The Optispan Podcast with Matt Kaeberlein PhD

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

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

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

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

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

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

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

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

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

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

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

On the Mortality in Husbands and Wives

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

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

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

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

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

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

What is Medicine 3.0?

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

How healthy is the healthspan concept?

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

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

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

Articulating the Case for the Longevity Dividend

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

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

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

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

An open science study of ageing in companion dogs

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

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

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

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

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

Dogs Test Drug Aimed at Humans’ Biggest Killer: Age

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

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

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

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

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

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

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

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

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

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

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

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

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

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

APOE2 is associated with longevity independent of Alzheimer’s disease

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

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

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

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

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

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

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

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

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

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

Rejuvant website

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

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

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

Is bigger always better?

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

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

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

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

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

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

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

Is height related to longevity?

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

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

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

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

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

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

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

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

Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan

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

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

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

Substrate-specific Activation of Sirtuins by Resveratrol

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

Mechanism of Human SIRT1 Activation by Resveratrol

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

Is red wine actually good for your heart?

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

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

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

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

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

Is our healthcare system broken?

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

The Patient Experience: Perspectives on Today's Healthcare

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

Fiscal Year 2024 Budget

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

The economic value of targeting aging

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

Major longevity gains termed unlikely

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

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.

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.

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.

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.

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.