The Optispan Podcast with Matt Kaeberlein PhD

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

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

mTOR inhibition improves immune function in the elderly - PubMed

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Is Aging A Disease?

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

Longevity FAQ: A beginner's guide to longevity research

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

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

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

From discoveries in ageing research to therapeutics for healthy ageing

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

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

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

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

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

Complaining About Hype in the Longevity Industry

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

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

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

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

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

DEXA FAQ

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

Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women

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

We've hit 6,000 subscribers!

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

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

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

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

Taurine deficiency as a driver of aging

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

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

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

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

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

Rapamycin news

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

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

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

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

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

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

Rapamycin News

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

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

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

Effect of caloric restriction and rapamycin on ovarian aging in mice

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

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

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

Optispan CEO Matt Kaeberlein takes questions about healthy aging.

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

Hallmarks of aging: An expanding Universe

This paper proposes twelve hallmarks of aging and extends the work of the original 2013 paper outlining nine hallmarks of aging. The framework of “aging hallmarks”—that is, specific and identifiable molecular mechanisms or alterations that accompany the aging process—has provided a useful paradigm for understanding how certain biochemical changes form the essence of aging and of the disease and disability that accompanies it. However, we still don’t know a lot about the hierarchy of these hallmarks’ impact on the aging process or how they might interact with each other, and the evidence linking them to age-related disease is mostly correlative.

A Reimagined Research Strategy for Aging

In another manifestation of the idea that several processes underpin the biological aging process, the SENS Research Foundation describes seven types of cellular and molecular damage that occur with age.

Inside Science: Introducing the Test of Rapamycin in Aging Dogs

Dogs are useful animals for helping us understand aging: they share an environment with humans, get similar diseases of aging, and suffer from elevated disease risk with age. Dogs can live for fewer than ten years or well into their teens, a lifespan that enables us to observe the impact of interventions far more quickly than we can in humans, who live for much longer. The Dog Aging Project, a long-term multi-institute study of how dogs age, is examining the effect of the FDA-approved immunosuppressant drug Rapamycin on healthy aging in dogs.

Optispan CEO Matt Kaeberlein is a co-founder of the Dog Aging Project.

Ultra-processed foods and how to identify them

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

Lifelong Physical Exercise Delays Age-Associated Skeletal Muscle Decline

You’ve probably heard that exercise is good for you, but don’t just take anyone’s word for it—check out the literature for yourself. This is one of many (many!) studies demonstrating that exercise works to modulate aging; in this case, by delaying the progression of age-related skeletal muscle degeneration.

Optispan CEO Matt Kaeberlein discusses common assumptions about longevity and healthspan.

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

Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan

Researchers published one of the first papers demonstrating the benefits of resveratrol on lifespan in 2003. This study laid the foundation for further research into the potential anti-aging effects of resveratrol, a natural compound found in certain plants, fruits, and beverages, such as grapes, red wine, peanuts, and berries, and its role in activating sirtuins, a class of proteins associated with longevity.

Resveratrol improves health and survival of mice on a high-calorie diet

This 2006 paper provided further evidence for the lifespan-extending effects of resveratrol in mice. It found that the physiology of mice eating calorie-dense diets and consuming resveratrol moved towards that of mice eating more moderate diets without any change in body weight. Resveratrol also modulated several longevity pathways and impvoed several measures of health such as insulin sensitivity and motor function.

Rapamycin, But Not Resveratrol or Simvastatin, Extends Life Span of Genetically Heterogeneous Mice

This study, which shares authors with previous papers demonstrating that resveratrol extends lifespan in model organisms, found that neither high nor low doses of resveratrol affected lifespan in mice of both sexes. Matt has described resveratrol as "the most debunked longevity molecule that exists".

Effect of Metformin on Testosterone Levels in Male Patients With Type 2 Diabetes Mellitus Treated With Insulin

This study presented evidence that metformin reduces testosterone levels in men with type 2 diabetes mellitus.

Objections and Their Counterarguments

Nick points out that some people view longevity interventions as a luxury for billionaires. This spreadsheet presents a few counterarguments to that idea, including that technologies typically become less expensive after their introduction to the public and it is therefore unlikely that aging-focused therapeutics will stay unaffordable for long. Other common objections to the study of aging biology that the spreadsheet addresses include ideas around how slowing aging will cause an overpopulation problem, slow progress and cause ideas to stagnate, and enable dictators to survive.

Optispan CEO Matt Kaeberlein discusses common assumptions about longevity and healthspan.

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

Objections and Their Counterarguments

Nick points out that some people believe that humans shouldn't live for too long to make room for fresh ideas from new generations. This spreadsheet presents a few counterarguments to that idea, including that a person being "old" need not imply that they are static and incapable of fostering innovation. Other common objections to the study of aging biology that the spreadsheet addresses include ideas around how slowing aging will cause an overpopulation problem, increase pension and healthcare costs, and enable dictators to survive.

222 ‒ How nutrition impacts longevity | Matt Kaeberlein, Ph.D.

Matt and physician Peter Attia dive into the nebulous world of nutrition and longevity in this episode of the Peter Attia Drive podcast. They cover caloric restriction, time-restricted feeding, high- and low-protein diets, Matt's 2021 review of anti-aging diets, and more.

The mouse as a model organism in aging research: Usefulness, pitfalls and possibilities

Researchers typically test longevity interventions in model organisms such as mice, worms, or yeast before they test them in people. Conducting experiments on model organisms first enables researchers to gather initial safety and efficacy data without exposing humans to potential risks, and also provides a controlled experimental environment where researchers can manipulate variables, such as genetic makeup and environmental conditions, to identify cause-and-effect relationships and validate therapeutic targets. This article discusses the reliability of mice as animal models for longevity research as well as some of the nuances that researchers should consider when using these animals in experiments.

Harvard study, almost 80 years old, has proved that embracing community helps us live longer, and be happier

People matter. The Harvard Study of Adult Development, which tracked the health trajectories and life events of over 700 men starting in the year 1938, found that close social ties outperformed social class, IQ, and genetics for predicting long, happy lives.