and improves various aging-associated phenotypes such as atherogenesis.

Matt recently attended the 52nd annual meeting of the American Aging Association in Madison, Wisconsin and met with several people doing fascinating work in or adjacent to the geroscience field.

One of these was Kevin White, physician at longevity-focused clinic Prime Health Associates in Oklahoma City, Oklahoma. Kevin spent two decades in emergency medicine before obtaining fellowship training in integrative and functional medicine, nutrition, and age management. He complete residency training in emergency medicine and trauma at Washington University in St. Louis, and received his M.D. from the University of Oklahoma College of Medicine. Matt describes him as "one of the few longevity docs who actually comes to the science meetings to learn more about the science of aging."

Ultimately, the geroscience field is nothing without the medical professionals who bring new discoveries to bedside. So we really enjoyed sitting down with Kevin and hearing his thoughts on interventions such as stem cell therapy as well as his questions about the geroscience field, which prompted a wide-ranging discussion of rapamycin, the hallmarks of aging, body composition, and more.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Testing Efficacy of Administration of the Antiaging Drug Rapamycin in a Nonhuman Primate, the Common Marmoset

Adam Salmon, whom Matt mentions in the podcast, is a coauthor on this paper about rapamycin administration in the common marmoset, a small-sized nonhuman primate. Marmosets received rapamycin for a short time period (3 months) and a long time period (14 months). The marmosets did not appear to suffer from clinical anemia, fibrotic lung changes, or mouth ulcers as a result of rapamycin dosing, and death rates did not differ from expected death rates given the marmosets' ages.

Long-term treatment with the mTOR inhibitor rapamycin has minor effect on clinical laboratory markers in middle-aged marmosets.

This study, which Adam Salmon also coauthored, examined the effects of rapamycin administration on marmoset blood biomarkers, with a view to understanding how rapamycin might affect marmoset aging. Nine months of rapamycin dosing had little impact on cellular blood counts, and rapamycin concentrations were higher in male marmosets compared to female marmosets. The authors concluded that this particular dose and duration of rapamycin administration likely does not produce detrimental effects on hematological biomarkers in marmosets.

Evaluation of off-label rapamycin use to promote healthspan in 333 adults

Matt and colleagues, including Optispan Chief Medical Officer George Haddad, collected self-reported data from over 300 adults with a history of off-label rapamycin use to capture data about the drug's potential side effects. The only side effect that was significantly more prevalent in rapamycin users compared to non-users was the presence of mouth sores, and several side effects typically associated with rapamycin use such as eye pain and anxiety occurred less frequently in rapamycin users than in non-users.

Rapamycin (AY-22,989), a new antifungal antibiotic I. Taxonomy of the producing streptomycete and isolation of the active principle

Published in 1975, this landmark paper describes the discovery of a new antifungal antibiotic called rapamycin, and characterizes rapamycin's morphological, physiological, and cultural properties and the streptomycete strain that produces it. It details the isolation of the streptomycete strain AY B-994 from an Easter Island soil sample as well as the strain's antimicrobial activity.

A masked, placebo-controlled, randomized clinical trial evaluating safety and the effect on cardiac function of low-dose rapamycin in 17 healthy client-owned dogs

Matt coauthored this paper exploring the effects of rapamycin administration on canine heart function. Seventeen healthy dogs received low-dose rapamycin over a six-month period. The researchers found no significant change, positive or negative, in the dogs' cardiac function, and no adverse effects. Some dog owners reported "positive changes" in their dogs' behavior with rapamycin administration, but these changes were subjective and difficult to characterize.

The R-Files is a series of episodes about rapamycin, a naturally occurring compound originally discovered in soil samples from Easter Island, also known as Rapa Nui (hence the drug's name). Rapamycin belongs to a class of drugs called macrolides and has potent immunosuppressive and anti-proliferative effects. The drug has garnered attention for its potential anti-aging properties and has attracted research interest for its ability to extend lifespan and delay age-related diseases in various model organisms, including yeast and mice.

As we've mentioned before, we read every comment on our social media and Youtube channels and often learn a lot from your questions and feedback. For this episode, we collected comments you left containing questions about rapamycin. Many of the questions focus on rapamycin dosing, diet and exercise changes while taking rapamycin, and potential side effects. We also appreciated your curiosity about the state of rapamycin research, evidence for benefit in different model organisms, and the nuances of experimental conditions in rapamycin studies. Keep the questions coming!

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Rapamycin News

Many of our podcast listeners are interested in questions about rapamycin dosing, how to get a prescription for rapamycin, and how rapamycin might interact with other supplements or drugs. This website is a great resource for getting more clarity on some of these questions, as well as for hearing about others' experiences with rapamycin and other longevity medications.

Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice

Many of those interested in rapamycin have questions about what the optimum rapamycin dosing regime looks like. While there is not yet any conclusive evidence suggesting an ideal dose for humans, researchers have demonstrated dosing regimes that work in mice. This study found that a single three-month rapamycin regimen increased life expectancy in middle-aged mice without overt detrimental side effects. It also shows some of the positive effects rapamycin has on mouse life- and healthspan.

Rapamycin fed late in life extends lifespan in genetically heterogeneous mice

This study found that rapamycin improved mouse survival by 14% and 9% for females and males respectively, even when rapamycin feeding began late in life. The authors propose several mechanisms by which rapamycin might delay aging, including modulation of nutrient dynamics and cellular stress resistance.

272 ‒ Rapamycin: potential longevity benefits, surge in popularity, unanswered questions, and more

In this episode of the Peter Attia Drive podcast, Matt joins physician Peter Attia and Institute of Organic Chemistry and Biochemistry senior group leader David Sabatini to talk about the discovery of rapamycin, its first uses in humans, the mTOR pathway, potential mechanisms by which rapamycin might influence human longevity, recent studies of the effects of rapamycin in model organisms, potential side effects, and more.

Evaluation of off-label rapamycin use to promote healthspan in 333 adults

Matt and colleagues, including Optispan Chief Medical Officer George Haddad, collected self-reported data from over 300 adults with a history of off-label rapamycin use to capture data about the drug's potential side effects. The only side effect that was significantly more prevalent in rapamycin users compared to non-users was the presence of mouth sores, and several side effects typically associated with rapamycin use such as eye pain and anxiety occurred less frequently in rapamycin users than in non-users.

We read every single comment on our social media and Youtube channels and enjoy hearing your feedback, questions, and comments on our podcast.

Our recent episode on the Interventions Testing Program's recent tests on various longevity interventions sparked some interesting debate on X. City of Hope National Medical Center's Alfred E. Mann Family Foundation Chair in Diabetes and Cancer Metabolism Charles Brenner made a remark about the potential negative effects of rapamycin on humans, while Ponce De Leon Health Chief Operating Officer Mike Muldoon plugged the calcium alpha-ketoglutarate supplement Rejuvant (the ITP tests reported no lifespan extension of alpha-ketoglutarate on mice). Matt responded to these comments on X and some interesting back and forth with Charles and Mike ensued.

In this episode, Matt and Nick take a magnifying glass to Charles' and Mike's feedback and examine the published data—and some unpublished data—to consider and respond to their claims. They also discuss the allure of phrases such as "scientifically proven" and "clinically proven" in marketing, and the importance of approaching such phrases with a critical mindset and an eye towards study robustness and methodology as well as the researchers' impartiality.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Lifespan effects in male UM-HET3 mice treated with sodium thiosulfate, 16-hydroxyestriol, and late-start canagliflozin

In this podcast episode, Matt discusses this paper in which researchers tested the effects of seven drugs—alpha-ketoglutarate, 2,4-dinitrophenol, hydralazine, nebivolol, 16α-hydroxyestriol, sodium thiosulfate, and canagliflozin—on mouse longevity. 16α-hydroxyestriol significantly increased male mouse lifespan, but decreased female mouse lifespan. Canagliflozin also increased male mouse lifespan and decreased female mouse lifespan when mice received it in later life. The other drugs—including alpha-ketoglutarate, which the supplement Mike Muldoon references in his post contains—produced no lifespan effects on mice.

Alpha-ketoglutarate, an endogenous metabolite, extends lifespan and compresses morbidity in aging mice

This study laid some of the groundwork for the investigation of alpha-ketoglutarate in the Interventions Testing Program. Researchers found that alpha-ketoglutarate reduced chronic inflammation and extended health- and lifespan in mice without inducing any significant adverse effects. Matt has said on several occasions that he did not find the lifespan data in this study particularly convincing as the effect size was small, but did find the frailty and healthspan data intriguing.

Rejuvant®, a potential life-extending compound formulation with alpha-ketoglutarate and vitamins, conferred an average 8 year reduction in biological aging, after an average of 7 months of use, in the TruAge DNA methylation test

Rejuvant is a sustained release alpha-ketoglutarate supplement that describes itself as "the first patented, science-backed longevity supplement that reduces biological age and gives you the focused energy you need today". This study reports an eight-year decrease in biological aging as measured by DNA methylation clocks after an average of seven months of Rejuvant supplementation. One of the study's coauthors is a Rejuvant scientific consultant.

Rejuvant website

Take a look at this website to see some of the claims made by Ponce de Leon Health about Rejuvant.

Sirolimus for treatment of patients with inclusion body myositis: a randomised, double-blind, placebo-controlled, proof-of-concept, phase 2b trial

This study tested the efficacy of rapamycin in treating the rare inflammatory muscle disorder inclusion body myositis, a common disorder in patients over the age of 50, and found no evidence that rapamycin was an effective drug for tackling the disease. The study did not observe any statistically significant changes in patient muscle function. The most commonly-reported side effect in this study was mouth sores, which have also been observed with rapamycin use in other studies.

Matt recently attended the 52nd annual meeting of the American Aging Association (AGE) in Madison, Wisconsin and met with several people doing fascinating work in the longevity field.

One of these was Berenice Benayoun, an Associate Professor (recently tenured!) of Gerontology, Biological Sciences, Biochemistry, and Molecular Medicine at the University of Southern California Leonard Davis School of Gerontology. Berenice delivered the keynote speech at the 2024 AGE meeting, where she received the 2024 Vincent Cristofalo Rising Star Award in Aging Research. Her research focuses on the influence of genomic regulation mechanisms, environmental stimuli, and factors such as biological sex on vertebrate aging and healthspan. Berenice was named a 2020 Pew Biomedical Scholar and a 2021 Nathan Shock new Investigator, and also received the 2019 Rosalind Franklin Young Investigator Award in Mammalian Genetics, an American Federation of Aging Research Junior Faculty Award, and a Global Consortium for Reproductive Longevity and Equality GCRLE Junior Scholar Award.

In this episode, Matt and Berenice chat about the ovaries as a vehicle for understanding aging, the difference between estropause and menopause, and the controversies associated with hormone replacement therapy, and how Berenice made her way into the lab of her dreams. They also discuss the African turquoise killifish, a new vertebrate model organism for longevity research, and address a couple of questions about research we have recently featured on this podcast (how pregnancy affects aging, and sex-specific differences in the effects of estradiol on mouse aging).

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

The Benayoun Lab

The Benayoun lab at the University of Southern California Leonard Davis School of Gerontology is looking for postdoctoral fellows, PhD students, undergraduate researchers interested in uncovering the molecular regulation of vertebrate aging. If you might be one of them, or simply want to learn more about what Berenice and her colleagues do, check out this page to find papers that have come out of the Benayoun lab, the lab's funding sources and affiliations, courses that Berenice is teaching, and more.

Microglia undergo sex-dimorphic transcriptional and metabolic rewiring during aging

This paper, which Berenice coauthored with colleagues, demonstrates that aging of the microglia—a type of immune cell located in the brain—occurs differently in male and female mice. More aging-associated changes happen in the microglia of female than in those of male mice, and these differences are particularly evident in old microglia compared to young microglia. The study outlines potential mechanisms that underpin these microglial changes.

Protection against APOE4-associated aging phenotypes with the longevity-promoting intervention 17α-estradiol in male mice

In this preprint, Berenice and colleagues examined the effect of 17α-estradiol, a type of estrogen, on outcomes in male mice with an age-accelerating allele called apolipoprotein E4 (APOE4). This allele is a major genetic risk factor for Alzheimer's disease and age-related cognitive impairment. The researchers found that 17α-estradiol administration to APOE4 mice conferred healthspan benefits across various systems. You may recall our discussion of the Interventions Testing Program’s finding that 17α-estradiol extends lifespan in male mice.

Estropausal gut microbiota transplant improves ovarian function in adult mice

Transplanting things—blood, ovaries, poop—can have surprising beneficial effects on aging. This preprint, which Berenice coauthored, found that mice receiving gut microbiota transplants experienced better fertility and ovarian health. They also identified clear differences between the gut microbiota of young and old mice as well as specific gut microbes that may be responsible for the improvements observed with transplants.

Menopause Is More Than Just Loss of Fertility

Berenice and Benayoun lab PhD Clayton Baker co-wrote this article reviewing the surprising negative effects of menopause on cognitive function, bone mass, and cardiovascular disease risk. They make the case for paying attention to biological differences between men and women and the resulting differences in drug pharmacokinetics in both genders, and for addressing limitations in women's health such as a lack of female representation across the age spectrum in interventional clinical trials.

Matt recently attended the 52nd annual meeting of the American Aging Association in Madison, Wisconsin and met with several people doing interesting work in the longevity field.

One of these was Mark McCormick, an Assistant Professor at the University of New Mexico (UNM) Department of Biochemistry and Molecular Biology. At UNM, Mark runs a lab that investigates age-delaying drug targets, develops machine learning tools for studying aging, and identifies conserved aging mechanisms and pathways in model organisms and humans. Mark previously completed a postdoc with Brian Kennedy at the Buck Institute for Research on Aging, a PhD in Biochemistry and Molecular Biology with Cynthia Kenyon at the University of California, San Francisco, and a B.S. in Mechanical Engineering as well as a B.S. in Biology from the University of Texas at Austin.

In this episode, Matt and Mark chat about aminoacyl-tRNA synthetases, a group of enzymes that play an essential role in protein synthesis. They discuss the promise and risks of tRNA synthetase inhibitors to treat diseases of aging and extend life- and healthspan (spoiler: don't take tRNA synthetase inhibitors yet). They also talk about why Mark's lab has held off on doing mouse experiments thus far, the challenges of proving causality in longevity experiments, interventions about which Mark is optimistic (or not), and more.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

McCormick lab

If you're an aspiring undergraduate researcher, PhD student, postdoc, collaborator, research sponsor, or even just someone who wants to know more about what Mark and his team get up to, here's where you can go to learn all about Mark's lab at the University of New Mexico. Many who know Mark can attest to the care and effort he puts into mentoring the next generation of scientists. On this page, you will also find a comprehensive list of Mark's lab publications from which you can learn more about some of the topics he discusses in this podcast (and more).

Induction of proteasomal activity in mammalian cells by lifespan-extending tRNA synthetase inhibitors

Mark coauthored this paper discussing a potential mechanism of action of tRNA synthetase inhibitors to increase lifespan. The researchers demonstrate that tRNA inhibitors may upregulate pathways that promote protein turnover, specifically proteasomal degradation and autophagy, a process of breaking down damaged proteins and other cellular components. Protein turnover is essential for maintaining cellular function and homeostasis, and disruptions in protein turnover can contribute to various diseases via the accumulation of damaged or misfolded proteins or the excessive degradation of functional proteins.

Cytosolic and mitochondrial tRNA synthetase inhibitors increase lifespan in a GCN4/atf-4-dependent manner

This paper, which Mark also coauthored, demonstrates lifespan extensions in both yeast and worms as a result of tRNA synthetase inhibitors. The study hypothesizes that these inhibitors act in yeast by upregulating the translation of General Control Nonderepressible 4 (Gcn4), a crucial yeast transcription factor that regulates the expression of genes required for amino acid biosynthesis and stress adaptation. Meanwhile, tRNA synthetase inhibitors act in worms in an Activating Transcription Factor 4 (ATF4)-dependent manner. ATF4 is a mammalian transcription factor that plays a key role in the cellular response to various forms of stress.

Roles of tRNA metabolism in aging and lifespan

This review provides an overview of how tRNA metabolism, including tRNA transcription, tRNA molecules, tRNA modifications, tRNA aminoacylation (where tRNA-synthetase comes in), and tRNA derivatives, influences aging and lifespan.

Acarbose improves health and lifespan in aging HET3 mice

Matt and Mark discuss the merits of acarbose, an antidiabetic drug that slows carbohydrate digestion and absorption, as a potential longevity intervention in this podcast episode. This study is one of several reporting lifespan increases in mice receiving acarbose, with some sex differences. The field doesn't yet have a lot of data about the effects of acarbose on human longevity.

We brought George Sutphin back on the podcast to bare his soul—or at least his DEXA scan and VO2 max test results.

A DEXA (dual-energy X-ray absorptiometry) scan is an advanced imaging procedure for measuring bone density and composition. DEXA scans utilize two different energy levels of low-dose X-ray beams—one absorbed mostly by soft tissue, and the other absorbed mainly by bone—to differentiate between bone, fat, and lean tissue. In so doing, they provide noninvasive and detailed information about bone health, risk of osteoporosis or fractures, and body composition. While medical practioners typically perform DEXA scans on the lower spine and hips, they can also perform DEXA scans on the whole body for the purposes of early detection and intervention.

A VO2 max test measures the maximum volume of oxygen an individual can utilize during high-intensity exercise. At its core, it provides an assessment of a person's cardiovascular fitness and aerobic endurance. During the test, the subject performs a graded exercise protocol, typically on a treadmill or stationary bike, while wearing a mask connected to a metabolic cart. The cart measures the volume and gas concentrations of inhaled and exhaled air. As the exercise intensity increases, the test measures the point at which oxygen consumption plateaus, despite further increases in workload. This point is the VO2 max, indicating the person's aerobic capacity and endurance potential. The results can provide valuable information for athletes to tailor their training programs, for clinicians to assess the efficacy of treatments, and for researchers studying the effects of various interventions on cardiovascular health. VO2 max levels are strongly correlated with all-cause mortality.

In this episode, we chat with George about what he did to change his readouts with time, how his body composition tracks his deadlines, his experiences with Ozempic, and more.

University of Arizona Assistant Professor of Molecular and Cellular Biology George Sutphin runs a lab that investigates genetic determinants of longevity, the effects of kynurenine-based interventions on lifespan, and environmental regulators of the aging process. George, who was an aerospace engineer before he discovered the promise of geroscience, completed his PhD at the University of Washington and worked as a postdoctoral associate at the Jackson Laboratory prior to his current faculty position. He currently serves as Chairperson of the American Aging Association.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Optispan uses the BodySpec DEXA scan in its concierge and corporate offerings.

What Is a DEXA Scan and How Can It Help You?

This is an introduction to DEXA scans that covers the history of DEXA scans, how DEXA scans work, what happens during a DEXA scan, and how DEXA scans compare to imaging techniques such as CT scans, magnetic resonance imaging (MRI) scans, and x-rays.

DEXA FAQ

This list of FAQs covers many questions people have about DEXA scans, including how much radiation exposure we receive from DEXA scans, height and weight limits, the safety of DEXA scans for pregnant women, and more.

Unexpected DEXA Scan Results? Here are Some Potential Causes

You may have gotten your DEXA scan results back and balked at what you saw. This list addresses some possible reasons for DEXA scan surprises.

Role of Visceral Adipose Tissue in Aging

This paper reviews and summarizes evidence suggesting that visceral fat accumulation and abdominal obesity predict high disease and mortality risk. It describes studies demonstrating that visceral fat removal from rats extends lifespan, and discusses the potential role visceral fat plays in the lifespan-extending effects of caloric restriction. It also reviews several treatment strategies for tackling visceral fat such as leptin administration.

VO2 Max

This is a useful collection of resources from Peter Attia about what VO2 max is, its relationship with longevity, training to improve your VO2 max, and more.

How do scientists decide which interventions are worth testing in humans for potential health- and/or lifespan benefits?

One way to start is to examine how interventions perform in model organisms such as mice. The Interventions Testing Program (ITP), a federally-funded initiative that began in 2002, tests drugs that may delay mouse aging, with the hope of eventually identifying new longevity interventions for humans. The program aims to take an unbiased approach to interventions testing as possible and to make all data publicly available.

In this episode, Matt goes over recent ITP tests of a broad range of interventions that includes a vasodilator, a beta-blocker, a drug to reverse cyanide poisoning, and more. The drugs are alpha-ketoglutarate, 2,4-dinitrophenol, hydralazine, nebivolol, 16α-hydroxyestriol, sodium thiosulfate, and canagliflozin. He discusses which of these interventions produces lifespan benefits in mice, gender differences in effects, results from previous studies of the interventions, and the importance of examining the life expectancy of controls when evaluating the results of lifespan experiments.

Matt has served on the ITP steering committee since 2012.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Lifespan effects in male UM-HET3 mice treated with sodium thiosulfate, 16-hydroxyestriol, and late-start canagliflozin

This is the paper Matt discusses in this podcast episode. Researchers tested the effects of seven drugs—alpha-ketoglutarate, 2,4-dinitrophenol, hydralazine, nebivolol, 16α-hydroxyestriol, sodium thiosulfate, and canagliflozin—on mice. 16α-hydroxyestriol significantly increased male mouse lifespan, but decreased female mouse lifespan. Canagliflozin also increased male mouse lifespan and decreased female mouse lifespan when mice received it in later life. The other drugs produced no lifespan effects on mice.

The impact of short-lived controls on the interpretation of lifespan experiments and progress in geroscience

Matt often mentions the importance of accounting for the lifespan of controls—a standard or baseline group of animals that researchers use to compare with the group that receives the treatment or intervention being tested—when evaluating geroscience experiments. This paper elaborates on why short-lived controls in mouse experiments can cause researchers to report exaggerated longevity effects of a given intervention. It also suggests ensuring a control mouse lifespan of around 900 days to ensure legitimacy of results.

Alpha-ketoglutarate, an endogenous metabolite, extends lifespan and compresses morbidity in aging mice

This study laid some of the groundwork for the investigation of alpha-ketoglutarate in the Interventions Testing Program. Researchers found that alpha-ketoglutarate reduced chronic inflammation and extended health- and lifespan in mice without inducing any significant adverse effects.

Rejuvant®, a potential life-extending compound formulation with alpha-ketoglutarate and vitamins, conferred an average 8 year reduction in biological aging, after an average of 7 months of use, in the TruAge DNA methylation test

Rejuvant is a sustained release alpha-ketoglutarate supplement that describes itself as "the first patented, science-backed longevity supplement that reduces biological age and gives you the focused energy you need today". This study reports an eight-year decrease in biological aging as measured by DNA methylation clocks after an average of seven months of Rejuvant supplementation. One of the study's coauthors is a Rejuvant scientific consultant.

Canagliflozin extends life span in genetically heterogeneous male but not female mice

This study reports the first Interventions Testing Program experiment with canagliflozin, a drug use to treat type 2 diabetes and to reduce the risk of several other diseases in people with type 2 diabetes. Male mice that started taking canagliflozin from a young age until their deaths experienced a median lifespan extension of 14 percent. The age for 90th percentile survival also increased by nine percent in male mice. Female mice did not experience similar benefits from taking the drug.

George Sutphin is back! So many of you enjoyed Matt's interview with him back in March 2024 about 3HAA and NAD+ that we decided to bring him on the podcast once again to chat about the potential effects of oral NMN supplementation.

You may have heard of over-the-counter supplements aimed at boosting nicotinamide adenine dinucleotide (NAD+) levels. Underlying these supplements is the hypothesis that levels of NAD+, a central coenzyme found in all living cells and involved in innumerable biochemical reactions that include DNA repair, glycolysis, and stress responses, decrease with age. The decrease, according to supplement manufacturers, may be associated with aging and age-related disease and thus restoring NAD+ levels via supplementation is likely to increase health- and/or lifespan.

In this episode, Matt and George examine a recent finding that oral supplementation of NAD+ boosters increases molecular signatures that indicate kidney damage. They discuss the NAD+ signaling pathway, models for how NAD+ might drive kidney damage, how they would expand upon the study for further research, and more.

University of Arizona Assistant Professor of Molecular and Cellular Biology George Sutphin runs a lab that investigates genetic determinants of longevity, the effects of kynurenine-based interventions on lifespan, and environmental regulators of the aging process. George, who was an aerospace engineer before he discovered the promise of geroscience, completed his PhD at the University of Washington and worked as a postdoctoral associate at the Jackson Laboratory prior to his current faculty position. He currently serves as Chairperson of the American Aging Association.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!


Metabolite accumulation from oral NMN supplementation drives aging-specific kidney inflammation

This is the preprint Matt and George discuss in the episode. The authors found that, contrary to their expectations that NAD+ boosters would help ameliorate kidney aging in mice, an NAD+ booster actually led to increased levels of potential kidney damage markers. These results do not conclusively demonstrate a negative effect of NAD+ boosters on kidney health, but there's smoke there, as Matt says, and the finding is worth further investigation.

NAD precursors cycle between host tissues and the gut microbiome

The gut microbiome seems to play a role in many biological processes, including NAD+ biosynthesis and metabolism. This paper suggests that the gut microbiome breaks down NAD+ intermediates such as nicotinamide riboside and nicotinamide mononucleotide into nicotinic acid, which you may know by its generic name niacin. Cells then generate NAD+ from nicotinic acid.

SS-31 and NMN: Two paths to improve metabolism and function in aged hearts

The NMN-kidney inflammation paper that Matt and George discuss in this episode has roots in this piece of research, which shares several authors with the later paper. Researchers administered two mitochondria-targeting drugs, including the NAD+ precursor NMN, to mice and found that treating mice with a combination of both drugs restored various aspects of mitochondrial and heart health.

Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women

How might NAD+ precursors such as NMN affect people? This study reported that overweight or obese prediabetic women who had undergone menopause showed improved muscle insulin sensitivity and insulin signaling with NMN supplementation. They also experienced higher levels of downstream muscle NMN metabolites, or nicotinamide byproducts.

Kynurenine pathway, NAD+ synthesis, and mitochondrial function: Targeting tryptophan metabolism to promote longevity and healthspan

This paper, which George co-authored, provides a useful review of the kynurenine pathway, a major metabolic pathway for the degradation of the amino acid tryptophan that ends in the production of either kynurenic acid or NAD+. He reviews the potential roles of NAD+ and kynurenine metabolism in aging and the potential of interventions targeting components of these pathways.

Save the Dog Aging Project!

In 2014, Matt co-founded the Dog Aging Project, an ambitious, large-scale study of canine health and longevity aimed at understanding how dogs—and, eventually, humans—age. The project has two broad goals: to help us understand the biology of aging, and to enable us to do something about it. A third goal that often goes unmentioned, but is (to some) no less important, is to give us more time with furry friends who often become part of the family.

Dogs are some of the best animals we can use to study longevity. While many of the model organisms such as yeast, worms, mice, and rats that we commonly use to study aging have certainly helped us unearth interesting insights, they typically live in highly controlled laboratory conditions that do not replicate the diverse environmental factors that humans experience. Researchers also often use inbred strains of these animals due to their genetic uniformity, a practice that offers experimental advantages but also introduces issues such as limited generalizability and undetected gene-environment interactions. Meanwhile, dogs share our environments in every way, develop the same age-related diseases as do humans, exhibit high genetic diversity, and age rapidly enough that we do not have to wait decades to observe the effects of interventions on dog life- and healthspan.

The Dog Aging Project has grown to become the world's largest study of aging. Over 50,000 dogs are currently enrolled in the project, enabling researchers to create an immense dataset comprising over 36 million data points and a biobank containing more than 10,000 samples that will be invaluable to helping us answer key questions about the biology of aging. Data from the project has contributed to the publication of over 50 peer-reviewed scientific papers. As this is a citizen science project that harnesses the collective power of volunteers to contribute to scientific research, the Dog Aging Project will make all data publicly available free of charge to academics and nonprofit institutions to facilitate the blooming of as much useful research as possible.

The Dog Aging Project needs your help. Federal funding to the project unfortunately stopped in 2023, and the project needs financial backing to support its veterinary and computational infrastructure as well as to complete a clinical trial of rapamycin in dogs. The project hopes to decrease its reliance on federal funding and thus hopes to encourage philanthropic funding as far possible. Top donors stand to receive a full Optispan Trailblazer concierge clinic experience and lunch with Matt, and other donors may receive Optispan swag.

Every contribution, no matter the size, makes a difference. We hope you will consider donating!

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

The Dog Aging Project - Funding required to continue the study

Here is where you can donate to the Dog Aging Project. Potential prizes include a full Optispan Trailblazer Gateway Day (a full-day longevity medical experience that includes the Optispan Trailblazer bloodwork panel, multiple biological age tests, an oral health screening, a DEXA scan, point-of-care ultrasound, continuous glucose monitoring, liquid biopsy cancer screening, VO2 max assessment, and more), a meal with Matt, Optispan swag, signed Peter Attia books, and more. You can also contribute prizes for donors!

The Dog Aging Institute

And here's another place to donate. The Dog Aging Institute is a 501(c)(3) nonprofit that Dog Aging Project cofounders Matt, Daniel Promislow, and Kate Creevy created to support research initiatives that enhance companion animal health. One of its initiatives is to help maintain the Dog Aging Project, but donations to this nonprofit may go to other projects as well.

Dog Aging Project

Learn all about the Dog Aging Project from this website. You'll get a high-level overview of the project's mission, a searchable list of publications that have come out of Dog Aging Project research, concise breakdowns of some of these scientific discoveries, a list of key Dog Aging Project staff and supporters, and more. You can also donate to the project or enroll your dog for participation on this website.

An open science study of ageing in companion dogs

The Dog Aging Project team published this paper in the scientific journal Nature to lay out the Dog Aging Project's mission, structural design, and data collection methodology.

Reproductive Capability Is Associated with Lifespan and Cause of Death in Companion Dogs

This is one of many examples of research that has benefited from Dog Aging Project data. The study, whose co-authors include Kate Creevy and Daniel Promislow, examines the impact of reproduction on longevity in dogs—a question that researchers are also actively investigating in humans. According to the paper, sterilizing male and female dogs increases their lifespan by 13.8 and 26.3 percent respectively, but also increases cancer risk.

We've hit 6,000 subscribers!

To celebrate this milestone and to thank you for your support, we've created an Ask Matt Anything (AMA) episode out of questions that you left on our previous podcast episodes. You guys ask great questions—we really enjoy thinking about the points you raise and gaining a more comprehensive and nuanced understanding of a given topic ourselves.

So here it is: an AMA buffet of longevity-related topics, from the effects of metformin and calorie restriction to methods for self-experimentation to what is special about long-lived species and much more.

We'll be releasing another special episode when we get to 10,000 subscribers, so stay tuned (and get your friends to subscribe).

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Taurine deficiency as a driver of aging

Matt and colleagues coauthored this paper demonstrating a decline in circulating taurine with age in mice, monkeys, and humans, as well as the ability to stem the decline via taurine supplementation. Taurine supplementation had positive effects on lifespan in worms and mice and on healthspan in monkeys, possibly by addressing several hallmarks of aging such as cellular senescence, DNA damage, inflammation, and more. Yeast did not experience any lifespan benefits from taurine supplementation. The researchers also found a correlation between lower taurine levels and several age-related pathologies in humans.

Lifespan effects in male UM-HET3 mice treated with sodium thiosulfate, 16-hydroxyestriol, and late-start canagliflozin

Matt discusses this paper in a different podcast episode. Researchers tested the effects of seven drugs, including alpha-ketoglutarate, on mice. 16α-hydroxyestriol significantly increased male mouse lifespan, but decreased female mouse lifespan. Canagliflozin also increased male mouse lifespan and decreased female mouse lifespan when mice received it in later life. Alpha-ketoglutarate and the other drugs produced no lifespan effects on mice.

Big mice die young: early life body weight predicts longevity in genetically heterogeneous mice

This study found that mice with a smaller body size outlived those with a larger body size. This association was present in both male and female mice and was stronger for weights taken earlier rather than later in life, suggesting that low body weight at earlier ages is particularly advantageous for mouse longevity. The authors hypothesize that body weight is likely a surrogate measure of biological changes that influence weight as well as later life outcomes.

Rapamycin news

Many of our podcast listeners are interested in questions about rapamycin dosing, how to get a prescription for rapamycin, and how rapamycin might interact with other supplements or drugs. This website is a great resource for getting more clarity on some of these questions, as well as for hearing about others' experiences with rapamycin and other longevity medications.

Reversal of biological age in multiple rat organs by young porcine plasma fraction

This paper details the experiment featured in a previous podcast episode on Harold Katcher's assertion that injecting young pig blood into rats made rats biologically younger. Scientists examined the effect of a plasma fraction from young adult pigs on epigenetic clocks for rat tissues, and found that the treatment reduced epigenetic age, as measured by the clocks, by up to 30 percent across several rat organs. E5 also improved other parameters such as inflammatory markers and grip strength. The paper did not present lifespan data for the treated rats.

Is bigger always better?

It depends. Throughout the human lifespan, body size plays an important role in determining health outcomes and quality of life. It's not just about body mass index, fat distribution, weight, or muscle mass: there also exists a relationship between body size and longevity across multiple species, including humans. On average, larger species seem to live longer and age more slowly—think about the fact that dogs age about seven times faster than do humans, who are both heavier and taller than dogs. But within species, that relationship flips around: larger individuals age more rapidly and live shorter lifespans than do smaller individuals.

As with seemingly everything in aging, the relationship between body size and the rate of aging is complex and the result of an interplay between genetic, environmental, and lifestyle factors, most of which scientists are still investigating. In this episode of Longevity Science, Matt dives into the nuances of body size and aging rate, discussing currently available data about how the two interact, intriguing outliers and exceptions, and potential molecular and evolutionary drivers.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Big mice die young: early life body weight predicts longevity in genetically heterogeneous mice

This study found that mice with a smaller body size outlived those with a larger body size. This association was present in both male and female mice and was stronger for weights taken earlier rather than later in life, suggesting that low body weight at earlier ages is particularly advantageous for mouse longevity. The authors hypothesize that body weight is likely a surrogate measure of biological changes that influence weight as well as later life outcomes.

Quantitative Translation of Dog-to-Human Aging by Conserved Remodeling of the DNA Methylome

There exists a common perception that there are seven dog years to every human year. That relationship is not quite correct—in reality, there are many more dog years to each human year early on in a dog's life, and then dog years more closely track human years later on in the dog's life. This paper presents a useful graphic to clarify the dog-human years relationship, which the researchers investigated using dog and human methylomes.

Is height related to longevity?

Good news for short people: according to this study, rates of diet-related chronic disease are lower in people of shorter height, especially after middle age. Shorter people also tend to live longer. Data from centenarians—people who reach 100 years of age—bear this finding out: the study reported that Japanese centenarians were around 10 centimeters shorter than 75 year-olds, and that Hungarian centenarians had an average height of 154cm (about five feet one inch).

A Single IGF1 Allele Is a Major Determinant of Small Size in Dogs

You've probably observed that there is tremendous diversity in the body size of dogs: a Great Dane can weigh 16 to 17 times more than a chihuahua. The dogs’ life expectancies also differ: the average Great Dane lives for 8-10 years, while the average chihuahua lives for 15-17 years. The paper describes a specific variant in a gene that codes for a hormone called insulin-like growth factor 1 (IGF-1) that influences body size in dogs. Smaller dogs have a variant that lowers IGF-1 levels during development, leading to lower growth.

Growth Hormone Receptor Deficiency is Associated With a Major Reduction in Pro-aging Signaling, Cancer and Diabetes in Humans

Over a 22-year period, researchers studied a population of Ecuadorians with restricted growth caused by growth hormone receptor gene mutations that caused deficiencies in the growth hormone receptor (GHR) and IGF-1 proteins. GHR deficiency was correlated with a very low incidence of age-related diseases such as cancer and diabetes compared to controls. Interestingly, despite a marked decrease in rates of age-related disease, GHR-deficient people did not live longer than controls, with many deaths being caused by accidents, alcohol toxicity, and other incidents unrelated to aging.

Resveratrol is a naturally occurring polyphenolic compound found in various plants, including in the skins of grapes, blueberries, raspberries, mulberries, and peanuts. Its association with red wine has contributed to the illusion of the "French Paradox": the observation that French people have a relatively low incidence of heart disease despite a diet rich in saturated fats. If you were alive in the 2000s, you may remember cheering at the news that drinking red wine would protect your heart and help you live longer.

Unfortunately, this claim is not true. Matt, who describes resveratrol as the "most debunked longevity molecule in history", spent several formative years of his scientific career in the depths of the resveratrol saga. Together with colleagues, and in parallel with other independent labs, he demonstrated that the apparent miracle powers of resveratrol were likely an artifact of the experimental methods used to test resveratrol-induced sirtuin activation, and that resveratrol actually had no significant lifespan-extending effects in vivo. In this episode, Matt presents a comprehensive analysis of the existing resveratrol literature, transports us to his earlier years of figuring the story out piece by piece with colleagues such as National University of Singapore Distinguished Professor of Biochemistry and Physiology Brian Kennedy, and shares his views on how bad science can have a profound influence on scientific fields, funding allocations, and public behavior.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan

This paper really kicked off the sirtuin story. The paper's authors developed an assay—a test or an analysis done to figure out the amount or presence of a specific substance or component in a sample—to identify drugs to activate the SIR2 gene and/or sirtuins, a family of proteins that help regulate important processes like metabolism, DNA repair, and stress response in the body. They found that resveratrol and several other compounds activated sirtuins and made yeast live longer.

The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms

Matt and his colleagues published this 1999 paper that laid some of the groundwork for the previous foundational resveratrol paper. They showed that over-expressing the SIR2 gene increased lifespan by about 30 percent in baker's yeast, and that SIR2 was a key lifespan regulator. Other research groups have since reproduced this result in yeast.

Substrate-specific Activation of Sirtuins by Resveratrol

Matt and colleagues examined the effects of resveratrol on yeast SIR2 and found that the resveratrol-induced activation of yeast SIR2 was entirely dependent upon the presence of a particular fluorescent group. Without that group, resveratrol no longer had a significant effect on yeast SIR2 activity.

Mechanism of Human SIRT1 Activation by Resveratrol

This paper independently reproduced the findings of Matt and colleagues that resveratrol did not, in fact, affect sirtuin activation. Researchers tested the effects of resveratrol on three enzymes—yeast SIR2, human SIRT1, and human SIRT2—using the same assay that the authors of the original yeast life-extension-by-resveratrol paper developed and presented. They found that resveratrol activated only one of the enzymes, SIRT1. Crucially, it seemed that removing a particular fluorescent group removed the effect of resveratrol on SIRT1, suggesting that the finding was an artifact. The rather mild title of both this paper and Matt's may have contributed to the resveratrol story's persistence in the public consciousness for many years after these findings should have called the molecule's effectiveness as a lifespan extension tool into question.

Is red wine actually good for your heart?

Key research and much of the resulting hype about the finding that compounds such as resveratrol that are present in red wine encourage slower aging came from Harvard Professor in the Department of Genetics David Sinclair. But several publications from Harvard, including this blogpost from Harvard Health Publishing, have questioned whether red wine actually provides substantial health benefits.

The journey towards prioritizing one's healthspan can be a circuitous path full of triumphs, setbacks and lessons. Challenges arise and old habits rear their ugly heads. Unforeseen obstacles test our resolve. The road is rarely linear and often leads us to unexpected places.

In this episode, Matt chats with former Microsoft Chief Technology Officer and one of our first Optispan Trailblazers Stuart McKee about Stuart's early forays into drugs, smoking, and alcohol consumption, how he stepped off the train to get his health (and life) in order, and how the healthcare system can shape our attitude to healthspan optimization, for better or for worse. Stuart shares his meticulous approach to finding the right primary care doctor, strategies for weight loss from an obese baseline, and experiences with clomid therapy. They also discuss the influence of mindset and external influence on our healthspan optimization trajectories.

Stuart is currently a Strategic Advisor to the software company Armada, where he collaborates with the executive team to identify opportunities, innovative solutions, and market priorities to drive awareness and growth for the company. He also serves as a substitute teacher for Washington's Northshore School District. He was previously Chief Operating Officer at the artificial intelligence and spatial analytics company Hayden AI and Chief Executive Officer of Optispan Geroscience LLC, a precursor to Optispan as it exists today. Stuart spent 16 years at Microsoft.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Why is it so challenging to find a primary care physician?

In the podcast, Stuart describes his selective search for the right primary care doctor. This blogpost details some of the reasons it may be hard to find a primary care provider: fewer people in the profession, high burnout rates, and challenges beyond the primary care provider's control, among others.

How to practically change your behaviors | Peter Attia & James Clear

This snippet of the Peter Attia Drive podcast features New York Times bestselling author James Clear, who wrote the book "Atomic Habits". Clear suggests focusing on displacing bad habits with better ones, and describes how it can sometimes take removing oneself from old environments to do this ("environment is like a form of gravity...it just pulls on you").

Ultra-Processed Diets Cause Excess Calorie Intake and Weight Gain: An Inpatient Randomized Controlled Trial of Ad Libitum Food Intake

Ultra-processed foods such as cereals, breads, and packaged snacks—the foods one often finds in the middle aisles at the grocery store—may be to blame for a lot of the American obesity crisis and make up a big part of the "obesogenic environment" Stuart mentions in this episode. This study compared a group of adults receiving ultra-processed foods to a group receiving unprocessed foods. The group on the ultra-processed diet consumed more calories and gained more weight than the group on the unprocessed diet, despite both groups' meals being matched for calories, energy density, macronutrients, sugar, sodium, and fiber.


Effects of Testosterone Treatment in Older Men

This study found that a year-long course of testosterone treatment had moderate benefits on sexual function and mood in men over 65 years of age. The trial found no significant effects on physical function (as measured by six-minute walking distance) or vitality (as assessed by a scale measuring fatigue during daily activities). Testosterone therapy is still relatively poorly-understood and needs further study.

If you're listening to this podcast, you've probably caught wind of at least some of the many things you can do to improve and take control of your health and wellbeing. For every legitimate healthspan intervention supported by rigorous research that's out there, there exist a bunch of dubious longevity solutions that have no real scientific backing behind them. The challenge lies not just in identifying what works, but also in resisting the allure of snake oil solutions that promise effortless transformations. Which interventions are actually crucial for optimizing your healthspan, which are just "nice-to-have", and which are downright pointless?

In this episode, Matt and Nick go through over twenty popular strategies for healthspan optimization and grade their usefulness from A to F.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Oral health for an ageing population: the importance of a natural dentition in older adults

Matt gave an A grade to regular dental visits and oral care as strategies for improving healthspan. This article makes the case for several benefits of maintaining natural teeth and oral function in older adults. One of these is an improved diet, as the loss of chewing ability and/or efficiency that often accompanies tooth loss can bring about a change in diet due to the limited foods one is able to consume. Tooth loss can also lead to issues such as bad breath or an altered facial appearance, which can then impact the social activity that is also an important component of wellbeing.

Does maintaining the number of present and functional teeth benefit the longevity of life in older people requiring nursing care?: A prospective cohort study

This preprint describes a one-year investigation into how the number of "present and functional" teeth in older Japanese people affects mortality. The study found no significant impact of the number of remaining teeth on mortality in these adults, possibly because of the participants' access to sound nutrition and oral care services.

Visceral Fat Is an Independent Predictor of All-cause Mortality in Men

In this study, researchers found that visceral fat, abdominal subcutaneous fat, liver fat, and waist circumference were all associated with a higher death risk for men, and that visceral fat was the sole mortality risk predictor among the four after adjusting for other measures of fat. DEXA scans help you measure your visceral fat levels.

Effects of Wearable Fitness Trackers and Activity Adequacy Mindsets on Affect, Behavior, and Health: Longitudinal Randomized Controlled Trial

According to this study, information about physical activity parameters such as step counts influence people's health and wellbeing. When participants received artificially deflated step counts, they experienced various negative effects, including worse mental health, higher blood pressure and heart rate, and poorer eating. Meanwhile, when participants received accurate feedback about their step counts, their mental health improved and they ate healthier foods.

How Old Do I Look?

If you want to see whether your "facial pores score" beats Nick's, here is the skin aging clock he used.

The R-Files is a series of episodes about rapamycin, a naturally occurring compound originally discovered in soil samples from Easter Island, also known as Rapa Nui (hence the drug's name). Rapamycin belongs to a class of drugs called macrolides and has potent immunosuppressive and anti-proliferative effects. The drug has garnered attention for its potential anti-aging properties and has attracted research interest for its ability to extend lifespan and delay age-related diseases in various model organisms, including yeast and mice.

In our fifth episode of the R-Files, Matt shares insights from his recent course of off-label rapamycin use, which he started in January 2024 and plans to continue for at least the next month or two. He describes improvements in joint pain and body fat loss as well as an unexpected bacterial infection, and speculates about whether rapamycin may have contributed to any of these effects. He also discusses rapamycin's half-life in his blood, which is significantly lower than that reported in the published literature.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Sirolimus steady-state trough concentrations are not affected by bolus methylprednisolone therapy in renal allograft recipients

Sirolimus is the common name for the pharmaceutical formulation of rapamycin, so for our purposes we can consider sirolimus and rapamycin to be interchangeable. This paper reports an elimination half-life of 63 hours for sirolimus, which means it should take around 63 hours for the concentration of the drug in the bloodstream to decrease by half. After another 63 hours, half of the remaining drug should be eliminated, and so on, until the drug is cleared from the body. The half-life of a drug can vary depending on factors such as an individual's metabolism, the route of administration, and whether an individual takes the drug regularly, and is an important pharmacokinetic parameter that helps determine dosing frequency and duration of action.

Rapamycin and Chloroquine: The In Vitro and In Vivo Effects of Autophagy-Modifying Drugs Show Promising Results in Valosin Containing Protein Multisystem Proteinopathy

This paper reports a rapamycin half-life of 58–63 hours, or around three days.


Single Rapamycin Administration Induces Prolonged Downward Shift in Defended Body Weight in Rats

This study found that administering a single dose of rapamycin to rats was enough to inhibit their food intake and daily weight gain in the first three to five days post-injection, with a greater reduction observed for higher rapamycin doses. The rapamycin dose also brought about a body weight reduction that lasted for about two months without any additional rapamycin injection. The authors speculate that the effect may be due to a rapamycin-induced change in body weight set point. A single rapamycin dose did not induce any glucose tolerance changes in the rats.


Chronic mTOR inhibition by rapamycin induces muscle insulin resistance despite weight loss in rats

This study also reported inhibited food intake and weight loss in rats receiving rapamycin, but found that rapamycin also brought about various metabolic defects including glucose intolerance (difficulties metabolizing glucose), hyperinsulinemia (too much insulin in the blood), and hyperglycemia (too much sugar in the blood). These defects were particularly pronounced in rats eating a high-fat diet.

Matt recently exchanged a lively correspondence about biological age with Harold Katcher, cofounder of a stealth biotechnology company and inventor of E5. E5 is a compound consisting of the purified exosome fraction of blood from young piglets—in other words, young pig blood. Katcher recently co-published a paper suggesting that injecting this young pig blood into rats made rats younger on several biological aging measures, including inflammatory markers and epigenetic aging signatures. Indeed, Katcher has injected E5 into his own right hand and presented differences in the appearance of his right and left hands on social media.

Putting pig blood into other animals (and into ourselves!) to reverse biological age might seem like a crazy thing to do. But this idea actually stems from a methodology with a decades-long history called heterochronic parabiosis, an area of research that explores the effects of joining the circulatory systems of different-aged organisms. In this experimental technique, researchers surgically connect two animals, typically mice, of disparate ages so that they share a common bloodstream. This union leads the older and younger individuals to exchange not just blood cells but also signaling molecules, growth factors, and other circulating factors. Remarkably, when an older animal is paired with a younger counterpart, it often experiences improvements in various aspects of health and tissue function, while the younger partner may exhibit corresponding signs of accelerated aging. The mechanisms underlying these effects are complex, multifaceted, and very much still under investigation.

In this episode, Matt takes a magnifying glass to E5: what we know about the compound, how it affects lifespan, and how its impact on lifespan stacks up with that of other longevity inventions such as caloric restriction and rapamycin. He discusses whether Harold's recent paper truly proves a reversal of biological age and where his findings fit into the larger body of literature in the field. He also gives us a window into the methodology of heterochronic parabiosis, what the primary data about life expectancy gains through this intervention show, and whether heterochronic parabiosis-inspired interventions such as E5 are realistic approaches to human lifespan extension.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Reversal of biological age in multiple rat organs by young porcine plasma fraction

This paper details the experiment featured in this podcast episode as well as the creation of epigenetic clocks for rat tissues. Scientists examined the effect of a plasma fraction from young adult pigs on these epigenetic clocks, and found that the treatment reduced epigenetic age, as measured by the clocks, by up to 30 percent across several rat organs. E5 also improved other parameters such as inflammatory markers and grip strength. The paper did not present lifespan data for the treated rats.

The Retardation of Aging in Mice by Dietary Restriction: Longevity, Cancer, Immunity and Lifetime Energy Intake

This decades-old paper presents results showing a significant lifespan extension in mice undergoing caloric restriction, an intervention that Matt describes as "arguably the gold standard" for rodent lifespan extension. The longest-lived mice in this paper averaged 53 months of life (average mouse lifespan is 12 to 18 months). It would have been interesting to do an apples-to-apples comparison of E5's effects on mouse lifespan to that of the caloric restriction this paper describes.

Studies that shed new light on aging

In this 2013 paper, Katcher describes his disagreement with the "wear and tear" or "accumulated damage" model of aging, which suggests that the primary driver of aging is a gradual accumulation of damage to cells and tissues over time that eventually leads to declines in their function and the onset of age-related diseases. He proposes paying greater attention to rejuvenation of aged cells, possibly via heterochronic plasma exchange, on the thesis that it is actually factors in the blood that regulate aging, and that young plasma carries factors that enable cellular youthfulness.

Harold Katcher's rejuvenated hand self-experiment

Katcher applied a topical version of E5 to his own right hand in 2022. This post from The Longevity Newsletter presents a side-by-side photographic comparison of his right (E5) and left (no E5) hands. According to Katcher, E5 thickened the skin and improved the color of as well as erased scars and wrinkles from his right hand.

Heterochronic parabiosis: historical perspective and methodological considerations for studies of aging and longevity

This review covers the history of heterochronic parabiosis, from the earliest documented instances of experimentation with animal grafting to 21st-century studies of regeneration. It also presents the methodology, technical challenges, and limitations of heterochronic parabiosis, such as mortality risk and parabiotic disease.

No single discipline or approach holds the key to making big strides in the longevity field. Human aging is incredibly complex, and we're going to need multiple shots on goal in our pursuit of human life- and healthspan extension. At the Optispan Podcast, we're always excited to learn about the various angles researchers and founders are taking to advance our understanding of longevity and get impactful therapeutics that will transform human health into the clinic.

In this episode, Ora Biomedical CEO and cofounder Mitchell Lee gives us the lowdown on doing high-throughput drug discovery using a combination of worms, robotics, AI, and the general public. Matt and Mitchell talk about the company's ambitious goal to create the world's largest and most rigorous database of longevity interventions, and how a new robotics and AI data analysis platform is helping the company get there. They discuss the state of drug discovery in the longevity field, whether we can really believe any data we get from worms, the intervention that killed all their worms in one day, and more.

Prior to cofounding Ora Biomedical, Mitchell spent his career focused on scientific research and mentorship, mentoring nearly 50 trainee researchers of all levels during his graduate and postdoctoral research periods. He was the founding Chair of the American Aging Association (AGE) trainee chapter, which offers early-career financial, career development, and networking benefits, and has served on the AGE Executive Committee and Board of Directors. Mitchell received a B.S. in biology, a B.A. in philosophy, and an M.S. in biology from Western Washington University. He completed his PhD in Experimental Pathology at the University of Washington School of Medicine, during which time he received a Howard Hughes Medical Institute (HHMI) Gilliam Fellowship for Advanced Study.

Matt is a cofounder and Chair of the Board of Directors of Ora Biomedical.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

WormBot: A high-throughput system for studying aging in C. elegans

This animation explains the mechanics of the WormBot-AI platform in a clear and accessible way.

The million-molecule challenge: a moonshot project to rapidly advance longevity intervention discovery

In this article, Mitchell, Matt, and their colleagues propose the Million Molecule Challenge, a plan to screen one million interventions in C. elegans, a nematode worm, for their effects on longevity. They describe their reasoning for using C. elegans as a model organism as well as the WormBot-AI robotics platform they have developed to facilitate this high-throughput screening. They also present a proof-of-principle screen of 1,266 compounds that they completed in one month using their WormBot-AI technology.

The Million Molecule Challenge for Life Extension - Matt Kaeberlein at Longevity Summit Dublin

Matt spoke at the Longevity Summit Dublin 2023, a gathering of researchers, founders, and other leaders in the longevity field, about moving longevity science into clinical practice, how close we are to "solving aging", and what we need to make an impact in the field. About halfway through the talk, he talks about the Million Molecule Challenge: why C. elegans are a reasonable model organism with which to study aging, how much of the intervention space we have explored, and why we need a Million Molecule Challenge at all. He also presents a time-lapse video of the WormBot-AI technology, an AI and robotics platform for studying the effect of interventions on C. elegans, in action.

Using C. elegans for aging research

This short article reviews the history of using C. elegans in geroscience research. It also discusses several reasons that C. elegans is a suitable model organism for studying aging, such as cost, short lifespans, and evolutionary conserved lifespan pathways; as well as the disadvantages of using C. elegans in geroscience research, including a lack of complexity in the organism and limits to biochemistry due to the worms' small size.

Rise of the WormBots: it’s time to scale up longevity R&D

Longevity.technology profiled Ora Biomedical and interviewed Mitchell about the company's development strategy, scale of operations, and plans for the future. Mitchell describes his aim to get from longevity biotech 1.0 to longevity biotech 2.0: "discovering the next generation, most efficacious interventions".

In April 2024, Matt delivered a presentation at a two-day congressional briefing on longevity science hosted at Washington, D.C.'s Mayflower Hotel by the Alliance for Longevity Initiatives (A4LI). Attendees included former Speaker of the House Newt Gingrich, Republican Congressman Gus Bilirakis, and Democratic Congressman Paul Tonko. We have decided to include Matt's presentation on our channel because we believe it delivers a valuable message.

Healthcare has historically taken a piecemeal approach to diseases, addressing ailments in isolation. While this method has been successful at curing and sometimes even eradicating multiple diseases, it has its limitations. Aging is the single greatest risk factor for many of the chronic diseases we worry about in later life—think cancer, Alzheimer's disease, diabetes—and involves a complex interplay of molecular, cellular, and physiological changes that underlie a myriad of health conditions. There is a reason that your average 80-year-old has more health problems than your average 18-year-old. As our understanding of human biology deepens, it is becoming increasingly evident that we need to broaden our focus beyond individual diseases and incorporate the biology of aging into strategies for improving human health and resilience to disease. Achieving this paradigm shift towards addressing the fundamental processes of aging, which will require interdisciplinary collaboration between scientists, clinicians, policymakers, and the public, will give us the potential to mitigate multiple age-related diseases simultaneously.

In this episode, Matt covers how we got here, the differences between 19th and 21st century medicine, and the importance of targeting the biological aging process to create transformative results in tackling healthcare challenges. He also discusses policy reforms that would be useful for the cause, including changes to FDA regulation, a rethinking of insurance reimbursement, and how he would reslice the federal funding pie.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Is our healthcare system broken?

This blogpost describes the US healthcare system as expensive, complicated, dysfunctional, and broken. It details some of the issues associated with the US healthcare system, including a poor cost-patient satisfaction ratio, access disparities for disadvantaged groups, and distorted incentives among health insurance providers. It also mentions a misguided focus on disease care rather than on preventative care such as nutrition, exercise, and mental health care, and notes that doctors in disease care specialties such as cardiology and surgery tend to have much higher incomes than doctors who work in primary care.

The Patient Experience: Perspectives on Today's Healthcare

Market research and analytics company The Harris Poll partnered with the American Academy of Physician Associates to survey over 2,500 adults in the United States in early 2023 about US healthcare. The survey found that many adults are dissatisfied with the US healthcare system: 34 percent gave the system a C grade, compared to 10 percent who gave it an A grade. An excessive focus on treating illness and injury when they happen, rather than on preventing them way before their onset, was one of the survey's most common complaints.

Fiscal Year 2024 Budget

The fiscal year 2024 budget of the National Institute on Aging (NIA), a division of the United States National Institutes of Health aimed at increasing healthy, active years of life in older adults, describes the NIA's research priorities. Several researchers in the geroscience field have expressed a wish for a greater proportion of the NIA budget to go toward studies of the biology of aging, rather than toward studies of individual diseases such as Alzheimer’s disease.

The economic value of targeting aging

Published in 2021, this paper showed that a one-year increase in healthy life expectancy via targeting aging, as opposed to individual diseases, is worth $38 trillion in economic value. That number climbs to $367 trillion at 10 years of increased life expectancy. Those numbers might seem too big to be true, but they make more sense if we consider that delaying aging via a geroscience approach could potentially delay a huge number of age-related diseases, such as Alzheimer’s disease, as well as diseases whose risk is far greater with advanced age, such as COVID-19.

Major longevity gains termed unlikely

In 1990, researchers at the University of Chicago published their findings that the average American lifespan would only enjoy a three-year gain even if scientists came up with a magic pill to cure all cancers and heart disease. This article covers that research and also presents views about aging that are quite different from those of geroscience today. "Barring a reversal of human aging on a molecular level, the rapid increases in life expectancy are over,” the study’s lead author S. Jay Olshansky said. Of course, 21st century geroscience is trying to investigate exactly what Olshansky mentions: the molecular specifics of human aging and how we can target those molecular mechanisms to address the functional declines and diseases of later life.

We talk a lot about the science of longevity and healthspan on the Optispan podcast—how DEXA scans work, what an optimal rapamycin dose might look like, how the intersection of optogenetics and mitochondria are helping us understand biological aging, what supplements one might consider taking and why.

But the longevity field runs on way more than just science. It takes a village—a community of researchers, engineers, entrepreneurs, investors, regulators, and beyond who believe in the value of tackling the biology of aging as a crucial strategy for extending healthy lifespan—to create tangible results that benefit as many people as possible. At Optispan, we're eager to support and interact with the many levers that keep this machine going. One of these is the Alliance for Longevity Initiatives (A4LI), a nonprofit organization focused on catalyzing social and political action that will benefit the longevity field.

In this episode, Matt chats with A4LI founder, president, and CEO Dylan Livingston about forming a bipartisan longevity science caucus, redirecting funding towards geroscience research, and engaging with policymakers to help them understand the importance of transitioning towards a proactive healthcare model. Dylan, who founded A4LI in 2021, served as a field organizer for President Joe Biden's 2020 presidential campaign. He also worked as a community organizer for Organizing Corps 2020, where he registered hundreds of Democratic voters in Pennsylvania for the 2020 presidential compaign. Dylan graduated from Haverford College with a B.S. in physics and a minor in economics.

Matt joined the A4LI Board of Directors in 2024.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Longevity Gets Political at an Unprecedented DC Event

Lifespan.io, a nonprofit organization that aims to help accelerate discovery in the aging field through journalism, crowdfunding, and community building, profiled a two-day congressional briefing on longevity science held at Washington, D.C.'s Mayflower Hotel in April 2024. The event included presentations from Matt and other longevity biotech startup founders such as Kristen Fortney (BioAge) and Joe Betts-Lacroix (Retro Biosciences). Attendees also heard from former Speaker of the House Newt Gingrich, Republican Congressman Gus Bilirakis, and Democratic Congressman Paul Tonko.

A Policymaker’s Guide the Longevity Therapeutics Industry

This guide serves as a primer on the ever-evolving longevity space for policymakers. It describes the dominance of aging as a risk factor in chronic diseases such as cancer and diabetes, the thesis behind the geroscience approach, and recent academic and industry initiatives in longevity medicine. It also addresses several arguments for and against tackling age-related diseases and lifespan—think overpopulation, economic disparity, and the "unnaturalness" of longer lifespans—and ends with concrete steps that policymakers can take to help advance the field.

The Advanced Approval Pathway for Longevity Medicines

This document proposes a special approval track for longevity medicines to accelerate the development process for drugs that tackle the biological aging process. It includes standards for designating a therapeutic as a longevity medicine and solutions for overcoming status quo barriers such as a priority review voucher system and patent term extensions.

How can ARPA-H be a transformative agency to advance the development of biotechnology that targets human aging?

The Advanced Research Projects Agency for Health (ARPA-H) is a National Institutes of Health (NIH) entity that aims to accelerate the development of transformative solutions to our greatest health challenges. The agency provides funding to support high-impact, high-risk, high-reward research in the private and public sectors under the leadership of a Program Manager who champions a core idea and uses their subject matter expertise to see the idea to fruition. This post provides several examples of how ARPA-H might support the longevity field.

Make Your Voice Heard: Contact Your Representative on Behalf of Longevity Science

A4LI has prepared a letter template for you to use in the event that you want to request that your congressperson provides support to longevity initiatives. You are welcome to customize the letter as you see fit, and may email A4LI at info@a4li.org if you need any assistance, such as contact information for your congressional office, to send the letter.

A DEXA (dual-energy X-ray absorptiometry) scan is an advanced imaging procedure for measuring bone density and composition. DEXA scans utilize two different energy levels of low-dose X-ray beams—one absorbed mostly by soft tissue, and the other absorbed mainly by bone—to differentiate between bone, fat, and lean tissue. In so doing, they provide noninvasive and detailed information about bone health, risk of osteoporosis or fractures, and body composition. While medical practioners typically perform DEXA scans on the lower spine and hips, they can also perform DEXA scans on the whole body for the purposes of early detection and intervention.

In our multi-part DEXA series, we go deep into DEXA scans: what they measure, how to interpret them, and how to use information from your own DEXA scan for healthspan optimization. Part I covers fundamental concepts related to body composition and its evaluation, current tools available for measuring body composition as well as their strengths and limitations, and Matt's personal experiences with DEXA scans.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Optispan uses the BodySpec DEXA scan in its concierge and corporate offerings.

What Is a DEXA Scan and How Can It Help You?

This is an introduction to DEXA scans that covers the history of DEXA scans, how DEXA scans work, what happens during a DEXA scan, and how DEXA scans compare to imaging techniques such as CT scans, magnetic resonance imaging (MRI) scans, and x-rays.

DEXA FAQ

This list of FAQs covers many questions people have about DEXA scans, including how much radiation exposure we receive from DEXA scans, height and weight limits, the safety of DEXA scans for pregnant wome, and more.

Unexpected DEXA Scan Results? Here are Some Potential Causes

You may have gotten your DEXA scan results back and balked at what you saw. This list addresses some possible reasons for DEXA scan surprises.

Role of Visceral Adipose Tissue in Aging

This paper reviews and summarizes evidence suggesting that visceral fat accumulation and abdominal obesity predict high disease and mortality risk. It describes studies demonstrating that visceral fat removal from rats extends lifespan, and discusses the potential role visceral fat plays in the lifespan-extending effects of caloric restriction. It also reviews several treatment strategies for tackling visceral fat such as leptin administration.

Visceral Fat Is an Independent Predictor of All-cause Mortality in Men

In this study, researchers found that visceral fat, abdominal subcutaneous fat, liver fat, and waist circumference were all associated with a higher death risk for men, and that visceral fat was the sole mortality risk predictor among the four after adjusting for other measures of fat.

Optogenetics is a cutting-edge field at the intersection of optics and genetics. This technique introduces microbial opsins, light-sensitive proteins naturally found in certain microorganisms such as algae and bacteria, into specific organelles, cells, or tissues to make them sensitive to light and thus precisely manipulable. Optogenetics has served as a powerful tool in neuroscience research, enabling scientists to dissect complex neural circuits and understand how they give rise to behavior, cognition, and disease; and is expanding its reach to other fields such as endocrinology, vision restoration, and muscle physiology.

In this episode, researcher Brandon Berry chats with Matt about the development and application of optogenetic tools to manipulate mitochondrial function in cells. He shares his experiences with engineering optogenetic proteins for mitochondrial targeting, the challenges involved in controlling mitochondrial charge, and the potential of optogenetics to manipulate mitochondrial membrane potential. He also discusses the complexities of mitochondrial dysfunction, the relationship between mitochondrial dysfunction and aging, and the role of mitochondrial membrane potential in longevity interventions, including caloric restriction.

Brandon, who is currently working on a stealth project, was a former postdoctoral research associate in Matt's lab at the University of Washington, where he did a lot of his work on developing tools for mitochondrial control. He received a PhD in Physiology from the University of Rochester.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Why Are Cells Powered by Proton Gradients?

This article discusses biochemist Peter Mitchell's model of proton gradients' role in cellular respiration. Proton gradients power the synthesis of adenosine triphosphate (ATP, an energy-providing nucleotide), providing a crucial mechanism for cellular metabolism. The article also explores how reliance on proton gradients might have constrained the evolution of complexity until the advent of eukaryotic cells, which harnessed mitochondria to control these gradients and may have facilitated the leap to multicellular life forms. Mitchell's proposition, though initially controversial, ultimately earned him a Nobel Prize and reshaped our understanding of cellular energy production.

Optogenetic control of mitochondrial metabolism and Ca2+ signaling by mitochondria-targeted opsins

This article describes an optogenetic approach that enables precise control of mitochondrial membrane potential through light-dependent activation of channelrhodopsins—light-sensitive proteins—targeted to the inner mitochondrial membrane. The method offers insights into cellular processes without the drawbacks of conventional pharmacological interventions.

Optogenetic control of mitochondrial protonmotive force to impact cellular stress resistance

Brandon is the lead author on this paper describing the engineering of an optogenetic technique for increasing the proton gradient, or protonmotive force, in worm mitochondria. "Charging up" mitochondria in this way has several beneficial effects for mitochondria, including increased resistance to toxins, better ATP synthesis, and hypoxia resistance.

Optogenetic rejuvenation of mitochondrial membrane potential extends C. elegans lifespan

In the podcast, Brandon discusses lifespan experiments he conducted to assess the impact of optogenetic mitochondrial manipulation on longevity. This study presents his finding that optogenetically controlling mitochondria slows aging and improves measures of healthspan in worms.

Extending lifespan by rejuvenating mitochondrial membrane potential - Dr Brandon Berry

Brandon chats with Eleanor Sheekey of The Sheekey Science Show about his mtON tool and its effects on worm lifespan. He provides an introduction to mitochondria ("the best organelles ever") and its role in cells, discusses the potential role of mitochondria in aging and age-related biological processes such as cellular senescence, offers some advice for aspiring academics, and more.

We talk a lot about making a shift from reactive disease care—a 20th century healthcare mindset—to preventative and proactive health measures designed to optimize longevity and healthspan before disease sets in. Rather than waiting for chronic conditions to manifest and treating their symptoms post hoc, we encourage investing resources in preemptive care and empowering individuals to act as partners with healthcare providers in their own wellbeing.

Preventative medicine can feel like a lot—cancer screenings, for example, are crucial for early detection and treatment, but can be logistically and emotionally daunting. But proactive healthcare doesn't always need to be complicated. In this episode, Matt goes through what he sees as low-hanging fruit in preventative medicine: simple steps that lend themselves to straightforward measurement, are easy to improve without invasive intervention or drastic lifestyle changes, and will pay dividends in increasing our overall health.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Examine.com

Examine is an independently-funded (no gifts, donors, sponsors, consulting clients, advertisements, or affliations) database of supplement research that provides information about benefits, dietary sources, dosage, side effects, and more about pretty much any supplement you can think of. It provides further references from the primary literature about each supplement it discusses.

Global and regional prevalence of vitamin D deficiency in population-based studies from 2000 to 2022: A pooled analysis of 7.9 million participants

This study found a high prevalence of vitamin D deficiency globally from the years 2000 to 2022. Women and people living in high-latitude areas, the Eastern Mediterranean region, and lower-middle-income countries were more susceptible to vitamin D deficiency. The prevalence of vitamin D deficiency in winter-spring was nearly twice that in summer-autumn.

Vitamin D deficiency 2.0: an update on the current status worldwide

This study reviews the literature on vitamin D deficiency and its nuances. It discusses prior research about the effectiveness of vitamin D supplementation, the impact of vitamin D supplementation on various endpoints, different vitamin D dosing regimes, vitamin D toxicity, and populations for which vitamin D supplementation is likely to be most useful.

Vitamin B12

Vitamin D

Omega-3 Fatty Acids

These fact sheets from the National Institutes of Health discuss recommended intakes, vitamin B12/D/omega-3 fatty acid sources, groups at risk of vitamin B12/D/omega-3 fatty acid deficiency, and more.

We typically think of prescription drugs as targeted treatments designed to address the underlying mechanisms and biochemical pathways associated with specific diseases or conditions. For example, healthcare providers commonly prescribe statins that lower cholesterol levels and reduce cardiovascular disease risk by inhibiting the enzyme involved in cholesterol synthesis. Similarly, doctors might prescribe antibiotics to target bacterial infections by disrupting the bacteria's growth or killing them outright.

But prescription drugs may have multiple uses or indications beyond their original intended purpose. A recent preprint from the biotech startup EPITERNA describes a study exploring the link between prescription drugs and human lifespan. Researchers analyzed more than 40 years of prescription drug data from over 500,000 patients in the UK Biobank to examine how commonly prescribed medications affect mortality risk. Many drugs have negative consequences for lifespan for reasons that include drug resistance, drug dependency, and side effects such as organ damage and immunosuppression—but a number of drugs actually appear to be beneficial for longevity. In this episode, Matt goes over the study's top-performing drugs for lifespan, and discusses how we might interpret and extend these intriguing findings about common prescription medications.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Association between prescription drugs and all-cause mortality risk in the UK population

This is the EPITERNA preprint Matt discusses in the podcast. The preprint describes the results of analyzing prescription medication and mortality data from over half a million patients recorded in the UK Biobank, a biomedical database and research resource of health-related data from participants aged between 40 and 69 years old in the United Kingdom, for a period of over 40 years. After comparing the mortality of patients taking the top 406 prescribed drugs to that of controls not taking a given drug, they found a number of prescription medications correlated with longer lifespans.

Effect of Aspirin on All-Cause Mortality in the Healthy Elderly

Aspirin, also known as acetylsalicylic acid, is one of the most widely used medications globally, renowned for its pain-relieving, anti-inflammatory, and blood-thinning properties. Its accessibility, affordability, and proven efficacy in pain relief contribute to its frequent use. This study found that healthy older adults taking daily aspirin had a higher risk of death than those taking placebo drugs, and that most deaths were cancer-related.

Geroscience-guided repurposing of FDA-approved drugs to target aging: A proposed process and prioritization

This article makes the case for a greater focus on repurposing existing drugs to target the biology of aging and age-related disease. The authors, who trawled the literature for FDA-approved drugs or drug classes that have a potential lifespan-extending effect in rodents, present a framework for assessing whether a given therapeutic might demonstrate geroprotective effects in a clinical trial.

The Mortality Toll of Estrogen Avoidance: An Analysis of Excess Deaths Among Hysterectomized Women Aged 50 to 59 Years

In the preprint Matt discusses in this podcast episode, six prescription medications containing estrogen had a positive impact on mortality risk. That is a striking result, and one worth further exploration. This paper examined the mortality toll of estrogen avoidance among middle-aged women who had undergone hysterectomies, and found that nearly 20,000 hysterectomized women had experienced premature death after the publication of findings that led to an aversion to hormone replacement therapy.

Canagliflozin extends life span in genetically heterogeneous male but not female mice

Matt mentions this study in the podcast as one showing that canagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor aimed at treating type 2 diabetes, was one of the more potent mouse lifespan-extending drugs to emerge from the Interventions Testing Program. Canagliflozin extended male mouse lifespan by 14 percent, and the age for 90th percentile survival by nine percent. The study found no lifespan extension effects in female mice.

Senescent cells, cells that cease to divide and proliferate while remaining metabolically active, are a complex and intriguing aspect of biological aging. They serve as both a protective mechanism against cancer, preventing damaged cells from uncontrollable replication, as well as a contributor to tissue dysfunction and age-related pathologies such as cardiovascular disease, neurodegenerative disorders, and diabetes. The precise mechanisms that underlie senescence and its contributions to the aging process remain areas of ongoing investigation and debate.

In this episode, Matt chats with Sapere Bio co-founder and CEO Natalia Mitin about measuring cellular senescence, using those measurements in the clinic, and the complex and heterogeneous role of cellular senescence in aging and disease. They also discuss Natalia's personal experiences using rapamycin off-label to improve energy levels and immune function, the importance of monitoring biomarkers when using off-label medications, and Natalia's thoughts on "rapamycin for all".

Prior to co-founding Sapere Bio, Natalia served as an assistant professor at the University of North Carolina at Chapel Hill's Department of Pharmacology. She spent over two decades developing assays for use in cancer research. She holds a B.S. in chemical engineering from the Mendeleev Institute for Chemical Technology and a PhD in biochemistry and molecular biology from Bowling Green State University.

Optispan uses the SapereX test in its healthspan optimization program.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders

This seminal paper demonstrated a potential causal link between cellular senescence and various aging phenotypes. Removing senescent cells exhibiting the kinase inhibitor and senescence biomarker p16 delayed the onset of age-related phenotypes in mouse skeletal muscle, adipose, and eye tissues.

Naturally occurring p16 Ink4a-positive cells shorten healthy lifespan

This paper, which shares several authors with the previous one, showed that clearing senescent cells impeded tumor and cataract formation as well as age-related deterioration of organs and tissues including kidney, heart, and fat in mice. It also extended lifespan in mice from two different genetic backgrounds that were eating different diets.

Senolytics improve physical function and increase lifespan in old age

If you want to prematurely age a mouse, give it a senescent cell transplant. Transplanting senescent cells into young mice led to physical dysfunction, the spread of cellular senescence to host tissues, and reduced survival in mice. Selective elimination of senescent cells via senolytic therapy alleviated these negative effects and increased survival after treatment by 36%.

Expression of p16(INK4a) in peripheral blood T-cells is a biomarker of human aging

This study found an association between the kinase inhibitor and senescence biomarker p16 and human chronological age. It also found a more rapid increase in p16 expression with older age in those who smoked compared with those who didn't smoke, a finding consistent with other evidence for tobacco smoke's age-accelerating effects; as well as a relationship between the expression of p16 and interleukin-6 (IL-6), a cytokine that plays an important role in cell signalling and can serve as a biomarker of inflammation.

A quantitative model for age-dependent expression of the p16INK4a tumor suppressor

This paper presents results from computational modeling of p16+ cellular senescence dynamics in healthy people. The model revealed how the p16 accumulation rate changes with chronological age and lifestyle factors such as smoking and exercise habits.

A DEXA (dual-energy X-ray absorptiometry) scan is an advanced imaging procedure for measuring bone density and composition. DEXA scans utilize two different energy levels of low-dose X-ray beams—one absorbed mostly by soft tissue, and the other absorbed mainly by bone—to differentiate between bone, fat, and lean tissue. In so doing, they provide noninvasive and detailed information about bone health, risk of osteoporosis or fractures, and body composition. While medical practioners typically perform DEXA scans on the lower spine and hips, they can also perform DEXA scans on the whole body for the purposes of early detection and intervention.

In our multi-part DEXA series, we go deep into DEXA scans: what they measure, how to interpret them, and how to use information from your own DEXA scan for healthspan optimization. Part I covers fundamental concepts related to body composition and its evaluation, current tools available for measuring body composition as well as their strengths and limitations, and Matt's personal experiences with DEXA scans.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

What Is a DEXA Scan and How Can It Help You?

This is an introduction to DEXA scans that covers the history of DEXA scans, how DEXA scans work, what happens during a DEXA scan, and how DEXA scans compare to imaging techniques such as CT scans, magnetic resonance imaging (MRI) scans, and x-rays.

DEXA FAQ

This list of FAQs covers many questions people have about DEXA scans, including how much radiation exposure we receive from DEXA scans, height and weight limits, the safety of DEXA scans for pregnant wome, and more.

Unexpected DEXA Scan Results? Here are Some Potential Causes

You may have gotten your DEXA scan results back and balked at what you saw. This list addresses some possible reasons for DEXA scan surprises.

Abdominal fat analyzed by DEXA scan reflects visceral body fat and improves the phenotype description and the assessment of metabolic risk in mice

This study found a high correlation between visceral fat content measured by DEXA scans and the actual excised visceral fat content of mice, suggesting that DEXA scans are accurate tools for noninvasive fat distribution measurement.

You asked, we listened. Ever since the February 2024 launch of our series "The R-Files", a series of episodes about all things rapamycin, we've received a ton of questions about this compound and how it works in the context of aging and longevity. We went through every comment you left on Youtube, Twitter, and LinkedIn to compile a list of your questions about combining interventions, optimizing rapamycin dosing, limitations in applying findings from mice and medical studies to off-label human usage of rapamycin and other supplements, and so much more.

Keep the questions coming—if there are more, we'll address them in a future AMA episode.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Rapamycin News

Many of our podcast listeners are interested in questions about rapamycin dosing, how to get a prescription for rapamycin, and how rapamycin might interact with other supplements or drugs. This website is a great resource for getting more clarity on some of these questions, as well as for hearing about others' experiences with rapamycin and other longevity medications.

Distinct and additive effects of calorie restriction and rapamycin in aging skeletal muscle

This study addresses the question of how much the effects of rapamycin recapitulate the effects of caloric restriction by profiling gene expression signatures and markers of muscle quality in mice undergoing caloric restriction and rapamycin treatment. The researchers found that rapamycin and caloric restriction likely act via mechanisms that are likely non-overlapping and complementary in mouse skeletal muscle.

Effect of caloric restriction and rapamycin on ovarian aging in mice

This study found that caloric restriction and rapamycin exert similar effects on ovarian aging in mice. Both interventions preserve the number of primordial follicles—immature egg cells at the earliest stage of ovarian follicle development—to a similar degree. Effects on metabolism differed, however: caloric restriction mice demonstrated lower weight gain and visceral fat as well as increased insulin sensitivity, while rapamycin-treated mice did not.

Evaluation of off-label rapamycin use to promote healthspan in 333 adults

Matt and colleagues, including Optispan Chief Medical Officer George Haddad, collected self-reported data from over 300 adults with a history of off-label rapamycin use to capture data about the drug's potential side effects. The only side effect that was significantly more prevalent in rapamycin users compared to non-users was the presence of mouth sores, and several side effects typically associated with rapamycin use such as eye pain and anxiety occurred less frequently in rapamycin users than in non-users.

At the Optispan Podcast, we aim to help you become your own detective of research in the geroscience field and beyond. Critical thinking is our compass. We want to help you dig into every aspect of a study: are the methods they used solid? Was the sample size big enough? Did they crunch the numbers right? What's the most reasonable interpretation of the data? Might a conflict of interest skew the results?

In Part II of a two-part series about a recent study of how a supplement called "Leap Years" affects canine cognitive function, Matt takes a magnifying glass to a bioRxiv preprint describing the clinical trial's methodology and findings. Beginning with a sentence-by-sentence dissection of the study's abstract, he describes various things he finds unusual or questionable about the way researchers ran and publicized the clinical trial: exclusion of certain data, a lack of disclosure around the supplement's ingredients, the use of an assessment tool that was not validated for its intended purpose, and more. He discusses conclusions we can actually draw from the study based on the information the researchers have supplied, and whether or not he would give the supplement to his own dog.

This episode is Part II of a two-part series. In part I, Matt talks about the press release announcing the drug's potential ability to reverse age-related decline and improve cognitive function in dogs, as well as the importance of interrogating bold advertising claims rather than taking them at face value.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

LeapYears

You can get more information about and purchase the LeapYears product here. Animal Biosciences, the company selling the product, describes LeapYears as "the only dual action dog supplement system that targets aging at the source – the cellular level." The website provides several resources about dog aging, cellular senescence, NAD boosters, and its clinical trial results.

A Randomized, Controlled Clinical Trial Demonstrates Improved Cognitive Function in Senior Dogs Supplemented with a Senolytic and NAD+ Precursor Combination

This is the preprint upon which the LeapYears product is based. Preprints are drafts of full papers that have not yet undergone peer review, a process of ensuring the credibility, validity, and reliability of published research by subjecting it to rigorous evaluation by independent experts. Preprint results can be exciting, valid, and spark interesting discussions, but should be interpreted with caution. This preprint provides some insight into the nuances of the clinical trial that led to the product's eventual introduction to the pet market.

NAD+ homeostasis in human health and disease

Nicotinamide adenine dinucleotide (NAD), an essential cofactor present in all living cells that modulates several metabolic pathways, became more prominent in the scientific literature in the last two decades when it was highlighted as a crucial component of sirtuin function. In this review, the authors discuss current knowledge of NAD's role in various human diseases as well as current therapeutic strategies that target NAD.

Age-Dependent Decline of NAD+—Universal Truth or Confounded Consensus?

This article questions the consensus view that NAD levels decline with age by examining NAD changes in various species, including yeast, worms, rats, mice, monkeys, and humans. They find that the evidence for age-dependent NAD declines is limited, in part due to a relative paucity of studies assessing how NAD levels change with age, and in part due to the many discrepancies in the literature about this topic, even down to the level of individual tissues. They note that human studies of age-related NAD changes are particularly limited and inconclusive, and call for larger-scale studies of and greater nuance in discussing the relationship between NAD levels and age.

A common signature of cellular senescence; does it exist?

At its core, cellular senescence represents a state of irreversible growth arrest in cells. Pinpointing a universal definition of senescence is challenging, however, because senescence manifests differently across cell types and contexts and encompasses a spectrum of phenotypic changes beyond just growth arrest, including alterations in gene expression, metabolic activity, and the secretion of pro-inflammatory factors. Subsets of senescent cells may exhibit distinct properties and functions. This review examines the question of whether there exists a common signature of cellular senescence.

Don't just swallow information whole—question it, test it, poke and prod it to see if it holds up under scrutiny.

One of our core goals at the Optispan Podcast is to help you become your own detective of research in the geroscience field and beyond. Critical thinking is our compass. We want to help you dig into every aspect of a study: are the methods they used solid? Was the sample size big enough? Did they crunch the numbers right? What's the most reasonable interpretation of the data? Might a conflict of interest skew the results?

In this episode, Matt puts the spotlight on a recent finding that made a splash in the longevity community: a combination senolytic/NAD booster product that researchers suggested had the potential to reverse age-related decline in dogs. Matt goes over what the product might contain (spoiler: we're not sure), what we do and don't know about it, and his personal feelings about whether it should actually be on the market for pet owners to purchase.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Leap Years

You can get more information about and purchase the LeapYears product here. Animal Biosciences, the company selling the product, describes LeapYears as "the only dual action dog supplement system that targets aging at the source – the cellular level." The website provides several resources about dog aging, cellular senescence, NAD boosters, and its clinical trial results.

A Randomized, Controlled Clinical Trial Demonstrates Improved Cognitive Function in Senior Dogs Supplemented with a Senolytic and NAD+ Precursor Combination

This is the preprint upon which the LeapYears product is based. Preprints are drafts of full papers that have not yet undergone peer review—a process of ensuring the credibility, validity, and reliability of published research by subjecting it to rigorous evaluation by independent experts. Preprint results can be exciting, valid, and spark interesting discussions, but should be interpreted with caution. This preprint provides some insight into the nuances of the clinical trial that led to the product's eventual introduction to the pet market.

CORRECTING and REPLACING Animal Biosciences Announces New Canine Clinical Research Evaluating Reversal of Age-Related Signs in Dogs

The press release covering the LeapYears drug, originally published in Feburary 2024, makes several claims that Matt interrogates in this episode. In response to pushback on one of the claims, the Animal Biosciences team made a correction to a quote by founder and Harvard genetics professor David A. Sinclair about the supplement's ability to reverse dog aging.

Can Your Dog Live Longer With a Pill?

This article breaks down how the clinical trial tested the LeapYears formulation for its effects on older dogs. It discusses the statistical significance of the clinical trial's findings, and offers a perspective on how to interpret statistically significant data points among a basket of other statistically insignificant outcomes. It also discusses external confounders that could have influenced the clinical trial results.

The R-Files is a series of episodes about rapamycin, a naturally occurring compound originally discovered in soil samples from Easter Island, also known as Rapa Nui (hence the drug's name). Rapamycin belongs to a class of drugs called macrolides and has potent immunosuppressive and anti-proliferative effects. The drug has garnered attention for its potential anti-aging properties and has attracted research interest for its ability to extend lifespan and delay age-related diseases in various model organisms, including yeast and mice.

In the fourth episode of the R-Files, Matt discusses research demonstrating that rapamycin rejuvenates the aged mouse immune system to respond to a flu vaccine as if it were in a youthful state. He also discusses papers suggesting that rapamycin may have similar effects on human immune systems.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Rapamycin fed late in life extends lifespan in genetically heterogeneous mice

This is the study that Matt describes at the beginning of this episode as one of the first demonstrations of lifespan extension via a treatment that starts in middle age. Researchers found that rapamycin improved mouse survival by 14% and 9% for females and males respectively, even when rapamycin feeding began late in life. The authors propose several mechanisms by which rapamycin might delay aging, including modulation of nutrient dynamics and cellular stress resistance.

mTOR Regulation and Therapeutic Rejuvenation of Aging Hematopoietic Stem Cells

Lots of big immunology words in this one—thankfully, Matt breaks them down for us in the podcast. This paper focuses on mouse hematopoietic stem cells (HSCs), which are cells that give rise to all types of blood cells. It describes two core findings that, taken together, strengthen the evidence for the role of mTOR (mammalian target of rapamycin) signalling in HSC aging. First, genetic manipulation in young mice over-activates mTOR activity and leads to an aged mouse HSC phenotype; and second, rapamycin rejuvenates HSC function, improves vaccination response, and increases lifespan.

Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice

Many of those interested in rapamycin have questions about what the optimum rapamycin dosing regime looks like. While there is not yet any conclusive evidence suggesting an ideal dose for humans, researchers have demonstrated dosing regimes that work in mice. This study found that a single three-month rapamycin regimen increased life expectancy in middle-aged mice without overt detrimental side effects, validating previous work on this question.

TORC1 inhibition enhances immune function and reduces infections in the elderly

This paper investigated the effects of rapamycin treatment on elderly humans. It found that a rapamycin derivative improved vacination response and decreased infection rates in healthy people over 65, with minimal adverse effects.

Targeting the biology of ageing with mTOR inhibitors to improve immune function in older adults: phase 2b and phase 3 randomised trials

This study describes a clinical trial of an oral mTOR inhibitor’s effects on antiviral immunity in people aged over 65. Patients who took the drug demonstrated a greater upregulation of antiviral responses compared to those who took a placebo drug. Those receiving the mTOR inhibitor also suffered from fewer respiratory tract infections, including coronavirus, rhinovirus, and the flu.

As a longevity scientist, Matt often receives questions about what supplements he takes—so we decided to make an episode where Matt discusses his supplements protocol.

This episode isn't meant to provide a playbook for you to follow. We want to emphasize the importance of approaching supplements with discernment and an understanding that they are not a substitute for wholesome nutrition and other healthy lifestyle practices. The allure of supplements is understandable: they promise us vitality, strength, and longevity in a convenient capsule. But their indiscriminate consumption can be risky. Blindly reaching for supplements without considering their necessity or potential interactions with medications could lead to adverse effects. Further, the supplement industry isn't rigorously regulated in many regions, leaving room for mislabeling and contamination. There is no such thing as a one-size-fits-all solution when it comes to supplements.

In this episode, Matt discusses his relatively conservative supplements approach, debunks some of the myths associated with supplement consumption, and provides some advice about how to evaluate products that come from a profit-driven industry with few guardrails in place.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Examine.com

Examine is an independently-funded (no gifts, donors, sponsors, consulting clients, advertisements, or affiliations) database of supplements research that provides information about benefits, dietary sources, dosage, side effects, and more for pretty much any supplement you can think of. The website provides further references from the primary literature about each supplement it discusses.

NAD and NAD precursors: help or hype? | Peter Attia, M.D. & Matt Kaeberlein, Ph.D.

Matt spoke with physician Peter Attia on the Peter Attia Drive podcast about the nuances of how nicotinamide adenine dinucleotide (NAD) precursors affect aging. He also discusses his views on the evidence for sirtuins' effects on lifespan.

Why EVERYONE Should Use Creatine Supplements

This episode of physician Brad Stanfield's Look & Feel Young podcast provides a quick primer on the benefits of creatine supplements, which include athletic performance and short-term memory improvements, among others. It also addresses concerns that people often have with creatine supplementation, such as hair loss.

While scientific papers are generally considered trustworthy sources of information, it's important to approach them with a critical mindset and to avoid blindly accepting their claims. The peer-review process, which helps ensure high research quality, is not foolproof. Errors or biases can slip through the cracks. In reading a paper, we should independently evaluate the evidence, scrutinize the methodology, and reflect on alternative interpretations of the data. Considering the influence of funding sources, conflicts of interest, and the potential for selective reporting can also help in maintaining a healthy skepticism about new information.

In this episode of Longevity This Week, Matt takes us through a recently-published paper about the effects of senolytic CAR T cell therapy on the aging process in mice to help us figure out whether the paper's claims hold water. He also analyzes a BBC article describing the findings. Popular press adaptations of the scientific literature often serve as a useful bridge between the complex world of research and the general public, but can be misleading in their attempts to make science accessible. They might, for example, inadvertently distort or oversimplify findings, exaggerate the significance of results, or selectively report research while ignoring contradictory or inconclusive evidence from other sources. We hope this episode will encourage viewers to approach science communication with a discerning eye, and to stay vigilant, curious, and open-minded in learning about the latest discoveries and developments.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Prophylactic and long-lasting efficacy of senolytic CAR T cells against age-related metabolic dysfunction

This is the paper Matt discusses in the podcast. It suggests that injections of chimeric antigen receptor (CAR) T cells with senoloytic, or senescent cell-eliminating, properties improves symptoms associated with physiological aging in mice.

Breakthrough anti-ageing cell discovery could help you stay younger for longer

This BBC article covered the paper describing the senolytic CAR T cell finding. Matt discusses the accuracy of its coverage in the podcast episode.

Naturally occurring p16Ink4a-positive cells shorten healthy lifespan

Senescent cells are cells that have entered a state of irreversible growth arrest, meaning they have stopped dividing and replicating. While senescence can serve a beneficial role in wound healing and preventing cancer, accumulated senescent cells can promote chronic inflammation and tissue dysfunction, and may contribute to the development of age-related conditions. This study found that clearing senescent cells from mice increased lifespan and delayed various age-associated pathologies, including cataracts and glomerulosclerosis.

Senolytic CAR T cells reverse senescence-associated pathologies

The lab that published the paper Matt discusses in this episode released this paper in 2020. This paper test the idea that CAR T cells can target a protein induced during cellular senescence, and in so doing improve pathology associated with liver fibrosis and lengthen the lifepsan of mice with lung adenocarcinoma.

At its best, healthcare isn't just about extending lifespan—it's also about enhancing the vitality of our years. Over the last century, the healthcare system has made enormous strides in keeping sick people alive. The next step is to use proactive, preventative healthcare to stop them from getting sick at all. The Lost Decade—the 10 or so years that many people spend suffering from poor health and/or disability in older age—doesn't have to be a given.

In this episode, Matt discusses why he left academia to help start a healthcare revolution, why sickness and decline don't have to define our final years, how decades of geroscience research have informed his views of healthcare, and what he thinks healthspan optimization should look like.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Healthy aging: The ultimate preventative medicine

Matt and colleagues make the case for placing greater emphasis on research into the biology of aging in a review for the journal Science. Traditional biomedical research has created significant advances in medical care by focusing primarily on understanding and treating individual diseases, but has not addressed the accumulation of age-related morbidities in aging populations. The study of aging biology, or geroscience, aims to plug this gap by identifying the mechanisms that underlie aging and developing interventions to extend healthy lifespan. By targeting aging processes themselves rather than individual diseases, researchers hope to delay the onset and progression of various age-related conditions.

It is Time to Embrace 21st-Century Medicine

In the journal Public Policy & Aging Report, Matt asserts that we are in a good position to extend human healthspan through more effective means than the 20th century’s reactive disease care model. Instead of taking a one-by-one approach to healthcare, where we tackle diseases one at a time as they occur, we should directly target the biological aging process—and in so doing, add years to people’s health- and lifespan. He lists sources of federal funding for geroscience research and calls for more initiatives within the biomedical research community that center on research into the biology of aging.

Translational geroscience: A new paradigm for 21st century medicine

Matt provides a high-level overview of the geroscience approach and its potential impact. He introduces several efforts to translate current research to the clinic, including clinical trials of rapamycin in humans and dogs as well as the Targeting Aging with Metformin (TAME) trial, which aims to investigate the impact of the antidiabetic drug metformin on non-diabetes comorbidities in older patients. The article also discusses some of the regulatory hurdles involved with developing interventions that target aging biology.

From lifespan to healthspan (1)

Matt spoke at the recent a16z crypto Founders Summit about his decision to leave academia to found a startup, opportunities for disruption in the healthcare space, and foundational concepts in geroscience. He notes that we are nowhere near close to “longevity escape velocity” or immortality, and advises skepticism of anyone who makes overoptimistic claims about the field.

Over a decade ago, five researchers published a paper proposing the Hallmarks of Aging paradigm: a set of cellular and molecular processes that underlie the aging process in different organisms. These hallmarks encompass a range of interconnected pathways, including genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient signaling, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, and dysbiosis. Together, the hallmarks contribute to the gradual decline in physiological function and increased susceptibility to age-related diseases that occurs with age, and provide a framework for understanding how we age.

In this episode, Matt takes us through a quick download of each hallmark of aging, talks about some of the paradigm's shortcomings and limitations, and discusses the implications of the Hallmarks of Aging paradigm for the geroscience field.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

The Hallmarks of Aging

This paper was the original “Hallmarks of Aging” paper that described nine common denominators of aging: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. The framework of “aging hallmarks”—that is, specific and identifiable molecular mechanisms or alterations that accompany the aging process—has provided a useful paradigm for understanding how certain biochemical changes form the essence of aging and of the disease and disability that accompanies it. However, we still don’t know a lot about the hierarchy of these hallmarks’ impact on the aging process or how they might interact with each other, and the evidence linking them to age-related disease is mostly correlative.

Hallmarks of aging: An expanding Universe

This paper proposes twelve hallmarks of aging and extends the work of the original 2013 paper outlining nine hallmarks of aging. The additional three hallmarks are disabled macroautophagy, chronic inflammation, and dysbiosis.

The hoverfly and the wasp: A critique of the hallmarks of aging as a paradigm

This paper is one of several sources offering a critique of the Hallmarks of Aging paradigm. It compares the hallmarks of aging to the hallmarks of cancer, the template from which the hallmarks of aging emerged. One of the papers criticisms includes that, unlike the clear causal chain in the hallmarks of cancer, the aging hallmarks' delineation of primary causes behind the aging process remains uncertain. The hallmarks of aging paradigm fails to elucidate how the hallmarks manifest as aging-related diseases. This disparity reflects, in part, a broader issue in geroscience concerning the definition of aging and its relationship with age-related diseases. The authors make suggestions for a new template encompassing various classes of primary mechanisms, including mechanical and molecular damage, infectious pathogens, and programmatic drivers of senescence.

Targeting the “hallmarks of aging” to slow aging and treat age-related disease: fact or fiction?

This paper offers another critique of the Hallmarks of Aging paradigm. The authors probe the evidence and assumptions upon which the paradigm stands—for example, that lifespan is a valid proxy for aging, or that certain animal models are appropriate for drawing inferences about aging. They conclude that the paradigm, along with other foundational geroscience concepts, may not actually hold water.

Do the Hallmarks of Aging Make SENS? (Part One)

This article compares two frameworks for understanding and addressing aging: the Hallmarks of Aging and the Strategies for Engineered Negligible Senescence (SENS) Seven (note that the SENS seven originated from the organization that published this article). It highlights that while the Hallmarks have gained widespread acceptance as a means to categorize aging-related changes, they focus on the metabolic processes contributing to aging rather than the damage itself. In contrast, the SENS approach targets the cellular and molecular damage directly, advocating for a "divide-and-conquer" strategy to repair or remove specific types of damage.

Everyone has different reactions to medications—you might experience indigestion after taking a new drug, while someone else might feel nothing at all. In this episode, Matt describes his recent experience developing a bacterial infection while taking a course of antibiotics and discusses the importance of being aware of and prepared for any medication-induced allergic reactions that may occur.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

American Academy of Allergy, Asthma & Immunology

The American Academy of Allergy, Asthma & Immunology offers helpful resources for anyone looking to understand allergies better. We found the Drug Guide, Conditions Library, and the Allergy, Asthma & Immunology Glossary particularly helpful.

University of Arizona Assistant Professor of Molecular and Cellular Biology George Sutphin runs a lab that investigates genetic determinants of longevity, the effects of kynurenine-based interventions on lifespan, and environmental regulators of the aging process. George, who was an aerospace engineer before he discovered the promise of geroscience, completed his PhD at the University of Washington and worked as a postdoctoral associate at the Jackson Laboratory prior to his current faculty position. He currently serves as Chairperson of the American Aging Association.

We sat down with George to talk about his research, including the effects of caffeine on lifespan and, more recently, his discovery of a new metabolite with the ability to greatly extend lifespan when given late in life. We also discuss George's thoughts on biological age clocks, his own healthspan optimization protocol, and much more.

The probiotic George mentions taking in this podcast episode is Garden of Life Probiotics Ultimate Care.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Caffeine extends life span, improves healthspan, and delays age-associated pathology in Caenorhabditis elegans

This paper began as a side project during George’s PhD work at the University of Washington. It showed that caffeine extended life- and healthspan in nematode worms, and also had positive effects on pathologies such as paralysis in a worm model of polyglutamine disease. The paper attracted a lot of interest, perhaps because it seemed to justify people’s coffee-drinking habits. No conclusive evidence about caffeine’s effects on human lifespan currently exists.

Lifespan extension in Caenorhabditis elegans by complete removal of food

What is the optimal amount of food to give worms so that they’ll live longer? According to this study, which also came out of George’s PhD at the University of Washington, the answer is no food at all. This paper found that completely taking away worms’ food in adulthood increased lifespan by up to 50%. While a starvation protocol like this one is unlikely to work in humans, these findings add an interesting set of data points to evolving research into how diet affects longevity in humans.

Dietary restriction by bacterial deprivation increases life span in wild-derived nematodes

This study was a follow up to the previous paper and investigates the effects of dietary restriction on the lifespan of wild worm populations collected from various locations worldwide. The results indicate that bacterial food deprivation extends lifespan across multiple wild C. elegans (a worm species) populations. Additionally, the longevity-enhancing effects of bacterial food deprivation are conserved in a related worm species, C. remanei. The study highlights the potential impact of genetic and environmental factors on worm lifespan variation and suggests that food-deprivation-induced lifespan extension may be a characteristic of wild-derived nematode populations.

Caenorhabditis elegans orthologs of human genes differentially expressed with age are enriched for determinants of longevity

This paper came out of George’s time at the Jackson Laboratory. The researchers conducted an RNA interference (RNAi) longevity screen on 82 genes in C. Elegans, chosen based on their orthology to human genes that show age-related changes in expression. Their results revealed a significant enrichment in genes where knockdown increased lifespan compared to previously published longevity screens, with 46 genes being newly identified as impacting lifespan. Knockdown of these genes, which included genes that encoded the enzyme kynureninase, a tetraspanin, and a voltage-gated calcium channel subunit, increased healthspan with no effects on reproduction. The kynureninase gene knockdown specifically delayed pathology in worm models of Alzheimer's and Huntington's diseases.

The Emerging Role of 3-Hydroxyanthranilic Acid on C. elegans Aging Immune Function

3-hydroxyanthranilic acid (3-HAA) is a metabolite within the kynurenine pathway, a metabolic pathway involved in the breakdown of the amino acid tryptophan. The kynurenine pathway plays a crucial role in various physiological processes, including immune response regulation, neurotransmitter synthesis, and inflammation modulation. This paper showed that the 3HAA appeared to slow age-associated immune function decline in addition to helping mice fend off pathogenic challenges. 3HAA is not sufficiently well-understood to be a candidate for supplementation in humans.

Everything we talk about on The Optispan Podcast has geroscience at its root, so we decided to make an episode about it. Geroscience is the study of the mechanisms connecting biological aging with disease and disability. The term first appeared in the scientific literature around 2008, and its use has steadily increased since as researchers have discovered more about the aging process and its impact on our health. While it's clear that aging biology is at the root of the diseases and disabilities that most people get sick with and die from in their later years, it's been a challenge to get the field the traction and support that other fields enjoy, in part because we are used to a "disease care" model of waiting until people get sick and only then addressing their symptoms and/or curing their disease.

In this episode, Matt dives into the geroscience hypothesis and how it underpins the way we age, entrenched cultures in industries from drug development to insurance to regulation, and why he's excited to create a geroscience-inspired disruption in the medical and healthcare industries.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Hallmarks of aging: An expanding Universe

As Matt notes in the podcast, the Hallmarks of Aging are an easy way to think about the biological mechanisms that underlie aging and the functional declines and diseases that accompany aging. They are not a comprehensive list of everything that happens as we age, but they give a good starting point to understand the idea that several things change in our bodies with age. This paper proposes twelve hallmarks of aging and extends the work of the original 2013 paper outlining nine hallmarks of aging. The framework of “aging hallmarks”—that is, specific and identifiable molecular mechanisms or alterations that accompany the aging process—has provided a useful paradigm for understanding how certain biochemical changes form the essence of aging and of the disease and disability that accompanies it. However, we still don’t know a lot about the hierarchy of these hallmarks’ impact on the aging process or how they might interact with each other, and the evidence linking them to age-related disease is mostly correlative.

Major longevity gains termed unlikely

In 1990, researchers at the University of Chicago published their findings that the average American lifespan would only enjoy a three-year gain even if scientists came up with a magic pill to cure all cancers and heart disease. This article covers that research and also presents views about aging that are quite different from those of geroscience today. "Barring a reversal of human aging on a molecular level, the rapid increases in life expectancy are over,” the study’s lead author S. Jay Olshansky said. Of course, 21st century geroscience is trying to investigate exactly what Olshansky mentions: the molecular specifics of human aging and how we can target those molecular mechanisms to address the functional declines and diseases of later life.

The economic value of targeting aging

Published in 2021, this paper showed that a one-year increase in healthy life expectancy via targeting aging, as opposed to individual diseases, is worth $38 trillion in economic value. That number climbs to $367 trillion at 10 years of increased life expectancy. Those numbers might seem too big to be true, but they make more sense if we consider that delaying aging via a geroscience approach could potentially delay a huge number of age-related diseases, such as Alzheimer’s disease, as well as diseases whose risk is far greater with advanced age, such as COVID-19.

Is aging without illness possible?

This article presents perspectives from various prominent geroscience researchers about the history of the field, compounds that have shown promise thus far for targeting aging, and key barriers to progress. One important obstacle is hype. The idea of “antiaging therapies” is, according to University of Illinois Chicago Professor of Epidemiology and Biostatistics, “associated with an industry that is trying to sell products to the public to separate people from their money.” Overselling the promise of supplements, prescription medications, and other therapies is likely to increase skepticism about the geroscience and set the field back.

Fiscal Year 2024 Budget

The fiscal year 2024 budget of the National Institute on Aging (NIA), a division of the United States National Institutes of Health aimed at increasing healthy, active years of life in older adults, describes the NIA's research priorities. Several researchers in the geroscience field have expressed a wish for a greater proportion of the NIA budget to go toward studies of the biology of aging, rather than toward studies of individual diseases such as Alzheimer’s disease.

Longevity This Week is a series of episodes discussing new findings or articles relevant to geroscience, longevity, and healthspan that may have popped up in the news.

This week we're featuring Richard Morgan, a 93-year-old rowing champion whom the Washington Post recently described as being "as fit as a 40-year-old". We talk about Richard's diet, exercise routine, and other aspects of his lifestyle that may have led to his enviable state in older age. We also discuss a recent Wall Street Journal article about how Americans are spending more of their lives in poor health, and about how "sickspan"—the amount of time we spend sick near the end of our lives—might change in years to come.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Physiological characteristics of a 92-yr-old four-time world champion rower

This is the study on which the article in The Washington Post that Matt references in this episode is based. The study measured the oxygen uptake, carbon dioxide production, ventilation, and heart rate of 92-year-old Irishman Richard Morgan at rest and while using an ergometer, and found that Richard’s oxygen uptake kinetics were similar to those of healthy young adults. It also outlines his training and nutritional habits, which include an “extremely consistent diet”, 40 minutes per day of rowing, and two to three days per week of resistance training. Richard only began rowing at 73 and was not involved in any structured exercise regime prior to that.

Americans are sick for more of their lives

This article, which Matt discusses in the podcast, describes the decline in time that Americans spend in good health towards the end of their lives. In 1990, Americans spent 85.8% of their lives in good health. In 2021, that number went down to 83.6%. This change is in part due to medical advances that prevent us from dying of certain diseases, so we live for a longer time, but continue to suffer from many of the functional declines and diseases that accompany old age. The article discusses how the growing gap between healthy life and death has significant implications for healthcare, the economy, and the wellbeing of patients and their caregivers.

How healthy is the healthspan concept?

In 2018, Matt published this article exploring the concept of healthspan and the lack of clarity in the usage of the term. He notes that while a common definition of healthspan is “the period of life spent in good health, free from the chronic diseases and disabilities of aging”, there are many issues with this definition—for example, are all diseases equal in heralding the end of healthspan? If you are simply frail and get sick more often, has your healthspan ended? He discusses the implications of imprecise definitions of healthspan for interpreting new findings in the geroscience field.

Life-long spontaneous exercise does not prolong lifespan but improves health span in mice

According to this study, spontaenous exercise does not impact how long mice live, but delays their age-associated decline as measured in strength, endurance and motor coordination. They propose mechanisms by which exercise may prolong healthy cognitive and skeletal muscle function such as increases in neurotropic factors, or proteins crucial roles in the development, survival, and function of neurons, and the formation of new mitochondria within cells.

Biological age—that is, how old your cells and tissues are based on physiological function—is a multifaceted and intricate concept that transcends numerical representation. Unlike chronological age, which refers simply to the number of years you have been alive, the concept of biological age delves into the dynamic interplay between physiological processes, genetic predispositions, and environmental influences that collectively shape an individual's health trajectory. Geroscientists are currently studying the biological mechanisms that might impact your biological aging rate and perhaps reverse some of the functional declines that accompany aging.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Epigenetic Predictor of Age

This study was one of the first to build a model to estimate biological age from DNA methylation patterns. One could imagine DNA as a set of instructions, like a recipe book, that tells our bodies how to work; and DNA methylation as little tags or markers that attach to these instructions. These tags can change as we age, a bit like how notes or highlights might change in a book as you read it again and again—and in changing, affect how genes get turned on and off.

Decreased epigenetic age of PBMCs from Italian semi-supercentenarians and their offspring

When people talk about “epigenetic clocks” or “epigenetic age”, they are typically referring to methods that use DNA methylation changes as a means for estimating biological age. Underpinning these methods is the idea that certain patterns of DNA methylation change with age. According to this study, the offspring of semi-supercentenarians—people who live up to 105-109 years—have a lower epigenetic age than control subjects. Centenarians are also nearly nine years “younger” biologically than their chronological age.

Modeling the Rate of Senescence: Can Estimated Biological Age Predict Mortality More Accurately Than Chronological Age?

This study compares the ability of five algorithms to predict biological age. The “winning algorithm”, the 2006 Klemera and Doubal method (KDM), predicted mortality better than chronological age as well as any of the other algorithms tested.

A new approach to the concept and computation of biological age

The researchers Petr Klemera and Stanislav Doubal developed the Klemera and Doubal method (KDM), an algorithm for calculating biological age that outperformed other algorithms (see previous article). They detail tools researchers typically use to compute biological age—multiple linear regression, factor analysis, principal components analysis—and describe the mathematics behind their own method.

How to measure biological age | Prof Brian Kennedy

National University of Singapore Distinguished Professor of Biochemistry and Physiology Brian Kennedy chats about biological age with Eleanor Sheekey of The Sheekey Science Show. He describes how, unlike chronological age, markers of biological age might oscillate in response to different circumstances—sleep, a virus, exercise levels—and vary from one week to the next. As such, single timepoints may not be informative. He also discusses ongoing research to collect multiple potential biomarkers of aging, merge them, and see if they correspond or interact.

The R-Files is a series of episodes about rapamycin, a naturally occurring compound originally discovered in soil samples from Easter Island, also known as Rapa Nui (hence the drug's name). Rapamycin belongs to a class of drugs called macrolides and has potent immunosuppressive and anti-proliferative effects. The drug has garnered attention for its potential anti-aging properties and has attracted research interest for its ability to extend lifespan and delay age-related diseases in various model organisms, including yeast and mice.

In the third episode of the R-Files, Matt, who studied rapamycin for over a decade of his career, talks about a recent study evaluating the benefits and side effects of taking rapamycin off-label—that is, for a purpose other than that for which the drug gained FDA approval. Physicians can prescribe any FDA-approved drug off-label as long as they believe it will be beneficial for the patient. Matt discusses noteworthy potential side effects of rapamycin use, the experiences of study participants who took rapamycin, and why off-label rapamycin use is not widespread despite considerable evidence for life- and healthspan benefits in laboratory animals.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Rapamycin News

Many of our podcast listeners are interested in questions about rapamycin dosing, how to get a prescription for rapamycin, and how rapamycin might interact with other supplements or drugs. This website is a great resource for getting more clarity on some of these questions, as well as for hearing about others' experiences with rapamycin and other longevity medications.

Evaluation of off-label rapamycin use to promote healthspan in 333 adults

Matt and colleagues, including Optispan Chief Medical Officer George Haddad, collected self-reported data from over 300 adults with a history of off-label rapamycin use to capture data about the drug's potential side effects. The only side effect that was significantly more prevalent in rapamycin users compared to non-users was the presence of mouth sores, and several side effects typically associated with rapamycin use such as eye pain and anxiety occurred less frequently in rapamycin users than in non-users.

Rapamycin and aging: Dosage, side effects, and success stories | Matt Kaeberlein

Matt discusses rapamycin on this podcast with Stanford Prevention Research Center lecturer Lucia Aronica. He makes several anecdotal observations about rapamycin, including that most people don’t seem to experience observable side effects on a weekly 3-6 mg dose. Side effects that seem real, he notes, are mouth sores and higher triglycerides. He also discusses differences in side effects observed in biohackers versus organ transplant patients taking rapamycin.

Rapamycin in aging and disease: maximizing efficacy while minimizing side effects

This article argues for several important considerations in future studies of rapamycin for successful translation to human use, including sex-dependent impacts on biological outcomes, the impact of short-term rapamycin treatment on a variety of healthspan metrics, the best regimen for extracting maximum benefits from rapamycin treatment while minimizing adverse effects, and more.

mTOR Inhibition: From Aging to Autism and Beyond

In this paper, Matt reviews the effects of mammalian target of rapamycin (mTOR) inhibitors on age-related disease and decline as well as on non-aging-related diseases such as tuberous sclerosis complex and epilepsy. He describes the side effects of chronic mTOR inhibition in mice, which include hyperlipidemia, insulin resistance, enhanced cataract formation and male sterility; as well as the adverse effects of mTOR inhibitors used in the clinic, which include mouth ulcers, diarrhea and nausea, hyperlipidemia, and infection.

The R-Files is a series of episodes about rapamycin, a naturally occurring compound originally discovered in soil samples from Easter Island, also known as Rapa Nui (hence the drug's name). Rapamycin belongs to a class of drugs called macrolides and has potent immunosuppressive and anti-proliferative effects. The drug has garnered attention for its potential anti-aging properties and has attracted research interest for its ability to extend lifespan and delay age-related diseases in various model organisms, including yeast and mice.

In this second episode of the R-Files, Matt, who has spent a significant chunk of his career studying rapamycin, discusses his own journey to using rapamycin off-label and how it all began with a persistent pain in his right shoulder that a doctor suggested might take a year to resolve. Matt conducted an n=1 experiment to test whether a short course of rapamycin might improve the age-related inflammation that was the likely cause of his shoulder issue.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

mTOR is a key modulator of ageing and age-related disease

This paper reviews the mechanistic target of rapamycin (mTOR) pathway, a nutrient sensing pathway that shows promise as a target for interventions to increase life- and healthspan. The mTOR pathway acts as a control center that helps cells decide what to do based on the nutrients available. When nutrients are abundant, mTOR tells cells to grow and divide; when nutrients are scarce, it signals cells to conserve energy and not grow too much. The article delves into the mechanisms by which the mTOR pathway influences longevity, including mRNA translation, autophagy, stress resistance and xenobiotic metabolism, mitochondrial function, inflammation, and stem cell rejuvenation.

mTOR Regulation and Therapeutic Rejuvenation of Aging Hematopoietic Stem Cells

The age-associated decline in function of hematopoietic stem cells (HSCs), cells in the bone marrow that give rise to all types of blood cells in the body, can lead to issues such as anemia and increased cancer risk. This study demonstrates that the mTOR pathway in HSCs is more active in older mice than in younger mice, and that activating this pathway accelerated HSC aging in young mice. Treating older mice with rapamycin, an mTOR inhibitor, extended their life- and healthspan. Taken together, these findings provide further evidence to suggest that the mTOR pathway plays a key role in aging.

Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice

Many of those interested in rapamycin have questions about what the optimum rapamycin dosing regime looks like. While there is not yet any conclusive evidence suggesting an ideal dose for humans, researchers have demonstrated dosing regimes that work in mice. This study found that a single three-month rapamycin regimen increased life expectancy in middle-aged mice without overt detrimental side effects.

Rapamycin fed late in life extends lifespan in genetically heterogeneous mice

This study found that rapamycin improved mouse survival by 14% and 9% for females and males respectively, even when rapamycin feeding began late in life. The authors propose several mechanisms by which rapamycin might delay aging, including modulation of nutrient dynamics and cellular stress resistance.

272 ‒ Rapamycin: potential longevity benefits, surge in popularity, unanswered questions, and more

In this episode of the Peter Attia Drive podcast, Matt joins physician Peter Attia and Institute of Organic Chemistry and Biochemistry senior group leader David Sabatini to talk about the discovery of rapamycin, its first uses in humans, the mTOR pathway, potential mechanisms by which rapamycin might influence human longevity, recent studies of the effects of rapamycin in model organisms, potential side effects, and more.

Matt and guest Jonathan An, Assistant Professor of Oral Health Sciences at the University of Washington School of Dentistry, discuss oral health and its relationship to aging, including published studies involving rapamycin effects on oral health. This is a 3-part episode.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Aging and Oral Health with Dr. Jonathan An!

Jonathan recently appeared on Lets Get Oral, a podcast that explores oral health from multiple angles—think the oral microbiome, taste, bad breath. In this episode, Jonathan talks about how our teeth change as we get older, the potential impact of medications on oral health, why he supports taking a more systemic approach to dental care, and more.

Oral health in geroscience: animal models and the aging oral cavity

Animal models are indispensable tools for studying the biology of aging. They provide insight into underlying mechanisms of aging, enable scientists to test interventions that promote healthy aging, and advance our understanding of age-related diseases. While animal models have their limitations, their use in research allows for controlled experimentation and the generation of valuable data that can ultimately benefit human healthspan and longevity. Jonathan and our host Matt Kaeberlein co-authored this journal article about which animal models are best suited for studying the intersection of aging and oral disease. They discuss rodents, the current premier preclinical models for geroscience research, as well as dogs and nonhuman primates such as the southern pig-tailed macaque.

Rapamycin rejuvenates oral health in aging mice

In 2020, Jonathan and Matt demonstrated that rapamycin treatment rejuvenated the aged oral cavity of older mice. The treatment reversed "clinically defining features of periodontal disease", including periodontal bone loss, periodontal inflammation, and pathogenic oral microbiome changes. This paper lends support to the idea that interventions that target mechanisms of biological aging may delay multiple age-related declines. Further work should investigate whether the rejuvenating effects of rapamycin persist after the treatment period as well as whether rapamycin improves other oral health declines that commonly occur with age, such as salivary function.

Oral health for healthy aging

This article calls for an end to the siloing of oral health from general health care. The authors note that the global prevalence of oral disease is higher than it should be, given the preventable nature of most oral diseases, and that this prevalence is likely to worsen with population aging. They make suggestions for concrete policy action and mindset shifts towards addressing the burden of oral disease care, including shifting dental care models away from curative and interventionist models and towards more preventative upstream action.

Aging and Dental Health

This is a short primer from the American Dental Association about the clinical and oral health context of older adults. By one estimate, 68 percent of adults aged 65 years and older have periodontis. The primer covers comorbid conditions; the potential impact of common medications for age-related conditions on oral health; and cognitive, physical, and sensory limitations affecting dental care and home oral care.

Matt and guest Jonathan An, Assistant Professor of Oral Health Sciences at the University of Washington School of Dentistry, discuss oral health and its relationship to aging, including published studies involving rapamycin effects on oral health. This is a 3-part episode.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Aging and Oral Health with Dr. Jonathan An!

Our guest, Assistant Professor of Oral Health Sciences and Faculty in the Healthy Aging and Longevity Institute at the University of Washington School of Dentistry Jonathan An, recently appeared on Lets Get Oral, a podcast that explores oral health from multiple angles—think the oral microbiome, taste, bad breath. In this episode, Jonathan talks about how our teeth change as we get older, the potential impact of medications on oral health, why he supports taking a more systemic approach to dental care, and more.

Oral health in geroscience: animal models and the aging oral cavity

Animal models are indispensable tools for studying the biology of aging. They provide insight into underlying mechanisms of aging, enable scientists to test interventions that promote healthy aging, and advance our understanding of age-related diseases. While animal models have their limitations, their use in research allows for controlled experimentation and the generation of valuable data that can ultimately benefit human healthspan and longevity. Jonathan and our host Matt Kaeberlein co-authored this journal article about which animal models are best suited for studying the intersection of aging and oral disease. They discuss rodents, the current premier preclinical models for geroscience research, as well as dogs and nonhuman primates such as the southern pig-tailed macaque.

Rapamycin rejuvenates oral health in aging mice

In 2020, Jonathan and Matt demonstrated that rapamycin treatment rejuvenated the aged oral cavity of older mice. The treatment reversed "clinically defining features of periodontal disease", including periodontal bone loss, periodontal inflammation, and pathogenic oral microbiome changes. This paper lends support to the idea that interventions that target mechanisms of biological aging may delay multiple age-related declines. Further work should investigate whether the rejuvenating effects of rapamycin persist after the treatment period as well as whether rapamycin improves other oral health declines that commonly occur with age, such as salivary function.

Oral health for healthy aging

This article calls for an end to the siloing of oral health from general health care. The authors note that the global prevalence of oral disease is higher than it should be, given the preventable nature of most oral diseases, and that this prevalence is likely to worsen with population aging. They make suggestions for concrete policy action and mindset shifts towards addressing the burden of oral disease care, including shifting dental care models away from curative and interventionist models and towards more preventative upstream action.

Aging and Dental Health

This is a short primer from the American Dental Association about the clinical and oral health context of older adults. By one estimate, 68 percent of adults aged 65 years and older have periodontis. The primer covers comorbid conditions; the potential impact of common medications for age-related conditions on oral health; and cognitive, physical, and sensory limitations affecting dental care and home oral care.

The R-Files is a series of episodes about rapamycin, a naturally occurring compound originally discovered in soil samples from Easter Island, also known as Rapa Nui (hence the drug's name). Rapamycin belongs to a class of drugs called macrolides and has potent immunosuppressive and anti-proliferative effects. The drug has garnered attention for its potential anti-aging properties and has attracted research interest for its ability to extend lifespan and delay age-related diseases in various model organisms, including yeast and mice.

In this first episode of the R-Files, Matt, who has spent a significant chunk of his career studying rapamycin, will discuss how fortuitous conversations, an appetite for unexplored territory, and an opportunity to look where others weren't looking helped him get deep into the study of rapamycin and uncover some interesting insights into how rapamycin can affect lifespan.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Rapamycin (AY-22,989), a new antifungal antibiotic I. Taxonomy of the producing streptomycete and isolation of the active principle

Published in 1975, this landmark paper describes the discovery of a new antifungal antibiotic called rapamycin, and characterizes rapamycin's morphological, physiological, and cultural properties and the streptomycete strain that produces it. It detailsthe isolation of the streptomycete strain AY B-994 from an Easter Island soil sample as well as the strain's antimicrobial activity.

Regulation of Yeast Replicative Life Span by TOR and Sch9 in Response to Nutrients

This 2005 paper was the first to describe the molecular pathway by which caloric restriction could influence yeast lifespan. Caloric restriction extended yeast replicative lifespan—that is, the number of times a yeast cell can divide and produce daughter cells before it stops dividing—by downregulating signaling through TOR1 and Sch9 genes. In yeast, the TOR1 gene codes for the TOR1 protein, a protein analogous to the mTOR protein in mice. Rapamycin inhibits mTOR1.

Extension of chronological life span in yeast by decreased TOR pathway signaling

This is the experiment involving nearly 5,000 yeast strains that Matt describes in the podcast.

The discovery & first uses of rapamycin | Peter Attia, David Sabatini, & Matt Kaeberlein

Matt joins physician Peter Attia and Institute of Organic Chemistry and Biochemistry senior group leader David Sabatini in this rapamycin-themed episode of the Peter Attia Drive podcast. In this clip, three longevity experts dig into the history of rapamycin’s discovery. They also discuss rapamycin’s clinical path as an immunosuppressant and how that path may have impacted the development of rapamycin for other uses, the decades-long gap between the discovery of rapamycin and its eventual use in the clinic, and the difficulty of disentangling side effects that come from rapamycin use versus that of other drugs.

Matt and guest Jonathan An, Assistant Professor of Oral Health Sciences at the University of Washington School of Dentistry, discuss oral health and its relationship to aging, including published studies involving rapamycin effects on oral health. This is a 3-part episode.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Aging and Oral Health with Dr. Jonathan An!

Our guest, Assistant Professor of Oral Health Sciences and Faculty in the Healthy Aging and Longevity Institute at the University of Washington School of Dentistry Jonathan An, recently appeared on Lets Get Oral, a podcast that explores oral health from multiple angles—think the oral microbiome, taste, bad breath. In this episode, Jonathan talks about how our teeth change as we get older, the potential impact of medications on oral health, why he supports taking a more systemic approach to dental care, and more.

Oral health in geroscience: animal models and the aging oral cavity

Animal models are indispensable tools for studying the biology of aging. They provide insight into underlying mechanisms of aging, enable scientists to test interventions that promote healthy aging, and advance our understanding of age-related diseases. While animal models have their limitations, their use in research allows for controlled experimentation and the generation of valuable data that can ultimately benefit human healthspan and longevity. Jonathan and our host Matt Kaeberlein co-authored this journal article about which animal models are best suited for studying the intersection of aging and oral disease. They discuss rodents, the current premier preclinical models for geroscience research, as well as dogs and nonhuman primates such as the southern pig-tailed macaque.

Rapamycin rejuvenates oral health in aging mice

In 2020, Jonathan and Matt demonstrated that rapamycin treatment rejuvenated the aged oral cavity of older mice. The treatment reversed "clinically defining features of periodontal disease", including periodontal bone loss, periodontal inflammation, and pathogenic oral microbiome changes. This paper lends support to the idea that interventions that target mechanisms of biological aging may delay multiple age-related declines. Further work should investigate whether the rejuvenating effects of rapamycin persist after the treatment period as well as whether rapamycin improves other oral health declines that commonly occur with age, such as salivary function.

Oral health for healthy aging

This article calls for an end to the siloing of oral health from general health care. The authors note that the global prevalence of oral disease is higher than it should be, given the preventable nature of most oral diseases, and that this prevalence is likely to worsen with population aging. They make suggestions for concrete policy action and mindset shifts towards addressing the burden of oral disease care, including shifting dental care models away from curative and interventionist models and towards more preventative upstream action.

Aging and Dental Health

This is a short primer from the American Dental Association about the clinical and oral health context of older adults. By one estimate, 68 percent of adults aged 65 years and older have periodontis. The primer covers comorbid conditions; the potential impact of common medications for age-related conditions on oral health; and cognitive, physical, and sensory limitations affecting dental care and home oral care.

Optispan CEO Matt Kaeberlein discusses common assumptions about longevity and healthspan.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Objections and Their Counterarguments

Nick points out that some people believe that humans shouldn't live for too long to make room for fresh ideas from new generations. This spreadsheet presents a few counterarguments to that idea, including that a person being "old" need not imply that they are static and incapable of fostering innovation. Other common objections to the study of aging biology that the spreadsheet addresses include ideas around how slowing aging will cause an overpopulation problem, increase pension and healthcare costs, and enable dictators to survive.

222 ‒ How nutrition impacts longevity | Matt Kaeberlein, Ph.D.

Matt and physician Peter Attia dive into the nebulous world of nutrition and longevity in this episode of the Peter Attia Drive podcast. They cover caloric restriction, time-restricted feeding, high- and low-protein diets, Matt's 2021 review of anti-aging diets, and more.

The mouse as a model organism in aging research: Usefulness, pitfalls and possibilities

Researchers typically test longevity interventions in model organisms such as mice, worms, or yeast before they test them in people. Conducting experiments on model organisms first enables researchers to gather initial safety and efficacy data without exposing humans to potential risks, and also provides a controlled experimental environment where researchers can manipulate variables, such as genetic makeup and environmental conditions, to identify cause-and-effect relationships and validate therapeutic targets. This article discusses the reliability of mice as animal models for longevity research as well as some of the nuances that researchers should consider when using these animals in experiments.

Harvard study, almost 80 years old, has proved that embracing community helps us live longer, and be happier

People matter. The Harvard Study of Adult Development, which tracked the health trajectories and life events of over 700 men starting in the year 1938, found that close social ties outperformed social class, IQ, and genetics for predicting long, happy lives.

Optispan CEO Matt Kaeberlein discusses common assumptions about longevity and healthspan.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan

Researchers published one of the first papers demonstrating the benefits of resveratrol on lifespan in 2003. This study laid the foundation for further research into the potential anti-aging effects of resveratrol, a natural compound found in certain plants, fruits, and beverages, such as grapes, red wine, peanuts, and berries, and its role in activating sirtuins, a class of proteins associated with longevity.

Resveratrol improves health and survival of mice on a high-calorie diet

This 2006 paper provided further evidence for the lifespan-extending effects of resveratrol in mice. It found that the physiology of mice eating calorie-dense diets and consuming resveratrol moved towards that of mice eating more moderate diets without any change in body weight. Resveratrol also modulated several longevity pathways and impvoed several measures of health such as insulin sensitivity and motor function.

Rapamycin, But Not Resveratrol or Simvastatin, Extends Life Span of Genetically Heterogeneous Mice

This study, which shares authors with previous papers demonstrating that resveratrol extends lifespan in model organisms, found that neither high nor low doses of resveratrol affected lifespan in mice of both sexes. Matt has described resveratrol as "the most debunked longevity molecule that exists".

Effect of Metformin on Testosterone Levels in Male Patients With Type 2 Diabetes Mellitus Treated With Insulin

This study presented evidence that metformin reduces testosterone levels in men with type 2 diabetes mellitus.

Objections and Their Counterarguments

Nick points out that some people view longevity interventions as a luxury for billionaires. This spreadsheet presents a few counterarguments to that idea, including that technologies typically become less expensive after their introduction to the public and it is therefore unlikely that aging-focused therapeutics will stay unaffordable for long. Other common objections to the study of aging biology that the spreadsheet addresses include ideas around how slowing aging will cause an overpopulation problem, slow progress and cause ideas to stagnate, and enable dictators to survive.

Optispan CEO Matt Kaeberlein chats with Prime Health Associates Physician Kevin White about improving bloodwork results, monitoring glucose readings, taking supplements, and more.

Optispan CEO Matt Kaeberlein chats with Prime Health Associates Physician Kevin White about making the transition from research to building a company, moving towards preventative medicine in the 21st century, incorporating new discoveries into medical practice, and more.

Optispan CEO Matt Kaeberlein discusses the popular Healthspan concept, how Healthspan is different from Lifespan, and why bouncing back from health challenges gets harder as we age.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

How healthy is the healthspan concept?

In 2018, Matt published this article exploring the concept of healthspan and the lack of clarity in the usage of the term. He notes that while a common definition of healthspan is “the period of life spent in good health, free from the chronic diseases and disabilities of aging”, there are many issues with this definition—for example, are all diseases equal in heralding the end of healthspan? If you are simply frail and get sick more often, has your healthspan ended? He discusses the implications of imprecise definitions of healthspan for interpreting new findings in the geroscience field.

Translational geroscience: A new paradigm for 21st century medicine

Matt provides a high-level overview of the geroscience approach and its potential impact. He introduces several efforts to translate current research to the clinic, including clinical trials of rapamycin in humans and dogs as well as the Targeting Aging with Metformin (TAME) trial, which aims to investigate the impact of the antidiabetic drug metformin on non-diabetes comorbidities in older patients. The article also discusses some of the regulatory hurdles involved with developing interventions that target aging biology.

Lifespan and Healthspan: Past, Present, and Promise

This article lays out the evidence for the life expectancy increase that has happened over the last century, and discusses recent trends in measures of population health such as cognitive functioning, severe disability, and the presence of diseases. The author notes that while infection used to be one of the primary causes of human death, death today generally occurs as a result of chronic diseases and disabilities that occur at older ages. She argues for beginning trials whose purpose is to delay the biological aging process early in life, as well as for taking a more preventative approach to healthcare.

Optispan CEO Matt Kaeberlein takes questions about healthy aging.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Hallmarks of aging: An expanding Universe

This paper proposes twelve hallmarks of aging and extends the work of the original 2013 paper outlining nine hallmarks of aging. The framework of “aging hallmarks”—that is, specific and identifiable molecular mechanisms or alterations that accompany the aging process—has provided a useful paradigm for understanding how certain biochemical changes form the essence of aging and of the disease and disability that accompanies it. However, we still don’t know a lot about the hierarchy of these hallmarks’ impact on the aging process or how they might interact with each other, and the evidence linking them to age-related disease is mostly correlative.

A Reimagined Research Strategy for Aging

In another manifestation of the idea that several processes underpin the biological aging process, the SENS Research Foundation describes seven types of cellular and molecular damage that occur with age.

Inside Science: Introducing the Test of Rapamycin in Aging Dogs

Dogs are useful animals for helping us understand aging: they share an environment with humans, get similar diseases of aging, and suffer from elevated disease risk with age. Dogs can live for fewer than ten years or well into their teens, a lifespan that enables us to observe the impact of interventions far more quickly than we can in humans, who live for much longer. The Dog Aging Project, a long-term multi-institute study of how dogs age, is examining the effect of the FDA-approved immunosuppressant drug Rapamycin on healthy aging in dogs.

Optispan CEO Matt Kaeberlein is a co-founder of the Dog Aging Project.

Ultra-processed foods and how to identify them

While most of the foods we consume are processed to at least a small degree, some processed foods are worse for you than others. This paper describes pragmatic and simple ways to identify whether a given food is “ultra-processed”—that is, made using specific ingredients and manufacturing processes designed to create low-cost, long shelf-life, convenient, and hyperpalatable foods.

Lifelong Physical Exercise Delays Age-Associated Skeletal Muscle Decline

You’ve probably heard that exercise is good for you, but don’t just take anyone’s word for it—check out the literature for yourself. This is one of many (many!) studies demonstrating that exercise works to modulate aging; in this case, by delaying the progression of age-related skeletal muscle degeneration.

Optispan CEO Matt Kaeberlein explains how aging affects our risk of disease and why proactive prevention is the 21st century solution to staying healthy.

Check out the links below for further information and/or reading about some of the things we discussed in this podcast episode. Note that we do not necessarily endorse or agree with the content of these readings, but present them as supplementary material that may deepen your understanding of the topic after you listen to our podcast. This list is in no way exhaustive, but it’s a good start!

Longevity and aging

In this 2013 article, Matt describes the geroscience hypothesis, or the idea that age-related diseases such as Alzheimer's disease and cancer share common causal biological mechanisms. He makes the case that interventions targeting these biological mechanisms will have an impact far higher than that of interventions aimed at treating individual diseases, because the biological mechanisms of aging have an impact on the onset and progression of multiple age-related disorders. The paper also discusses model organisms used in geroscience research and the translatability of research involving these model organisms to humans.


Why Is Aging Conserved and What Can We Do about It?

This article describes pathways that influence longevity and appear to be conserved across a range of organisms such as yeast, fruit flies, and mice. It also discusses the cellular processes regulated by these pathways that may modulate health- and lifespan.


Longevity FAQ: A beginner's guide to longevity research

This FAQ provides a high-level introduction to the geroscience field. It describes the goals of research into the biology of aging and core areas of interest within the field, along with interventions that scientists have tested in mice for effects on life- and/or healthspan.