The Optispan Podcast with Matt Kaeberlein

How much longer might humans live?

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

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

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

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

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

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

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

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

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

The slowing pace of life expectancy gains since 1950

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

Life Expectancy

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

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

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

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

Ozempic could delay ageing, researchers suggest

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

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

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

Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes

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

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

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

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

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

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

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

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

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

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

Is Andrew Huberman Ruining Your Morning Coffee?

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

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

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

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

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

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

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

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

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

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

Metformin decelerates aging clock in male monkeys

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

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

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

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

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

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

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

The Targeting Aging with Metformin (TAME) Trial

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

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

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

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

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

The UK Biobank

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

A new approach to the concept and computation of biological age

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

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

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

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

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

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

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

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

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

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

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

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

Primer on ventilatory thresholds

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

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

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

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

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

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

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

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

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

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

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

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

Results of the PEARL Trial: An Expert Analysis

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

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

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

TORC1 inhibition enhances immune function and reduces infections in the elderly

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

A novel rapamycin analog is highly selective for mTORC1 in vivo

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

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

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

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

Inhibition of IL-11 signalling extends mammalian healthspan and lifespan

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

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

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

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

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

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

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

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

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

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

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

Inhibition of IL-11 signalling extends mammalian healthspan and lifespan

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

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

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

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

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

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

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

Functional conservation in genes and pathways linking ageing and immunity

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

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

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

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

Matt has served on the ITP steering committee since 2012.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Studies that shed new light on aging

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

Harold Katcher's rejuvenated hand self-experiment

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

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

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

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.

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.

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.

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.