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CHAPTERS
- 0:04 – 8:20
Intro and Barzilai's path into aging research
Peter Attia introduces Nir Barzilai and previews topics including metformin, TAME, insulin resistance, IGF/GH, centenarians and NAD. Barzilai describes his Israeli background, his early metformin work at Yale, and a childhood interest in aging sparked by his grandfather.
- •Barzilai directs the Institute for Aging Research and leads the TAME trial
- •He studied metformin's mechanism at Yale in 1987 before its US approval
- •Childhood time with his grandfather sparked his interest in biological versus chronological age
- •He chose endocrinology because he assumed hormonal changes drive aging, though he did not see hormone replacement as the answer
- 8:20 – 12:02
Skepticism about hormone replacement and the WHI
Attia asks about hormone changes with aging, and Barzilai explains why he doubted the Women's Health Initiative premise. He notes that men age too without a dramatic estrogen drop, and that estrogen helped young animals but worsened stroke outcomes in old ones.
- •Men age similarly to women without an estrogen-style hormone decline
- •Replacing one hormone among many seemed a poor study design to Barzilai
- •Animal stroke studies found estrogen helped young animals but harmed old ones
- •Attia criticizes the WHI's oral conjugated estrogen and synthetic progestin protocol
- 12:02 – 21:28
Metformin's history, FDA delay, and mechanism of action
Barzilai explains why metformin reached the US so late despite decades of use in Europe, and why he thinks it might not be approved today. They discuss its hepatic glucose action, phenformin, the French lily origin, and lactic acidosis.
- •The FDA required new phase III trials, so metformin came to the US long after Europe
- •Barzilai showed in humans that it mainly lowers hepatic glucose production
- •Phenformin was more potent but caused more lactic acidosis because it does not need a transporter
- •Barzilai views metformin-associated lactic acidosis as largely an association with kidney failure or heart attacks
- 21:28 – 34:58
What insulin resistance really means
Attia admits confusion about insulin resistance, and Barzilai reframes it with the daf-2 worm paper and his rat visceral fat removal experiments. He argues insulin resistance can be a protective stress response, which explains why it extends life in some models and shortens it in others.
- •Barzilai says metformin's diabetes properties may not be its aging properties
- •Reducing the insulin receptor in nematodes extended life despite fat accumulation
- •Removing visceral fat in rats extended lifespan about 20%, versus more for caloric restriction
- •Muscle insulin resistance may protect against nutrient overload
- •Rapamycin causes insulin resistance, while PTP1B-type models are insulin sensitive yet short-lived
- 34:58 – 49:25
Glucose uptake, hepatic insulin sensitivity, and hyperinsulinemia
Attia and Barzilai walk through GLUT4 translocation, non-insulin-mediated glucose uptake, and brain control of liver metabolism. They discuss how clinicians define insulin resistance, hyperinsulinemia in a glucose tolerance test, and why the liver is more insulin sensitive than muscle.
- •Insulin drives GLUT4 translocation in muscle, while the liver uses GLUT2 driven largely by gradient
- •Non-insulin-mediated glucose uptake exists and is exercise-dependent
- •The hypothalamus can control peripheral insulin action through nerves such as the vagus
- •Clinically, insulin resistance is defined by insulin's ability to clear glucose
- •Elderly people can suppress hepatic glucose production at low insulin but fail at muscle uptake after meals
- 49:25 – 57:46
Origins of metformin as an aging drug: the UK mortality study
Barzilai recounts early rodent work on metformin and the UK database study that convinced him to pursue a trial. Metformin users with diabetes had 17% lower mortality than non-diabetic matched controls, while sulfonylurea users had much higher mortality. Attia describes his own finding of less cancer in metformin users.
- •Anatoly Asimov's rodent studies found metformin extended lifespan about 10% and improved healthspan
- •The UK study matched 78,000 metformin users with 78,000 non-diabetic controls
- •Metformin users had 17% lower mortality despite being sicker
- •Hundreds of studies link metformin with fewer cancers, with prostate cancer the exception
- 57:46 – 1:11:52
Designing TAME: FDA hurdles, composite outcomes, and funding
Barzilai explains TAME's goal of getting the FDA to recognize aging as an indication. They cover why metformin was chosen over rapamycin, FDA resistance to diabetes as an endpoint, the composite outcome design, NIH reviewer pushback, and the funding picture.
- •TAME stands for Targeting Aging with Metformin and aims to establish an aging indication
- •The FDA was not interested in diabetes as an outcome
- •The study uses a composite of age-related diseases and mortality rather than single-disease trials
- •NIH reviewers in disease silos pushed for separate studies, which would have raised the budget
- •Half of the roughly $70 million is raised via AFAR philanthropy, with NIH institutes contingent
- 1:11:52 – 1:16:27
TAME logistics: enrollment, dose, and power
Barzilai gives the practical details of the planned trial, including centers, subjects, age range, dose, and power assumptions. He also explains why it is US-only and why the study should not be stopped early for a single effect.
- •14 US centers, 3,000 subjects aged 65 to 80, randomized one to one
- •Dose is 1,500 mg, with metformin supplied by Merck
- •The study is powered at 90% for a 22% effect, below the roughly 30% seen in preliminary data
- •A six-year grant allows flexibility to finish in four to six years
- •Start was expected in early 2019
- 1:16:27 – 1:28:03
How metformin may act on the pillars of aging
Barzilai walks through metformin's cellular mechanisms, including OCT1 uptake, complex I inhibition, AMPK and mTOR, autophagy, and epigenetic effects. He argues many measured effects may be secondary to aging being slowed, and calls metformin a tool to prove aging can be targeted.
- •Metformin enters cells via OCT1 and binds mitochondrial complex I
- •Some effects are AMPK-dependent and some are not, including histone deacetylation effects in cells without mitochondria
- •Downstream effects include lower mTOR activity, more autophagy, less ROS and less inflammation
- •Barzilai says many measured changes may be secondary to fixing aging
- •He calls metformin a tool, expecting better and combination drugs in the future
- 1:28:03 – 1:34:16
Centenarians: compressed morbidity and genetics
Attia and Barzilai discuss how centenarians get a healthspan bonus and die quickly, with lower end-of-life costs. Barzilai explains why centenarian phenotypes are hard to interpret and describes his study of their offspring, and the genetic variants found, including the surprising number of pathogenic mutations.
- •Centenarians experience compression of morbidity, and the CDC found end-of-life costs after 100 are about a third of those at 70
- •Centenarian phenotypes may reflect markers of imminent death, so Barzilai studies their offspring
- •The offspring have about half the diseases of controls and appear to age slower
- •44 centenarian genomes carried over 230 mutations expected to cause disease, including APOE4 in two people
- •Longevity genes may protect against bad genotypes via gene-to-gene interaction
- 1:34:16 – 1:55:18
Growth hormone/IGF genetics and sex differences
Barzilai describes the centenarian findings in the growth hormone/IGF axis, including IGF receptor mutations, a growth hormone receptor exon 3 deletion, and microRNA-142. He stresses that effects differ between women and men, and that IGF-1 levels were not associated with muscle function.
- •Low IGF-1 was linked to longer survival in female centenarians but not males
- •IGF receptor mutations occurred in about 2% of centenarians and the growth hormone receptor exon 3 deletion in 12%
- •About 30% of centenarians show overexpressed microRNAs targeting IGF receptor signaling, and 22% carry FOXO3A mutations
- •Aging research neglected sex differences by studying males only
- •GWAS single-SNP analysis is limited; pathway-based analysis is needed
- 1:55:18 – 2:05:30
CETP, Lp(a), and the puzzle of protective genotypes
The conversation turns to why Lp(a) genotype concentrates in centenarians. Barzilai explains that cross-sectional patterns and gene-to-gene interactions suggest it is protected by the CETP VV longevity genotype, and Attia questions the logic and the lack of an HDL function assay.
- •Lp(a) genotype declines until about 80 then rises in centenarians
- •Barzilai's analysis suggests Lp(a) carriers who reach 100 were mostly CETP VV
- •CETP VV carriers have higher HDL, larger particles, lower CETP, and cognitive protection
- •Attia wonders whether virulent and non-virulent Lp(a) phenotypes exist
- •No available HDL functional assay limits interpretation
- 2:05:30 – 2:21:47
Growth hormone, IGF receptor antibody, and fasting
Attia asks whether exogenous growth hormone is helpful or harmful. Barzilai describes a new Nature paper in which an IGF receptor antibody improved healthspan and extended lifespan in old female mice, and says the data suggest growth hormone is not beneficial in elderly women. They then discuss fasting, IGF, and autophagy timing in humans.
- •The IGF receptor antibody extended lifespan about 10% and improved healthspan in female mice
- •Males showed no clear benefit and had increased inflammatory markers
- •Barzilai thinks growth hormone treatment is likely dangerous for elderly women but is unsure for men
- •Caloric restriction trials in humans did not lower IGF-1 while rodent studies were effectively intermittent fasting
- •Barzilai's group aims to establish the timeline of autophagy in humans
- 2:21:47 – 2:29:35
Human metformin biopsy study and weight loss
Barzilai describes a small crossover study in which 15 older adults received metformin and placebo with muscle and fat biopsies. Transcript changes included non-metabolic aging-related genes and upstream regulators like AMPK and mTOR. Attia and Barzilai also discuss metformin-associated weight loss.
- •Washout was likely too short, so those who took metformin first showed carryover effects
- •Transcript changes were tissue-specific, including DNA repair genes such as BRCA1
- •Upstream regulators pointed back to AMPK and mTOR
- •Attia describes his dosing approach and the variability of weight loss
- 2:29:35 – 2:47:45
NAD precursors, remaining metformin thoughts, and where they could be wrong
Barzilai gives a cautious view of NR and NMN, citing the Rabinowitz tracer paper's critics and his own anecdotal sleep changes. He then reflects on public enthusiasm for metformin, the Vatican talk, the need for TAME evidence, and where the field could be wrong.
- •Barzilai says that without well-controlled clinical studies, NAD precursor claims remain uncertain
- •He reports better deep sleep and REM on NMN but calls it anecdotal
- •Half of a lay audience of non-diabetics said they took metformin, which worries him for the trial
- •Barzilai stresses that TAME is needed because metformin's benefits are not yet shown in a clinical trial
- •He admits most pillar-of-aging data come from animals but believes aging's universality supports the approach
