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categories: ["people", "longevity"]categories: ["people", "longevity"]tags: ["aging", "centenarians", "genetics", "metformin", "clinical trials", "geroscience", "regulation"]tags: ["aging", "centenarians", "genetics", "metformin", "clinical trials", "geroscience", "regulation"]summary: "Israeli-American physician-scientist whose centenarian genetics work and proposed TAME trial aim to make aging itself an acceptable regulatory indication."summary: "Israeli-American physician-scientist whose centenarian genetics work and proposed TAME trial aim to make aging itself an acceptable regulatory indication."updated: "2026-07-27"updated: "2026-10-29"------ ```infobox```infoboxlines 29–45 → 29–4415 unchanged lines not shown
**Nir Barzilai** is an Israeli-American physician-scientist at the Albert Einstein College of**Nir Barzilai** is an Israeli-American physician-scientist at the Albert Einstein College ofMedicine in New York, where he directs the Institute for Aging Research and leads a long-runningMedicine in New York, where he directs the Institute for Aging Research and leads a long-runningstudy of exceptionally long-lived Ashkenazi Jewish families. He is best known as the principalstudy of exceptionally long-lived Ashkenazi Jewish families. He is best known as the principaldesigner of TAME, a proposed trial of [[metformin]] whose endpoint wasdesigner of TAME, a proposed trial of [[metformin]] whose endpoint was constructed to force aconstructed to force a regulator to treat aging as something a drug can be approved to address. Asregulator to treat aging as something a drug can be approved to address. As of 2026 TAME had notof 2026 TAME had not been funded at the scale it requires, had not enrolled, and had reported nobeen funded at the scale it requires, had not enrolled, and had reported no results.results. ## Overview## Overview Barzilai's two bodies of work rest on different kinds of evidence. One is observational humanBarzilai's two bodies of work rest on different kinds of evidence. One is observational humangenetics: a cohort of centenarians and their children,genetics: a cohort of centenarians and their children, assembled to ask which inherited variantsassembled to ask which inherited variants separate people who reach extreme age from people who doseparate people who reach extreme age from people who do not. The other is regulatory strategy: annot. The other is regulatory strategy: an argument that the [[geroscience-hypothesis]] cannot beargument that the [[geroscience-hypothesis]] cannot betested until an endpoint exists that a health authority will accept for a drug aimed at agingtested until an endpoint exists that a health authority will accept for a drug aimed at agingrather than at a named disease. The genetics is descriptive and largely uncontested. The trialrather than at a named disease. The genetics is descriptive and largely uncontested. The trialbuilt to settle the second question has never been funded at the scale it requires.built to settle the second question has never been funded at the scale it requires.lines 49–61 → 48–603 unchanged lines not shown
Barzilai took his MD at the Technion in Haifa and trained in internal medicine and endocrinologyBarzilai took his MD at the Technion in Haifa and trained in internal medicine and endocrinologybefore joining the faculty of the Albert Einstein College of Medicine in the Bronx. His earlybefore joining the faculty of the Albert Einstein College of Medicine in the Bronx. His earlylaboratory work concerned insulin action, visceral fat, and the metabolic changes that accompanylaboratory work concerned insulin action, visceral fat, and the metabolic changes that accompanyaging in rodents, which is the route by which he arrived at the question of why some people escapeaging in rodents, and that work led him to ask why some people escape those changes. He is thethem. He is the founding director of Einstein's Institute for Aging Research and directs its Nathanfounding director of Einstein's Institute for Aging Research and directs its Nathan Shock Center ofShock Center of Excellence in the Basic Biology of Aging, one of a small number designated by the USExcellence in the Basic Biology of Aging, one of a small number designated by the US NationalNational Institute on Aging. He co-founded CohBar, a company formed toInstitute on Aging. He co-founded CohBar, a company formed to developdevelop [[mitochondrial-dysfunction|mitochondria-derived peptides]] as drugs, and holds advisory[[mitochondrial-dysfunction|mitochondria-derived peptides]] as drugs, and holds advisory rolesroles across the sector. His 2020 trade book *Age Later* sets out the case foracross the sector. His 2020 trade book *Age Later* sets out the case for treating aging as thetreating aging as the shared upstream cause of the diseases of old age.[^agelater2020]shared upstream cause of the diseases of old age.[^agelater2020] ```timeline```timeline[[lines 74–95 → 73–9512 unchanged lines not shown
From the late 1990s Barzilai's group recruited several hundred Ashkenazi Jewish people aged 95 andFrom the late 1990s Barzilai's group recruited several hundred Ashkenazi Jewish people aged 95 andover, along with their adult children and a comparison group of similar age whose parents hadover, along with their adult children and a comparison group of similar age whose parents hadordinary lifespans. The children are the analytically useful part of the design: young enough to beordinary lifespans. The children are the analytically useful part of the design. They are youngmeasured directly, sharing half the genome of a demonstrated survivor, and comparable on diseaseenough to be measured directly, share half the genome of a demonstrated survivor, and can berates with their contemporaries, which is how the project connects tocompared on disease rates with their contemporaries, which connects the project to[[compression-of-morbidity|compressed morbidity]] rather than to lifespan alone.[[compression-of-morbidity|compressed morbidity]] rather than to lifespan alone. The most-quoted result is negative. On self-reported alcohol use, physical activity, diet and bodyThe most-quoted result is negative. On self-reported alcohol use, physical activity, diet and bodyweight, the people in the cohort who had passed 95 looked no more virtuous than a general-populationweight, the people in the cohort who had passed 95 looked no more virtuous than a general-populationsample from their own birth cohort.[^rajpathak2011] The finding says that in this population extremesample from their own birth cohort.[^rajpathak2011] The finding says that in this populationlongevity is not explained by behaviour; it does not say that behaviour is irrelevant to ordinary lifespan, andbehaviour does not explain extreme longevity. It does not say that behaviour is irrelevant toBarzilai has been careful in print to keep the two apart. The distinction is routinely lost inordinary lifespan, and Barzilai has been careful in print to keep the two apart. Popular coveragepopular coverage, where the result is read as licence to ignore the evidence behindroutinely loses the distinction, where the result is read as licence to ignore the evidence behind[[exercise-and-aging|exercise]], and it sits awkwardly beside the lifestyle-first framing of[[exercise-and-aging|exercise]], and it sits awkwardly beside the lifestyle-first framing of[[blue-zones|long-lived population studies]].[[blue-zones|long-lived population studies]]. The genetic findings are associations, and are described here as such. A variant of the cholesteryl ester transfer protein gene, CETP, was over-represented among theThe genetic findings are associations, and are described here as such. A variant of the cholesteryllong-lived, and carriers had larger high- and low-density lipoprotein particles.[^barzilai2003]ester transfer protein gene, CETP, was over-represented among the long-lived, and carriers had largerhigh- and low-density lipoprotein particles.[^barzilai2003]Functionally significant mutations in the insulin-like growth factor 1 receptor were later reportedFunctionally significant mutations in the insulin-like growth factor 1 receptor were later reportedas enriched among centenarian women, connecting the human cohort to the insulin and IGF-1 signallingas enriched among centenarian women, connecting the human cohort to the insulin and IGF-1 signallingaxis that governs lifespan in nematodes and mice, the pathway opened byaxis that governs lifespan in nematodes and mice, the pathway opened bylines 106–113 → 106–11410 unchanged lines not shown
### From variant to drug### From variant to drug The CETP story shows how far an association sits from a therapy. Pharmaceutical companies pursued CETP inhibition hard on the strength of its lipid biology. TheThe CETP story shows how far an association sits from a therapy. Pharmaceutical companies pursuedfirst such drug to reach a large outcome trial, torcetrapib, raised HDL cholesterol and also raisedCETP inhibition hard on the strength of its lipid biology. The first such drug to reach a largeoutcome trial, torcetrapib, raised HDL cholesterol and also raisedmortality, and the trial was stopped.[^barter2007] Later compounds in the class were safer and didmortality, and the trial was stopped.[^barter2007] Later compounds in the class were safer and didlittle; none became a longevity drug. The inference that a variant carried by long-lived peoplelittle; none became a longevity drug. The inference that a variant carried by long-lived peoplenames a druggable target has not held.names a druggable target has not held.lines 127–135 → 128–13613 unchanged lines not shown
unrelated age-related events.[^barzilai2016] The design and the evidence behind the drug are set outunrelated age-related events.[^barzilai2016] The design and the evidence behind the drug are set outunder [[metformin]].under [[metformin]]. The composite is the substance of the proposal. Regulators approve drugs for diseases, and there isThe composite endpoint is the core of the proposal. Regulators approve drugs for diseases, and thereno approval pathway for aging, so a drug that modestly delayed several conditions at once would failis no approval pathway for aging, so a drug that modestly delayed several conditions at once wouldevery existing trial design while doing exactly what geroscience predicts. US regulators met thefail every existing trial design while doing exactly what geroscience predicts. US regulators met theinvestigators in the mid-2010s and indicated that such an endpoint could be acceptable in principle.investigators in the mid-2010s and indicated that such an endpoint could be acceptable in principle.A related workgroup Barzilai convened set out which blood-based [[aging-biomarkers|biomarkers]] aA related workgroup Barzilai convened set out which blood-based [[aging-biomarkers|biomarkers]] ageroscience trial should collect, an attempt to build the measurement infrastructure such angeroscience trial should collect, an attempt to build the measurement infrastructure such anlines 139–152 → 140–1543 unchanged lines not shown
The trial has never been fully funded. Metformin is generic, so no sponsor can recover a budget inThe trial has never been fully funded. Metformin is generic, so no sponsor can recover a budget inthe tens of millions of dollars from sales, and public money has arrived in amounts far short ofthe tens of millions of dollars from sales, and public money has arrived in amounts far short ofwhat a multi-centre outcome trial costs. That the field's most discussed trial has gone a decadewhat a multi-centre outcome trial costs. The field's most discussed trial has gone a decade withoutwithout enrolling, through years of fundraising, is itself a substantive fact: the interventionsenrolling, through years of fundraising. That is itself informative: the interventions cheap enoughcheap enough to give to everyone are the ones nobody owns.to give to everyone are the ones nobody owns. ## Reception## Reception Barzilai is taken seriously as a clinician-scientist and is among the field's most effectiveBarzilai is taken seriously as a clinician-scientist and is among the field's most effectiveadvocates with funders and regulators. The criticism is aimed at the vehicle rather than the design.advocates with funders and regulators. Criticism is aimed at the choice of drug rather than at thetrial design.Metformin's geroprotective evidence in people without diabetes is weak, resting largely onMetformin's geroprotective evidence in people without diabetes is weak, resting largely onobservational comparisons vulnerable to confounding by indication; the US National Institute onobservational comparisons vulnerable to confounding by indication; the US National Institute onAging's Interventions Testing Program has not reported a lifespan extension from metformin inAging's Interventions Testing Program has not reported a lifespan extension from metformin inlines 164–195 → 166–19711 unchanged lines not shown
> result usable everywhere.> result usable everywhere. His public framing is more restrained than that of several contemporaries. He argues for delayingHis public framing is more restrained than that of several contemporaries. He argues for delayingthe onset of disease and extending [[healthspan]] rather than for indefinite lifespan, a positionthe onset of disease and extending [[healthspan]] rather than for indefinite lifespan. The positionwell short of [[longevity-escape-velocity|escape-velocity]] claims of the kind associated withstops well short of [[longevity-escape-velocity|escape-velocity]] claims of the kind associated with[[aubrey-de-grey]], and unaccompanied by the supplement advocacy that has drawn criticism onto[[aubrey-de-grey]], and he does not engage in the supplement advocacy that has drawn criticism onto[[david-sinclair]]. Colleagues who reject the drug rarely reject the framing, which is part of why[[david-sinclair]]. Colleagues who reject the drug rarely reject the framing, which is part of whythe proposal keeps a hearing.the proposal keeps a hearing. ## Legacy## Legacy The design has outlasted the effort to pay for it. Composite age-related endpoints, offspring-of-centenarianThe design has outlasted the effort to pay for it. Composite age-related endpoints,cohorts, and the language of the [[longevity-dividend]] — the economic argument that delaying agingoffspring-of-centenarian cohorts, and the language of the [[longevity-dividend]] (the economicreturns more than curing any single disease — now appear routinely in geroscience proposals.argument that delaying aging returns more than curing any single disease) now appear routinely inAging-biology centres such as the [[buck-institute]] frame their work as one upstream target withgeroscience proposals. Aging-biology centres such as the [[buck-institute]] frame their work as onemany diseases downstream, and the [[xprize-healthspan]] competition defines winning as functionupstream target with many diseases downstream, and the [[xprize-healthspan]] competition definesrestored across several domains rather than one disease improved.winning as function restored across several domains rather than one disease improved. His insistenceHis insistence that regulatory acceptance, not molecular novelty, is the binding constraint is nowthat the binding constraint is regulatory acceptance rather than molecular novelty is now close toclose to consensus among people who want geroprotectors deployed rather than discussed, and itconsensus among people who want geroprotectors deployed rather than discussed, and it shapes howshapes how [[senolytics]] and other candidate classes plan their trials.[[senolytics]] and other candidate classes plan their trials. The counterfactual is instructive. While TAME waited, the [[glp-1-receptor-agonists]] accumulatedThe [[glp-1-receptor-agonists]] offer a comparison. While TAME waited, they accumulated largelarge randomized outcome data across weight, cardiovascular, and kidney endpoints in adults withrandomized outcome data across weight, cardiovascular, and kidney endpoints in adults with obesityobesity or diabetes, because a patented class had sponsors who could pay. Whether those results sayor diabetes, because a patented class had sponsors who could pay. Whether those results say anythinganything about aging as such is unsettled, but they show how multi-organ evidence actually getsabout aging as such is unsettled, but they show how multi-organ evidence actually gets produced, andproduced, and it is not the route TAME was designed to take.it is not the route TAME was designed to take. Barzilai's career leaves a question that goes beyondThe open question Barzilai's career poses is not whether the [[hallmarks-of-aging]] describe awhether the [[hallmarks-of-aging]] describe a shared biology: whether a public good with no ownershared biology. It is whether a public good with no owner can be tested at all, andcan be tested at all, and [[access-and-inequality|who is left out]] if the answer arrives only[[access-and-inequality|who is left out]] if the answer arrives only through drugs someone can sell.through drugs someone can sell. ## See also## See also removed, struck through added, underlinedLine numbers count the serialised markdown of each revision, frontmatter included.
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