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Peter Attia MD#70–David Sinclair, PhD: How cellular reprogramming could slow our aging clock, & the latest on NAD
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CHAPTERS
- 0:04 – 9:10
Why the show runs no ads and what this episode covers
Peter Attia explains his subscriber-support model instead of ads, then introduces David Sinclair's return to the show. He outlines the episode: the information theory of aging, Sinclair's new book, and an update on NAD and NR.
- •Attia avoids ads because of trust and because he can't enthuse about things he isn't passionate about
- •Members get exclusive show notes, AMA access and discounts on products he already likes
- •The episode is timed to Sinclair's book release
- •Topics include the information theory of aging and recent NAD/NR papers
- 9:10 – 14:34
Shannon, sirtuins and the information theory of aging
Attia asks why mathematician Claude Shannon matters to aging. Sinclair explains how SIR genes silence other genes, leave to repair DNA breaks, and over time lose the cell's identity, mapping this onto Shannon's idea of a backup "observer".
- •SIR stands for Silent Information Regulator and the gene extends yeast lifespan
- •Repeated DNA repair pulls SIR proteins away, so cells lose their gene on/off program
- •Sinclair uses a Hurricane Katrina first-responder analogy
- •Shannon's idea of a backup copy suggests information can be restored
- 14:34 – 23:56
Epigenetics, methylation and the Waddington landscape
Attia asks for a primer on gene silencing and methylation. Sinclair explains how DNA spooling and methyl groups fix cell identity, using Waddington's hills-and-valleys metaphor, and describes aging as loss of that pattern, like entropy or noise.
- •Different cell types share the same DNA but turn on different genes
- •DNA methylation is the deepest layer of silencing
- •Waddington's landscape: cells roll into valleys but get jostled up over hills with age
- •Sinclair argues a backup of the youthful methylation pattern still exists in cells
- 23:56 – 33:11
The Horvath methylation clock and how telomeres compare
The two discuss how methylation patterns work as a clock, like carbon dating for cells. Sinclair describes Horvath's machine-learning-built clock, its universality, and how lifestyle shifts it, and contrasts it with telomere length.
- •Methylation age tracks chronological age and is shaped by lifestyle
- •Exercise and calorie restriction slow the clock while smoking speeds it
- •Telomeres can change within days, as in the twin astronaut study, making them a weaker clock
- •Horvath's clock matched medical records of smoking better than patients' own recall
- 33:11 – 41:44
Partial reprogramming and the epigenetic backup copy
Sinclair explains partial reprogramming with Yamanaka genes, which resets cells without erasing identity. He says the backup information seems to be intrinsic to each cell, and describes the epigenome in three levels that standard interventions barely reach.
- •Full reprogramming makes stem cells and can cause tumors or death in mice
- •Partial reprogramming restores youthful gene expression while keeping cell identity
- •Sinclair uses the checksum and observer analogy to describe cellular backup
- •Rapamycin, NAD boosters and metformin slow the clock but don't appear to reverse it
- 41:44 – 51:13
Restoring vision in mice with reprogramming
Sinclair describes the retina experiments: an AAV carrying three Yamanaka genes with a doxycycline switch, tested on crushed optic nerve, glaucoma and aged mice. Genes that changed with age were pushed back toward their young levels.
- •cMyc was left out and proved unnecessary
- •Doxycycline controls the on/off switch and the genes were turned on after damage
- •Optic nerves regenerated and vision returned in glaucoma and old mice
- •Hundreds of genes, including odd olfactory receptors, reverted toward youthful expression
- 51:13 – 1:02:52
Gene therapy delivery, safety and the path to human trials
Attia raises the delivery challenge and past gene therapy setbacks. Sinclair explains why the eye is a good first target, the bottleneck of making enough virus, the state of gene therapy and its high prices, and the plan for a clinical trial.
- •The limit is getting the virus into enough cells; AAVs favor the liver
- •The eye is immune-protected and already has approved viral drugs
- •Virus manufacturing is the main obstacle to a phase two eye trial
- •One-shot gene therapies cost high hundreds of thousands, prompting new payment models
- 1:02:52 – 1:14:53
Using the clock to guide interventions and senescent cells
Attia asks whether methylation clocks could measure the effect of fasting, exercise and rapamycin. They then turn to senescent cells, which Sinclair describes as zombie cells that stress their neighbors and may not be reversible by reprogramming.
- •Annual or six-monthly methylome tests could track rate of change
- •Sinclair and Horvath doubted the science was ready to say which supplements fix the clock
- •Senescent cells secrete signals that disrupt neighboring cells' epigenomes
- •Beta-galactosidase staining shows senescent cells accumulating in older fat
- •Whether reprogramming reverses senescence is the next experiment in his lab
- 1:14:53 – 1:29:24
Can reprogramming extend life to 100 and beyond?
Attia probes whether reprogramming will be organ-specific or global and whether it could make lifestyle effort unnecessary. Sinclair discusses vector options, information loss limits, optionality of future technology, and debate over maximum lifespan.
- •A first eye clinical trial is hoped for within about eighteen months
- •Dozens of AAV variants target different tissues
- •Sinclair says he thought extending life far beyond 100 was impossible three years ago
- •Maximum lifespan has not risen even as average lifespan in leading countries has
- 1:29:24 – 1:33:52
Pulsing stress: metformin, rapamycin and Sinclair's habits
Attia asks how Sinclair reads papers suggesting metformin may blunt exercise benefits. Sinclair describes pulsing biological stress and how he adjusted his own metformin timing, and mentions rapamycin and resveratrol use.
- •Metformin mildly inhibits mitochondria, which may interfere with post-exercise adaptation
- •Sinclair says to pulse stress and allow recovery, such as skipping metformin on intense exercise days
- •He takes metformin on travel days and takes rapamycin only experimentally
- •He takes a gram of resveratrol each morning with yogurt
- 1:33:52 – 1:40:04
Resveratrol and the SIRT1 mutation mouse
The conversation covers whether resveratrol is still worth taking and Sinclair's unpublished mouse experiment. A mutation blocking resveratrol's activation of SIRT1 was put into mice to test which of its benefits depend on that enzyme.
- •The ITP found no lifespan extension in healthy mice on a lean diet
- •Sinclair's lab saw 20–30% extension in mice on a poor diet at two doses
- •The mutated SIRT1 mouse is resistant to resveratrol
- •Sinclair says the data show resveratrol extends lifespan by activating SIRT1
- 1:40:04 – 1:46:16
NAD basics and whether NAD boosting helps
Attia explains why he gets so many NAD questions. Sinclair describes NAD as fuel for sirtuins, why benefits may show mainly in unhealthy or older subjects, and why IV NAD is less supported than oral precursors like NR.
- •NAD is essential for sirtuin activity and was long seen as a boring molecule
- •Benefits appear largest in obese, diseased or older animals
- •In mice, NAD boosters improved running only when combined with exercise
- •IV NAD is poorly studied and NAD may need to be broken down before entering cells
- 1:46:16 – 1:57:49
NR, NMN and the debate over absorption
They go through how NR converts to NAD and why nicotinamide may inhibit sirtuins. They then debate the Rabinowitz tracer study versus a new bioRxiv human trial, plus gut microbiome effects and sublingual delivery.
- •NR becomes NMN then NAD; nicotinamide can inhibit sirtuins
- •The Rabinowitz mouse study suggested NR is mostly converted in the liver
- •A preprint at 1,000 mg of NR raised muscle NAD in humans but with little mitochondrial benefit
- •Sinclair says the gut microbiome may strip nicotinamide before uptake
- •Sinclair says what matters is whether it works in humans
- 1:57:49 – 2:05:18
Clinical evidence, ITP trials and next-generation NAD prodrugs
They discuss the pending ITP study of NR, an ALS trial of NR with pterostilbene, and the idea that benefits appear in stressed populations. Sinclair describes his lab's NAD-booster prodrugs, now in phase one at Brigham and Women's Hospital.
- •The ITP study of NR is not yet out and Sinclair wasn't consulted on dosing
- •The ALS study showed improvements but was small and combined NR with pterostilbene
- •Pterostilbene is chemically similar to resveratrol, with no data showing it is superior
- •Sinclair's prodrugs aim to improve absorption and avoid gut breakdown
- •Companies target rare diseases with unmet need for funding reasons
- 2:05:18 – 2:10:14
Sinclair's book illustrations and closing remarks
Attia asks about the drawings in Sinclair's book. Sinclair explains his art background and the rush to draw 28 original faces after legal advice. They close by praising the book's fresh take on aging.
- •Sinclair drew the illustrations himself as a hobby
- •Publisher's lawyers required original art, so he drew 28 faces in 28 days
- •Drawings are viewable on lifespanbook.com
- •Sinclair calls the information theory of aging a new way of looking at aging
