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Peter Attia MD#27 – David Sinclair, Ph.D.: Slowing aging – sirtuins, NAD, and the epigenetics of aging
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CHAPTERS
- 0:04 – 7:37
Episode Intro and Guest Background
Peter Attia introduces Professor David Sinclair and the topics ahead: sirtuins, resveratrol, NAD and its precursors. He also mentions a paper on oral NAD precursors that he learned about only after the recording.
- •Sinclair's role at Harvard and his work on sirtuins and sirtuin activators
- •Resveratrol's rise to fame and the grape and wine connection
- •NAD, NR and NMN will be covered
- •Sinclair openly discusses what he takes himself
- •His book is due next year
- 7:37 – 15:18
From Australia to Lenny Guarente's Lab at MIT
Sinclair explains his lifelong interest in aging and how he came to join Lenny Guarente's lab. He recounts finding his own funding, the interview with Doug Melton, and early doubts from other postdocs.
- •Interest in aging began in early childhood and grew with new genetic technology
- •Met Guarente at a dinner in Australia and asked to join his lab
- •Had to bring his own funding; sold his car to fly to an interview
- •Postdocs warned him that studying aging in yeast was a mistake
- •Considered quitting but persisted
- 15:18 – 20:58
Discovering SIR2: Gene Silencing and Aging in Yeast
Sinclair describes the SIR genes Lenny's lab was studying and how a gene-silencing complex turned out to relate to aging. He explains the sterility marker in old yeast and how SIR2 gets distracted by DNA repair.
- •SIR stands for silent information regulator, an unexpected link to aging
- •Sterility is a hallmark of aged yeast cells
- •SIR2 moves away from silencing duty to help repair broken chromosomes
- •Sirtuins act on non-histone proteins in the cytoplasm, nucleus and mitochondria
- 20:58 – 25:37
Yeast Experiments: Werner Syndrome, rDNA and Sirtuin Overexpression
Sinclair walks through the experiments showing where SIR proteins go in aging cells. These include the rDNA in the nucleolus, the SGS1 premature aging model, and Matt Kaeberlein's overexpression result that extended lifespan.
- •SIR proteins relocate to the nucleolus and rDNA during aging
- •SGS1 mutants, a Werner syndrome model, give accelerated aging for study
- •DNA breaks at the unstable rDNA distract the SIR complex
- •Extra sirtuin extends yeast lifespan
- 25:37 – 32:34
Sirtuins, Calorie Restriction and Evolutionary Conservation
The conversation turns to how sirtuins relate to calorie restriction and why the two might go together. Sinclair describes sirtuins as ancient stress sensors that help organisms survive adversity and says the pathway is conserved across species.
- •Sirtuins appear necessary and sufficient to mimic calorie restriction
- •The sirtuin family can compensate when one member is knocked out
- •Sirtuins evolved to sense stress and help organisms survive
- •Longevity pathways are conserved from yeast to mammals
- 32:34 – 38:48
Moving to Harvard and the NAD Connection
Sinclair explains why he stayed in Boston and the three major 1999 developments. One of these was the finding that NAD is required for sirtuin activity. They discuss NAD levels and the mitochondrial oasis hypothesis.
- •Chose Boston over returning to Australia
- •1999 brought the DNA repair link, the NAD requirement and the calorie restriction link
- •NAD levels vary with age, diet and circadian rhythm
- •PARP1 depletes NAD after DNA damage
- •Mitochondrial NAD proved especially important for cell survival
- 38:48 – 49:41
PNC1, Nicotinamide Inhibition and the Path to Resveratrol
Sinclair describes his early work on boosting NAD in yeast, including the finding that high-dose nicotinamide inhibits sirtuins. He then tells how a collaboration with Biomol led to the discovery of sirtuin-activating plant molecules and resveratrol.
- •Lenny asked him not to work on sirtuins for a year after he left
- •Nicotinamide inhibits sirtuins through negative feedback
- •PNC1 is upregulated by calorie restriction and other stresses
- •Biomol's assay found plant molecules that activated SIRT1
- •Resveratrol's structure resembled the first hits, and it was tested in yeast, worms and flies
- 49:41 – 57:00
The 2006 Mouse Study and Resveratrol Dosing
They discuss the 2006 Nature mouse paper, its results in overfed and lean mice, and the dose and absorption issues. Sinclair explains why later ITP studies in regular food did not show lifespan extension.
- •The 2006 paper brought resveratrol global attention
- •Lifespan gains in mice on a Western diet; lean mice benefited only with every-other-day feeding
- •High doses also activate AMPK, which complicates interpretation
- •Resveratrol is poorly soluble and absorbed better with fat
- •Later ITP studies gave it in regular food and found no extension
- 57:00 – 1:00:12
Resveratrol Clinical Trials and Sinclair's Personal Regimen
Sinclair describes why resveratrol was treated as a proof-of-concept molecule and how pharma moved on to more potent compounds. He explains his own use of resveratrol and low-dose metformin and how he thinks about dosing.
- •Resveratrol was seen as a poor drug candidate at micromolar potency
- •A large pharma company deprioritized it after a trial with renal failure in cancer patients
- •Newer, more potent molecules worked in mice on regular diets
- •Takes about a gram of resveratrol with fat and metformin at a low dose, recently raised
- •Says pathway overlap means combinations call for caution
- 1:00:12 – 1:14:59
NR, NMN and the Supplement Landscape
They discuss over-the-counter NR products and the race among pathways. Sinclair also covers NR versus NMN, how each raises NAD, and the difficulty of measuring tissue NAD in humans.
- •Pterostilbene is a methylated version of resveratrol
- •Sinclair and Lenny have taken different routes: pharmaceuticals versus supplements
- •NR converts to NMN, which converts to NAD
- •Whether NMN is transported into cells is debated
- •MRS and tracer studies are planned to see where NAD goes in tissues
- 1:14:59 – 1:19:42
Drug Development: Fertility, Life Biosciences and Name Misuse
Sinclair describes the NAD-related work in his companies, including fertility trials based on the BubR1–SIRT2 pathway. He also describes Life Biosciences and unauthorized use of his name on products.
- •MetroBiotech is making better NAD precursors
- •NAD precursors improve egg quality in animals by acting on spindle quality
- •IVF clinic trials are planned for next year
- •Life Biosciences groups eight aging-focused companies
- •No over-the-counter product with his name is endorsed by him
- 1:19:42 – 1:24:01
Hallmarks of Aging and the Epigenetic Information Theory
Sinclair lists the hallmarks of aging and then presents his unifying idea, not yet published. The genome is digital and stays intact, while analog epigenetic information is lost over time, partly because sirtuins are distracted by DNA break repair.
- •Hallmarks include epigenetic change, senescence, protein misfolding, telomere loss and nutrient signaling
- •Old genomes remain largely intact, but gene expression patterns degrade
- •Waddington's landscape: cells lose identity as they jump between valleys
- •Repeated DNA break responses disrupt chromatin and antagonistic pleiotropy is invoked
- •Sinclair thinks the information is still there to be accessed
- 1:24:01 – 1:33:50
Future Outlook: Human Trials and Combined NMN-Sirtuin Results in Old Mice
Attia asks how confident Sinclair is about step-change longevity gains, and Sinclair describes an ideal human trial. He also shares unpublished data on NMN in very old mice and on combining NMN with extra sirtuin genes, and explains his focus on NAD.
- •Sinclair is increasingly confident of major advances
- •A trial of about 5,000 people over three to four years could show a change in mortality
- •NMN extended lifespan in mice started very late in life
- •Adding all seven sirtuin genes plus NMN gave additive effects
- •Focus on NAD is to activate all seven sirtuins
- 1:33:50 – 1:41:31
Mortality, Family, the Book and Closing
Sinclair explains how he first learned about death and how he talked about it with his own children. The conversation ends with his book, social media and the shared struggle of finishing a book amid new findings.
- •His honest grandmother Vera first made him aware of death
- •Children typically grasp death between ages four and seven and then suppress it
- •His eldest daughter was distressed when he told her he would die
- •He is on Twitter and LinkedIn; the book comes out in 2019
- •Both hosts and guest relate to the pull to keep updating a book
