Peter Attia MD333 ‒ Longevity roundtable—the science of aging, geroprotective molecules, & lifestyle interventions
CHAPTERS
- 0:00 – 9:16
Why longevity has gone mainstream
Peter Attia opens by asking why public interest in longevity looks like a bubble. Steven Austad and Richard Miller point to tech entrepreneurs, aging individuals, mouse drug results, and commercial hucksters selling untested products. Miller also argues that lifespan and healthspan are linked rather than a trade-off.
- •Austad is surprised by the popularity of the word longevity, which the field once avoided
- •Miller cites 1990s discoveries and mouse results of 20-30% extension as drivers of interest
- •Miller says marketers profit from selling products without evidence
- •Miller calls the seesaw view of healthspan versus lifespan ridiculous
- •Miller lists reasons for the lag since the first rapamycin ITP result, including the belief that aging can't be changed and weak commercial incentives
- 9:16 – 19:15
Healthspan, lifespan, and the US life expectancy paradox
Austad pushes back, noting that the gap between healthspan and lifespan is growing in people, and Attia explains the US data on middle-age deaths and strong life expectancy after 65. The group then debates whether healthspan is a useful term, and Attia describes his marginal decade exercise for personalizing it.
- •Austad cites papers showing the healthspan-lifespan gap growing fastest in the US and among women
- •Attia notes US life expectancy is dragged down by middle-age deaths, while older Americans do well
- •Kaeberlein says most people spend decades in sickspan if healthspan ends at the first chronic disease
- •Miller calls healthspan a useless term, while Kaeberlein finds it useful as a concept
- •Attia describes the marginal decade exercise across physical, cognitive, emotional and social goals
- 19:15 – 20:47
Is the longevity boom a bubble?
Matt Kaeberlein gives his view of why longevity has gone mainstream, citing mature science and influencers. He sees a hockey-stick moment and a large gray area between real science and snake oil.
- •Science has matured enough that more people believe biological aging can be modulated
- •Influencers popularized the concept, sometimes less scientifically than they should
- •Kaeberlein hopes the field becomes more scientific and less snake-oily
- •Nobody at the table can say where the line in the gray area falls
- 20:47 – 33:31
NIH funding, turf wars, and the case for aging research
The panel discusses how little of the NIH budget goes to biology of aging, about half of 1% by Kaeberlein's account. They examine the turf defense by disease institutes and lobbying, while Austad points to growing private-sector money. Kaeberlein notes that nine of the top ten causes of death have aging as the greatest risk factor.
- •NIA gets roughly 3% of NIH, and biology of aging within it about half a percent
- •Miller is near zero on NIH optimism and describes disease-group lobbying power
- •Kaeberlein says the field's reputation as less rigorous also hinders funding
- •Austad argues private-sector money makes this a good time but warns about flashy bad science
- •Research follows where the dollars go, so shifting funding would pull in scientists
- 33:31 – 35:36
Is aging a disease?
Attia raises the question of whether aging is a disease. Miller, Kaeberlein and Austad all reject it, though Austad and Miller say the framing is a marketing ploy aimed at funding. Kaeberlein dismisses the claim that FDA requires calling aging a disease.
- •Miller says aging is a risk factor for disease and calling it a disease obscures that relationship
- •Austad sees the label as a marketing attempt to get Congress's attention
- •Miller objects to lying to people for marketing purposes
- •Kaeberlein says the label creates negative feelings about the field and that the FDA argument misunderstands the FDA
- 35:36 – 51:31
Biological age versus chronological age and epigenetic clocks
The panel debates whether biological age is a meaningful single number. Kaeberlein argues biological aging is real, citing dogs and single-gene effects, and describes his test of four direct-to-consumer epigenetic kits with widely varying results. Attia and Miller argue a composite of functional measures already tells more than any clock.
- •Austad and Miller doubt a single biological age number, while agreeing biological aging is real
- •Kaeberlein's duplicate tests across four companies ranged from 42 to 63 against a true age of about 54
- •Attia asks whether a clock predicts remaining life better than chronological age does
- •Attia says he already knows dozens of measures for each patient, and Miller says a few measures predict mortality
- •Kaeberlein hopes epigenetic algorithms may eventually replace some biomarkers
- 51:31 – 1:06:24
Hallmarks of aging and whether epigenetic change is causal
Attia asks whether epigenetic change is the most important hallmark and whether it is causal. Miller argues the hallmarks list set the field back by narrowing grant thinking, and Kaeberlein calls it a double-edged sword. They discuss what experiments could prove causality, including partial reprogramming.
- •Miller says branding something a hallmark lets grants skip proving cause and effect
- •Austad says he would not give epigenetics primacy over other hallmarks
- •Kaeberlein says the hallmarks helped communication but caused premature narrowing of funding
- •Miller says epigenetic change is too broad, spanning thousands of changes in many cell types, to call causal
- •Kaeberlein would be convinced by transient reprogramming extending mouse life dramatically
- 1:06:24 – 1:23:08
Aging versus age-related disease and Medicine 2.0 and 3.0
Kaeberlein explains that age-related disease is downstream of aging and, past a point, no longer responds to anti-aging interventions, using cancer and rapamycin as an example. Attia argues for running disease treatment and aging-focused medicine in parallel, and the group discusses the political resistance, including Alzheimer's advocacy. The conversation also touches on immune dysfunction.
- •Kaeberlein says rapamycin can prevent cancer but fails against established cancers
- •Austad says disease-based medicine is not about the biology of aging
- •Attia proposes Medicine 2.0 and 3.0 in parallel, though funding would require reallocation
- •Attia recounts congressional pushback when shifting Alzheimer's funds was suggested
- •Attia would add immune dysfunction as a fifth horseman, with Austad noting pneumonia stays in the top 10 causes of death
- 1:23:08 – 1:40:32
Aging rate indicators versus biomarkers, and mouse-to-human translation
Miller distinguishes biomarkers of aging, like an odometer, from aging rate indicators, like a speedometer, which change early in all slow-aging mice. The group debates how to validate such indicators in people, whether mouse findings translate, and how to deal with the FDA.
- •Miller says about a dozen indicators change in every slow-aging mouse, including UCP1 and shifts in fat macrophages
- •Miller's group has a new grant to test them against ineffective drugs
- •Austad warns most mouse findings fail in people and a four-year lifespan study is slow
- •Kaeberlein asks how to trust these indicators in humans and the FDA
- •Attia proposes an extreme lifestyle-intervention study in humans, and Miller says he would want cognition, cataracts, hearing and vaccine response checked too
- 1:40:32 – 1:48:26
Does exercise slow aging?
The group asks whether exercise slows aging or just extends life and healthspan. Miller points to molecules like GPLD1 and irisin that rise with exercise and in slow-aging mice, and notes the ITP has never tested exercise. Kaeberlein cautions about interpreting exercise in caged mice.
- •Attia is unsure whether exercise slows aging or just extends life
- •Austad says exercise's effect on longevity is small but its effect on quality of life is enormous
- •Miller says GPLD1 and irisin rise with exercise and in all slow-aging mice studied
- •The ITP has not tested exercise because of limited resources
- •Kaeberlein notes mice live in a small cage, so lack of effect from a wheel wouldn't rule exercise out
- 1:48:26 – 1:54:34
Are GLP-1 agonists geroprotective?
Attia asks if GLP-1 agonists are geroprotective beyond caloric restriction. The panel is uncertain, and Miller explains why the ITP hasn't tested injectable or oral semaglutide. They end on the resource constraints and the economic value of healthspan.
- •Kaeberlein separates caloric-restriction effects from calorie-independent effects
- •Attia notes existing studies are in obese and diabetic patients, so effects can't be separated
- •Miller says weekly injections and sham controls make testing laborious and he'd wait for an easy oral pill
- •Attia says tirzepatide effects in lean people depend on dose
- •Kaeberlein cites a $38 trillion estimate per year of healthspan, which Miller attributes to an economist, Andrew Scott
- 1:54:34 – 2:12:11
Senescent cells and senolytics
Miller argues the senescence concept stems from a historical accident and blocks productive thinking, and describes failed ITP tests of fisetin and attempts to replicate senolytic mouse results. Austad and Kaeberlein counter that evidence for health benefits from clearing p16-positive cells exists, though definitions are muddled. The discussion then turns to NIH funding for geroscience across institutes.
- •Miller recounts Hayflick's cell division limit and says in vitro senescence became a model of aging
- •The ITP found fisetin had no effect on lifespan or on senescent cell markers
- •Miller says he could not detect depletion of senescent cells in the Van Deursen and Baker mouse model
- •Austad and Kaeberlein cite evidence of health benefits and note the definition of senescent cells keeps broadening
- •Austad says a group lobbying Congress asked NIH to report geroscience spending across institutes
- 2:12:11 – 2:25:03
Metformin and canagliflozin
Miller and Austad discuss metformin's geroprotective potential, with Miller skeptical and citing the flawed Bannister paper, and Austad finding observational evidence promising. They cover the TAME trial, mechanism questions, and canagliflozin's effect in male mice.
- •Miller thinks metformin evidence is unanswered and would choose canagliflozin instead
- •Austad sees enough smoke in observational data on dementia, cancer and cardiovascular disease to test it
- •TAME is enrolling at small scale after years without full funding
- •Attia notes metformin does not reach muscle but concentrates in the liver and gut
- •Miller says canagliflozin worked in male mice and weight loss didn't explain it, so mechanism is unknown
- 2:25:03 – 2:35:21
Rapamycin dosing, mTOR biology, and human use
Attia asks why daily rapamycin in the ITP always worked when many people dose weekly. Kaeberlein and Miller discuss the mTORC1 and mTORC2 model, downstream effects, and a paper pairing rapamycin with an ERK inhibitor. Kaeberlein explains how once-weekly dosing evolved from Joan Mannick's work.
- •The ITP delivers rapamycin in food and the dosing was never optimized
- •Kaeberlein doubts the evidence that side effects come solely through mTORC2
- •Miller describes rapamycin changing substrate levels and mTORC2 behavior in slow-aging mice
- •Partridge's ERK inhibitor combined with rapamycin improved lifespan
- •Kaeberlein describes weekly dosing based on Mannick's everolimus trial and says dogs are dosed weekly
- 2:35:21 – 2:43:11
Resveratrol and NAD precursors
In a speed round, the panel finds nothing positive about resveratrol and explains why it persists, with Miller recounting the coconut oil diet mouse study. Austad and Kaeberlein are skeptical of NAD precursors, citing the negative ITP data and concerns about the NMN marketing.
- •Kaeberlein and Miller say there is nothing positive to say about resveratrol
- •Miller explains the resveratrol lifespan result occurred in mice on a 60% coconut oil diet dying of liver expansion
- •Austad finds NAD interesting but says the evidence is not compelling and the ITP evidence is negative
- •Kaeberlein notes NAD precursors may all break down to niacin in the gut and one mouse study showed kidney inflammation with NMN
- •Kaeberlein is bothered by NMN marketing for pets
- 2:43:11 – 2:55:00
Parabiosis, plasmapheresis, and closing nominations
The panel discusses whether young blood and plasma exchange could slow aging in humans. Austad and Kaeberlein are hopeful, and Miller prefers identifying the active factors. They close by nominating guests for a future roundtable.
- •Austad finds the mouse evidence compelling and says transfusion is not exotic medicine
- •Miller says the useful goal is to identify which molecules in young or old blood matter
- •Kaeberlein and Attia say proof of principle needs no mechanism, and plasma exchange for albumin is the simplest trial
- •Kaeberlein notes parabiosis itself shortens rodent lifespan
- •They nominate Vadim Gladyshev, Brian Kennedy and Morgan Levine for a future roundtable
