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 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 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.

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.

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.

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.

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

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.

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.

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.

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.

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".

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.

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.

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.

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.

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 chats with Prime Health Associates Physician Kevin White about improving bloodwork results, monitoring glucose readings, taking supplements, 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!

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.

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.

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.