The Optispan Podcast with Matt Kaeberlein

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

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

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

Is our healthcare system broken?

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

The Patient Experience: Perspectives on Today's Healthcare

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

Fiscal Year 2024 Budget

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

The economic value of targeting aging

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

Major longevity gains termed unlikely

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

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

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

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

Matt joined the A4LI Board of Directors in 2024.

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

Longevity Gets Political at an Unprecedented DC Event

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

A Policymaker’s Guide the Longevity Therapeutics Industry

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

The Advanced Approval Pathway for Longevity Medicines

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

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

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

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

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

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

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

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

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

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

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

DEXA FAQ

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

Unexpected DEXA Scan Results? Here are Some Potential Causes

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

Role of Visceral Adipose Tissue in Aging

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

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

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

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

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

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

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

Why Are Cells Powered by Proton Gradients?

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

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

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

Optogenetic control of mitochondrial protonmotive force to impact cellular stress resistance

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

Optogenetic rejuvenation of mitochondrial membrane potential extends C. elegans lifespan

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

Extending lifespan by rejuvenating mitochondrial membrane potential - Dr Brandon Berry

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

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

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

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

Examine.com

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

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

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

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

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

Vitamin B12

Vitamin D

Omega-3 Fatty Acids

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Optispan uses the SapereX test in its healthspan optimization program.

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

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

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

Naturally occurring p16 Ink4a-positive cells shorten healthy lifespan

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

Senolytics improve physical function and increase lifespan in old age

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

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

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

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

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

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

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

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

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

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

DEXA FAQ

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

Unexpected DEXA Scan Results? Here are Some Potential Causes

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

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

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

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

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

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

Rapamycin News

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

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

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

Effect of caloric restriction and rapamycin on ovarian aging in mice

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

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

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

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

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

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

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

LeapYears

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

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

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

NAD+ homeostasis in human health and disease

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

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

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

A common signature of cellular senescence; does it exist?

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

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

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

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

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

Leap Years

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

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

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

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

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

Can Your Dog Live Longer With a Pill?

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

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

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

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

Rapamycin fed late in life extends lifespan in genetically heterogeneous mice

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

mTOR Regulation and Therapeutic Rejuvenation of Aging Hematopoietic Stem Cells

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

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

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

TORC1 inhibition enhances immune function and reduces infections in the elderly

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

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

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

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

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

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

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

Examine.com

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

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

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

Why EVERYONE Should Use Creatine Supplements

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

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

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

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

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

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

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

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

Naturally occurring p16Ink4a-positive cells shorten healthy lifespan

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

Senolytic CAR T cells reverse senescence-associated pathologies

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

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

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

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

Healthy aging: The ultimate preventative medicine

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

It is Time to Embrace 21st-Century Medicine

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

Translational geroscience: A new paradigm for 21st century medicine

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

From lifespan to healthspan (1)

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

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

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

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

The Hallmarks of Aging

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

Hallmarks of aging: An expanding Universe

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

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

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

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

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

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

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

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

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

American Academy of Allergy, Asthma & Immunology

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

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

We sat down with George to talk about his research, including the effects of caffeine on lifespan and, more recently, his discovery of a new metabolite with the ability to greatly extend lifespan when given late in life. We also discuss George's thoughts on biological age clocks, his own healthspan optimization protocol, and much more.

The probiotic George mentions taking in this podcast episode is Garden of Life Probiotics Ultimate Care.

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

Caffeine extends life span, improves healthspan, and delays age-associated pathology in Caenorhabditis elegans

This paper began as a side project during George’s PhD work at the University of Washington. It showed that caffeine extended life- and healthspan in nematode worms, and also had positive effects on pathologies such as paralysis in a worm model of polyglutamine disease. The paper attracted a lot of interest, perhaps because it seemed to justify people’s coffee-drinking habits. No conclusive evidence about caffeine’s effects on human lifespan currently exists.

Lifespan extension in Caenorhabditis elegans by complete removal of food

What is the optimal amount of food to give worms so that they’ll live longer? According to this study, which also came out of George’s PhD at the University of Washington, the answer is no food at all. This paper found that completely taking away worms’ food in adulthood increased lifespan by up to 50%. While a starvation protocol like this one is unlikely to work in humans, these findings add an interesting set of data points to evolving research into how diet affects longevity in humans.

Dietary restriction by bacterial deprivation increases life span in wild-derived nematodes

This study was a follow up to the previous paper and investigates the effects of dietary restriction on the lifespan of wild worm populations collected from various locations worldwide. The results indicate that bacterial food deprivation extends lifespan across multiple wild C. elegans (a worm species) populations. Additionally, the longevity-enhancing effects of bacterial food deprivation are conserved in a related worm species, C. remanei. The study highlights the potential impact of genetic and environmental factors on worm lifespan variation and suggests that food-deprivation-induced lifespan extension may be a characteristic of wild-derived nematode populations.

Caenorhabditis elegans orthologs of human genes differentially expressed with age are enriched for determinants of longevity

This paper came out of George’s time at the Jackson Laboratory. The researchers conducted an RNA interference (RNAi) longevity screen on 82 genes in C. Elegans, chosen based on their orthology to human genes that show age-related changes in expression. Their results revealed a significant enrichment in genes where knockdown increased lifespan compared to previously published longevity screens, with 46 genes being newly identified as impacting lifespan. Knockdown of these genes, which included genes that encoded the enzyme kynureninase, a tetraspanin, and a voltage-gated calcium channel subunit, increased healthspan with no effects on reproduction. The kynureninase gene knockdown specifically delayed pathology in worm models of Alzheimer's and Huntington's diseases.

The Emerging Role of 3-Hydroxyanthranilic Acid on C. elegans Aging Immune Function

3-hydroxyanthranilic acid (3-HAA) is a metabolite within the kynurenine pathway, a metabolic pathway involved in the breakdown of the amino acid tryptophan. The kynurenine pathway plays a crucial role in various physiological processes, including immune response regulation, neurotransmitter synthesis, and inflammation modulation. This paper showed that the 3HAA appeared to slow age-associated immune function decline in addition to helping mice fend off pathogenic challenges. 3HAA is not sufficiently well-understood to be a candidate for supplementation in humans.

Everything we talk about on The Optispan Podcast has geroscience at its root, so we decided to make an episode about it. Geroscience is the study of the mechanisms connecting biological aging with disease and disability. The term first appeared in the scientific literature around 2008, and its use has steadily increased since as researchers have discovered more about the aging process and its impact on our health. While it's clear that aging biology is at the root of the diseases and disabilities that most people get sick with and die from in their later years, it's been a challenge to get the field the traction and support that other fields enjoy, in part because we are used to a "disease care" model of waiting until people get sick and only then addressing their symptoms and/or curing their disease.

In this episode, Matt dives into the geroscience hypothesis and how it underpins the way we age, entrenched cultures in industries from drug development to insurance to regulation, and why he's excited to create a geroscience-inspired disruption in the medical and healthcare industries.

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

Hallmarks of aging: An expanding Universe

As Matt notes in the podcast, the Hallmarks of Aging are an easy way to think about the biological mechanisms that underlie aging and the functional declines and diseases that accompany aging. They are not a comprehensive list of everything that happens as we age, but they give a good starting point to understand the idea that several things change in our bodies with age. This paper proposes twelve hallmarks of aging and extends the work of the original 2013 paper outlining nine hallmarks of aging. The framework of “aging hallmarks”—that is, specific and identifiable molecular mechanisms or alterations that accompany the aging process—has provided a useful paradigm for understanding how certain biochemical changes form the essence of aging and of the disease and disability that accompanies it. However, we still don’t know a lot about the hierarchy of these hallmarks’ impact on the aging process or how they might interact with each other, and the evidence linking them to age-related disease is mostly correlative.

Major longevity gains termed unlikely

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

The economic value of targeting aging

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

Is aging without illness possible?

This article presents perspectives from various prominent geroscience researchers about the history of the field, compounds that have shown promise thus far for targeting aging, and key barriers to progress. One important obstacle is hype. The idea of “antiaging therapies” is, according to University of Illinois Chicago Professor of Epidemiology and Biostatistics, “associated with an industry that is trying to sell products to the public to separate people from their money.” Overselling the promise of supplements, prescription medications, and other therapies is likely to increase skepticism about the geroscience and set the field back.

Fiscal Year 2024 Budget

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

Longevity This Week is a series of episodes discussing new findings or articles relevant to geroscience, longevity, and healthspan that may have popped up in the news.

This week we're featuring Richard Morgan, a 93-year-old rowing champion whom the Washington Post recently described as being "as fit as a 40-year-old". We talk about Richard's diet, exercise routine, and other aspects of his lifestyle that may have led to his enviable state in older age. We also discuss a recent Wall Street Journal article about how Americans are spending more of their lives in poor health, and about how "sickspan"—the amount of time we spend sick near the end of our lives—might change in years to come.

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

Physiological characteristics of a 92-yr-old four-time world champion rower

This is the study on which the article in The Washington Post that Matt references in this episode is based. The study measured the oxygen uptake, carbon dioxide production, ventilation, and heart rate of 92-year-old Irishman Richard Morgan at rest and while using an ergometer, and found that Richard’s oxygen uptake kinetics were similar to those of healthy young adults. It also outlines his training and nutritional habits, which include an “extremely consistent diet”, 40 minutes per day of rowing, and two to three days per week of resistance training. Richard only began rowing at 73 and was not involved in any structured exercise regime prior to that.

Americans are sick for more of their lives

This article, which Matt discusses in the podcast, describes the decline in time that Americans spend in good health towards the end of their lives. In 1990, Americans spent 85.8% of their lives in good health. In 2021, that number went down to 83.6%. This change is in part due to medical advances that prevent us from dying of certain diseases, so we live for a longer time, but continue to suffer from many of the functional declines and diseases that accompany old age. The article discusses how the growing gap between healthy life and death has significant implications for healthcare, the economy, and the wellbeing of patients and their caregivers.

How healthy is the healthspan concept?

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

Life-long spontaneous exercise does not prolong lifespan but improves health span in mice

According to this study, spontaenous exercise does not impact how long mice live, but delays their age-associated decline as measured in strength, endurance and motor coordination. They propose mechanisms by which exercise may prolong healthy cognitive and skeletal muscle function such as increases in neurotropic factors, or proteins crucial roles in the development, survival, and function of neurons, and the formation of new mitochondria within cells.

Biological age—that is, how old your cells and tissues are based on physiological function—is a multifaceted and intricate concept that transcends numerical representation. Unlike chronological age, which refers simply to the number of years you have been alive, the concept of biological age delves into the dynamic interplay between physiological processes, genetic predispositions, and environmental influences that collectively shape an individual's health trajectory. Geroscientists are currently studying the biological mechanisms that might impact your biological aging rate and perhaps reverse some of the functional declines that accompany aging.

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

Epigenetic Predictor of Age

This study was one of the first to build a model to estimate biological age from DNA methylation patterns. One could imagine DNA as a set of instructions, like a recipe book, that tells our bodies how to work; and DNA methylation as little tags or markers that attach to these instructions. These tags can change as we age, a bit like how notes or highlights might change in a book as you read it again and again—and in changing, affect how genes get turned on and off.

Decreased epigenetic age of PBMCs from Italian semi-supercentenarians and their offspring

When people talk about “epigenetic clocks” or “epigenetic age”, they are typically referring to methods that use DNA methylation changes as a means for estimating biological age. Underpinning these methods is the idea that certain patterns of DNA methylation change with age. According to this study, the offspring of semi-supercentenarians—people who live up to 105-109 years—have a lower epigenetic age than control subjects. Centenarians are also nearly nine years “younger” biologically than their chronological age.

Modeling the Rate of Senescence: Can Estimated Biological Age Predict Mortality More Accurately Than Chronological Age?

This study compares the ability of five algorithms to predict biological age. The “winning algorithm”, the 2006 Klemera and Doubal method (KDM), predicted mortality better than chronological age as well as any of the other algorithms tested.

A new approach to the concept and computation of biological age

The researchers Petr Klemera and Stanislav Doubal developed the Klemera and Doubal method (KDM), an algorithm for calculating biological age that outperformed other algorithms (see previous article). They detail tools researchers typically use to compute biological age—multiple linear regression, factor analysis, principal components analysis—and describe the mathematics behind their own method.

How to measure biological age | Prof Brian Kennedy

National University of Singapore Distinguished Professor of Biochemistry and Physiology Brian Kennedy chats about biological age with Eleanor Sheekey of The Sheekey Science Show. He describes how, unlike chronological age, markers of biological age might oscillate in response to different circumstances—sleep, a virus, exercise levels—and vary from one week to the next. As such, single timepoints may not be informative. He also discusses ongoing research to collect multiple potential biomarkers of aging, merge them, and see if they correspond or interact.

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

In the third episode of the R-Files, Matt, who studied rapamycin for over a decade of his career, talks about a recent study evaluating the benefits and side effects of taking rapamycin off-label—that is, for a purpose other than that for which the drug gained FDA approval. Physicians can prescribe any FDA-approved drug off-label as long as they believe it will be beneficial for the patient. Matt discusses noteworthy potential side effects of rapamycin use, the experiences of study participants who took rapamycin, and why off-label rapamycin use is not widespread despite considerable evidence for life- and healthspan benefits in laboratory animals.

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

Rapamycin News

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

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

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

Rapamycin and aging: Dosage, side effects, and success stories | Matt Kaeberlein

Matt discusses rapamycin on this podcast with Stanford Prevention Research Center lecturer Lucia Aronica. He makes several anecdotal observations about rapamycin, including that most people don’t seem to experience observable side effects on a weekly 3-6 mg dose. Side effects that seem real, he notes, are mouth sores and higher triglycerides. He also discusses differences in side effects observed in biohackers versus organ transplant patients taking rapamycin.

Rapamycin in aging and disease: maximizing efficacy while minimizing side effects

This article argues for several important considerations in future studies of rapamycin for successful translation to human use, including sex-dependent impacts on biological outcomes, the impact of short-term rapamycin treatment on a variety of healthspan metrics, the best regimen for extracting maximum benefits from rapamycin treatment while minimizing adverse effects, and more.

mTOR Inhibition: From Aging to Autism and Beyond

In this paper, Matt reviews the effects of mammalian target of rapamycin (mTOR) inhibitors on age-related disease and decline as well as on non-aging-related diseases such as tuberous sclerosis complex and epilepsy. He describes the side effects of chronic mTOR inhibition in mice, which include hyperlipidemia, insulin resistance, enhanced cataract formation and male sterility; as well as the adverse effects of mTOR inhibitors used in the clinic, which include mouth ulcers, diarrhea and nausea, hyperlipidemia, and infection.

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

In this second episode of the R-Files, Matt, who has spent a significant chunk of his career studying rapamycin, discusses his own journey to using rapamycin off-label and how it all began with a persistent pain in his right shoulder that a doctor suggested might take a year to resolve. Matt conducted an n=1 experiment to test whether a short course of rapamycin might improve the age-related inflammation that was the likely cause of his shoulder issue.

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

mTOR is a key modulator of ageing and age-related disease

This paper reviews the mechanistic target of rapamycin (mTOR) pathway, a nutrient sensing pathway that shows promise as a target for interventions to increase life- and healthspan. The mTOR pathway acts as a control center that helps cells decide what to do based on the nutrients available. When nutrients are abundant, mTOR tells cells to grow and divide; when nutrients are scarce, it signals cells to conserve energy and not grow too much. The article delves into the mechanisms by which the mTOR pathway influences longevity, including mRNA translation, autophagy, stress resistance and xenobiotic metabolism, mitochondrial function, inflammation, and stem cell rejuvenation.

mTOR Regulation and Therapeutic Rejuvenation of Aging Hematopoietic Stem Cells

The age-associated decline in function of hematopoietic stem cells (HSCs), cells in the bone marrow that give rise to all types of blood cells in the body, can lead to issues such as anemia and increased cancer risk. This study demonstrates that the mTOR pathway in HSCs is more active in older mice than in younger mice, and that activating this pathway accelerated HSC aging in young mice. Treating older mice with rapamycin, an mTOR inhibitor, extended their life- and healthspan. Taken together, these findings provide further evidence to suggest that the mTOR pathway plays a key role in aging.

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

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

Rapamycin fed late in life extends lifespan in genetically heterogeneous mice

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

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

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

Matt and guest Jonathan An, Assistant Professor of Oral Health Sciences at the University of Washington School of Dentistry, discuss oral health and its relationship to aging, including published studies involving rapamycin effects on oral health. This is a 3-part episode.

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

Aging and Oral Health with Dr. Jonathan An!

Jonathan recently appeared on Lets Get Oral, a podcast that explores oral health from multiple angles—think the oral microbiome, taste, bad breath. In this episode, Jonathan talks about how our teeth change as we get older, the potential impact of medications on oral health, why he supports taking a more systemic approach to dental care, and more.

Oral health in geroscience: animal models and the aging oral cavity

Animal models are indispensable tools for studying the biology of aging. They provide insight into underlying mechanisms of aging, enable scientists to test interventions that promote healthy aging, and advance our understanding of age-related diseases. While animal models have their limitations, their use in research allows for controlled experimentation and the generation of valuable data that can ultimately benefit human healthspan and longevity. Jonathan and our host Matt Kaeberlein co-authored this journal article about which animal models are best suited for studying the intersection of aging and oral disease. They discuss rodents, the current premier preclinical models for geroscience research, as well as dogs and nonhuman primates such as the southern pig-tailed macaque.

Rapamycin rejuvenates oral health in aging mice

In 2020, Jonathan and Matt demonstrated that rapamycin treatment rejuvenated the aged oral cavity of older mice. The treatment reversed "clinically defining features of periodontal disease", including periodontal bone loss, periodontal inflammation, and pathogenic oral microbiome changes. This paper lends support to the idea that interventions that target mechanisms of biological aging may delay multiple age-related declines. Further work should investigate whether the rejuvenating effects of rapamycin persist after the treatment period as well as whether rapamycin improves other oral health declines that commonly occur with age, such as salivary function.

Oral health for healthy aging

This article calls for an end to the siloing of oral health from general health care. The authors note that the global prevalence of oral disease is higher than it should be, given the preventable nature of most oral diseases, and that this prevalence is likely to worsen with population aging. They make suggestions for concrete policy action and mindset shifts towards addressing the burden of oral disease care, including shifting dental care models away from curative and interventionist models and towards more preventative upstream action.

Aging and Dental Health

This is a short primer from the American Dental Association about the clinical and oral health context of older adults. By one estimate, 68 percent of adults aged 65 years and older have periodontis. The primer covers comorbid conditions; the potential impact of common medications for age-related conditions on oral health; and cognitive, physical, and sensory limitations affecting dental care and home oral care.

Matt and guest Jonathan An, Assistant Professor of Oral Health Sciences at the University of Washington School of Dentistry, discuss oral health and its relationship to aging, including published studies involving rapamycin effects on oral health. This is a 3-part episode.

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

Aging and Oral Health with Dr. Jonathan An!

Our guest, Assistant Professor of Oral Health Sciences and Faculty in the Healthy Aging and Longevity Institute at the University of Washington School of Dentistry Jonathan An, recently appeared on Lets Get Oral, a podcast that explores oral health from multiple angles—think the oral microbiome, taste, bad breath. In this episode, Jonathan talks about how our teeth change as we get older, the potential impact of medications on oral health, why he supports taking a more systemic approach to dental care, and more.

Oral health in geroscience: animal models and the aging oral cavity

Animal models are indispensable tools for studying the biology of aging. They provide insight into underlying mechanisms of aging, enable scientists to test interventions that promote healthy aging, and advance our understanding of age-related diseases. While animal models have their limitations, their use in research allows for controlled experimentation and the generation of valuable data that can ultimately benefit human healthspan and longevity. Jonathan and our host Matt Kaeberlein co-authored this journal article about which animal models are best suited for studying the intersection of aging and oral disease. They discuss rodents, the current premier preclinical models for geroscience research, as well as dogs and nonhuman primates such as the southern pig-tailed macaque.

Rapamycin rejuvenates oral health in aging mice

In 2020, Jonathan and Matt demonstrated that rapamycin treatment rejuvenated the aged oral cavity of older mice. The treatment reversed "clinically defining features of periodontal disease", including periodontal bone loss, periodontal inflammation, and pathogenic oral microbiome changes. This paper lends support to the idea that interventions that target mechanisms of biological aging may delay multiple age-related declines. Further work should investigate whether the rejuvenating effects of rapamycin persist after the treatment period as well as whether rapamycin improves other oral health declines that commonly occur with age, such as salivary function.

Oral health for healthy aging

This article calls for an end to the siloing of oral health from general health care. The authors note that the global prevalence of oral disease is higher than it should be, given the preventable nature of most oral diseases, and that this prevalence is likely to worsen with population aging. They make suggestions for concrete policy action and mindset shifts towards addressing the burden of oral disease care, including shifting dental care models away from curative and interventionist models and towards more preventative upstream action.

Aging and Dental Health

This is a short primer from the American Dental Association about the clinical and oral health context of older adults. By one estimate, 68 percent of adults aged 65 years and older have periodontis. The primer covers comorbid conditions; the potential impact of common medications for age-related conditions on oral health; and cognitive, physical, and sensory limitations affecting dental care and home oral care.

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

In this first episode of the R-Files, Matt, who has spent a significant chunk of his career studying rapamycin, will discuss how fortuitous conversations, an appetite for unexplored territory, and an opportunity to look where others weren't looking helped him get deep into the study of rapamycin and uncover some interesting insights into how rapamycin can affect lifespan.

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

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

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

Regulation of Yeast Replicative Life Span by TOR and Sch9 in Response to Nutrients

This 2005 paper was the first to describe the molecular pathway by which caloric restriction could influence yeast lifespan. Caloric restriction extended yeast replicative lifespan—that is, the number of times a yeast cell can divide and produce daughter cells before it stops dividing—by downregulating signaling through TOR1 and Sch9 genes. In yeast, the TOR1 gene codes for the TOR1 protein, a protein analogous to the mTOR protein in mice. Rapamycin inhibits mTOR1.

Extension of chronological life span in yeast by decreased TOR pathway signaling

This is the experiment involving nearly 5,000 yeast strains that Matt describes in the podcast.

The discovery & first uses of rapamycin | Peter Attia, David Sabatini, & Matt Kaeberlein

Matt joins physician Peter Attia and Institute of Organic Chemistry and Biochemistry senior group leader David Sabatini in this rapamycin-themed episode of the Peter Attia Drive podcast. In this clip, three longevity experts dig into the history of rapamycin’s discovery. They also discuss rapamycin’s clinical path as an immunosuppressant and how that path may have impacted the development of rapamycin for other uses, the decades-long gap between the discovery of rapamycin and its eventual use in the clinic, and the difficulty of disentangling side effects that come from rapamycin use versus that of other drugs.

Matt and guest Jonathan An, Assistant Professor of Oral Health Sciences at the University of Washington School of Dentistry, discuss oral health and its relationship to aging, including published studies involving rapamycin effects on oral health. This is a 3-part episode.

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

Aging and Oral Health with Dr. Jonathan An!

Our guest, Assistant Professor of Oral Health Sciences and Faculty in the Healthy Aging and Longevity Institute at the University of Washington School of Dentistry Jonathan An, recently appeared on Lets Get Oral, a podcast that explores oral health from multiple angles—think the oral microbiome, taste, bad breath. In this episode, Jonathan talks about how our teeth change as we get older, the potential impact of medications on oral health, why he supports taking a more systemic approach to dental care, and more.

Oral health in geroscience: animal models and the aging oral cavity

Animal models are indispensable tools for studying the biology of aging. They provide insight into underlying mechanisms of aging, enable scientists to test interventions that promote healthy aging, and advance our understanding of age-related diseases. While animal models have their limitations, their use in research allows for controlled experimentation and the generation of valuable data that can ultimately benefit human healthspan and longevity. Jonathan and our host Matt Kaeberlein co-authored this journal article about which animal models are best suited for studying the intersection of aging and oral disease. They discuss rodents, the current premier preclinical models for geroscience research, as well as dogs and nonhuman primates such as the southern pig-tailed macaque.

Rapamycin rejuvenates oral health in aging mice

In 2020, Jonathan and Matt demonstrated that rapamycin treatment rejuvenated the aged oral cavity of older mice. The treatment reversed "clinically defining features of periodontal disease", including periodontal bone loss, periodontal inflammation, and pathogenic oral microbiome changes. This paper lends support to the idea that interventions that target mechanisms of biological aging may delay multiple age-related declines. Further work should investigate whether the rejuvenating effects of rapamycin persist after the treatment period as well as whether rapamycin improves other oral health declines that commonly occur with age, such as salivary function.

Oral health for healthy aging

This article calls for an end to the siloing of oral health from general health care. The authors note that the global prevalence of oral disease is higher than it should be, given the preventable nature of most oral diseases, and that this prevalence is likely to worsen with population aging. They make suggestions for concrete policy action and mindset shifts towards addressing the burden of oral disease care, including shifting dental care models away from curative and interventionist models and towards more preventative upstream action.

Aging and Dental Health

This is a short primer from the American Dental Association about the clinical and oral health context of older adults. By one estimate, 68 percent of adults aged 65 years and older have periodontis. The primer covers comorbid conditions; the potential impact of common medications for age-related conditions on oral health; and cognitive, physical, and sensory limitations affecting dental care and home oral care.

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

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

Objections and Their Counterarguments

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

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

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

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

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

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

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

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

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

Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan

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

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

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

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

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

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

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

Objections and Their Counterarguments

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

Optispan CEO Matt Kaeberlein chats with Prime Health Associates Physician Kevin White about improving bloodwork results, monitoring glucose readings, taking supplements, and more.

Optispan CEO Matt Kaeberlein chats with Prime Health Associates Physician Kevin White about making the transition from research to building a company, moving towards preventative medicine in the 21st century, incorporating new discoveries into medical practice, and more.

Optispan CEO Matt Kaeberlein discusses the popular Healthspan concept, how Healthspan is different from Lifespan, and why bouncing back from health challenges gets harder as we age.

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

How healthy is the healthspan concept?

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

Translational geroscience: A new paradigm for 21st century medicine

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

Lifespan and Healthspan: Past, Present, and Promise

This article lays out the evidence for the life expectancy increase that has happened over the last century, and discusses recent trends in measures of population health such as cognitive functioning, severe disability, and the presence of diseases. The author notes that while infection used to be one of the primary causes of human death, death today generally occurs as a result of chronic diseases and disabilities that occur at older ages. She argues for beginning trials whose purpose is to delay the biological aging process early in life, as well as for taking a more preventative approach to healthcare.

Optispan CEO Matt Kaeberlein takes questions about healthy aging.

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

Hallmarks of aging: An expanding Universe

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

A Reimagined Research Strategy for Aging

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

Inside Science: Introducing the Test of Rapamycin in Aging Dogs

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

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

Ultra-processed foods and how to identify them

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

Lifelong Physical Exercise Delays Age-Associated Skeletal Muscle Decline

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

Optispan CEO Matt Kaeberlein explains how aging affects our risk of disease and why proactive prevention is the 21st century solution to staying healthy.

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

Longevity and aging

In this 2013 article, Matt describes the geroscience hypothesis, or the idea that age-related diseases such as Alzheimer's disease and cancer share common causal biological mechanisms. He makes the case that interventions targeting these biological mechanisms will have an impact far higher than that of interventions aimed at treating individual diseases, because the biological mechanisms of aging have an impact on the onset and progression of multiple age-related disorders. The paper also discusses model organisms used in geroscience research and the translatability of research involving these model organisms to humans.


Why Is Aging Conserved and What Can We Do about It?

This article describes pathways that influence longevity and appear to be conserved across a range of organisms such as yeast, fruit flies, and mice. It also discusses the cellular processes regulated by these pathways that may modulate health- and lifespan.


Longevity FAQ: A beginner's guide to longevity research

This FAQ provides a high-level introduction to the geroscience field. It describes the goals of research into the biology of aging and core areas of interest within the field, along with interventions that scientists have tested in mice for effects on life- and/or healthspan.