#27 - David Sinclair, Ph.D.: Slowing aging – sirtuins, NAD, and the epigenetics of aging
In this episode, David A. Sinclair, Ph.D., a Professor in the Department of Genetics at Harvard Medical School and co-Director of the Paul F. Glenn Center for the Biological Mechanisms of Aging, discusses why we age and strategies to slow its effects. He delves into the role of sirtuins and NAD in health and aging, and presents a unifying theory centered on stabilizing the epigenetic landscape.
Deep Dive Analysis
14 Topic Outline
David Sinclair's Path to Studying Aging at MIT
The Discovery and Early Understanding of Sirtuins
SIRT2's Role in DNA Repair and Accelerated Aging Models
Evolutionary Purpose of Sirtuins and Caloric Restriction Connection
NAD's Critical Role in Sirtuin Activity and Mitochondrial Function
Nicotinamide's Inhibitory Effect and PNC1's Activation of Sirtuins
The Serendipitous Discovery of Resveratrol as a Sirtuin Activator
Resveratrol's Effects in Mice and Challenges in Human Trials
David Sinclair's Personal Longevity Regimen and Rationale
Understanding NAD Precursors: NR, NMN, and Pterostilbene
NAD Precursors' Potential in Enhancing Female Fertility
A Unifying Theory of Aging: Epigenetic Information Loss
Ideal Human Longevity Experiment and Late-Life Interventions
Additive Effects of Combining Sirtuin Genes and NMN
6 Key Concepts
Sirtuins
Sirtuins are a class of protein deacetylases (formerly HDACs) that play a protective role in responding to energy and nutrients. They are involved in gene silencing and DNA repair, and their activity is dependent on NAD.
Gene Silencing
Gene silencing is the process by which certain genes are turned off, controlled by proteins like sirtuins. In yeast, this process is linked to mating type and sterility, and its disruption can lead to hallmarks of aging.
Mitochondrial Oasis Hypothesis
This hypothesis suggests that as long as mitochondria maintain active NAD levels, a cell can survive and recover from stress, even if cytoplasmic NAD is depleted. Mitochondrial NAD levels are considered even more important than cytoplasmic NAD levels for cell survival.
Epigenetic Information
Epigenetic information refers to the analog pattern of gene expression (which genes are turned on and off) inherited from parents. This information is thought to degrade over time during aging, causing cells to lose their identity as they no longer read the correct genes at the right time.
Waddington's Epigenetic Landscape
An analogy describing cell differentiation and identity, where cells are like marbles rolling down a mountainscape into different valleys representing distinct cell types. In aging, the 'noise' of epigenetic information loss causes these 'marbles' to jump into different valleys, leading to cells losing their proper identity and function.
Antagonistic Pleiotropy
This evolutionary concept suggests that traits beneficial early in life can become detrimental later. In aging, the cell's stress response (e.g., sirtuins repairing DNA breaks) is crucial when young but can disrupt chromatin structure over decades, leading to the loss of epigenetic information.
10 Questions Answered
Sirtuins are a class of protein deacetylases that play a protective role in response to energy and nutrients. They are involved in gene silencing and DNA repair, and their activity is dependent on NAD.
The connection was discovered through genetic studies in yeast, where a gene called SIR2 (a sirtuin) was found to control gene silencing and, when overexpressed, extended lifespan, while its knockout led to accelerated aging.
Sirtuins are NAD-dependent deacetylases, meaning they require NAD to function. NAD levels fluctuate with age and stress, influencing sirtuin activity, and maintaining mitochondrial NAD levels is crucial for cell survival.
Caloric restriction activates sirtuins, and sirtuins are necessary for many of the benefits of caloric restriction, including lifespan extension. This suggests sirtuins are key mediators of the body's response to nutrient scarcity.
Resveratrol is a plant molecule, famously found in red wine, that was discovered to be an allosteric activator of SIRT1, one of the mammalian sirtuins. It was one of the first molecules found to extend lifespan in organisms through a defined genetic pathway.
Yes, high doses of nicotinamide can inhibit sirtuins. Nicotinamide is a product of the sirtuin reaction, and its accumulation acts as a negative feedback loop, signaling the sirtuins to slow down.
The theory suggests that aging is primarily caused by the loss of epigenetic information, not the digital DNA code itself. DNA damage events distract sirtuins and other gene expression regulators, causing them to move away from their normal silencing positions to repair damage, and they don't always return perfectly, leading to a gradual loss of proper gene expression patterns.
NR is converted by the body into NMN, and NMN is then immediately converted to NAD. In lab settings, NMN has been found to be more stable than NR when in solution or on the shelf.
Preliminary research suggests that NAD precursors may improve female fertility by enhancing egg health. This is thought to be due to NAD's role in regulating spindle quality via the SIRT2 protein, which prevents aneuploidy (incorrect chromosome separation) in older eggs.
Yes, evidence from animal studies, including those with rapamycin and NMN, suggests that lifespan extension is possible even when interventions are started in middle-aged or elderly organisms, challenging the idea that interventions must begin early.
15 Actionable Insights
1. Avoid High-Dose Nicotinamide
Avoid taking really high doses of nicotinamide (Vitamin B3) as it acts as an inhibitor of sirtuins, which are important for longevity pathways.
2. Review Rabinowitz NAD Paper
Consult the Josh Rabinowitz paper in Cell Metabolism (linked in show notes) for a potentially compelling case regarding the futility of orally administered NAD precursors.
3. Enhance Resveratrol Absorption
Take resveratrol with a fatty food, such as oil or yogurt, to significantly improve its absorption and increase blood levels.
4. Cautious Supplement Stacking
When combining multiple longevity-focused molecules like metformin and resveratrol, start with a reasonable low dose and gradually increase, monitoring well-being and blood tests due to potential additive effects and unknown interactions.
5. Prioritize NAD Precursors
Prioritize NAD precursors (like NMN or NR) over single sirtuin activators (like resveratrol) for broader activation of all seven sirtuins and to replenish age-related NAD decline, as NMN has shown lifespan extension in wild-type mice.
6. Consider Expert’s Personal Regimen
Consider David Sinclair’s personal regimen of taking resveratrol, metformin, and NMN, acknowledging it’s an individual experiment based on available data for potential health benefits.
7. Beware Unendorsed Supplements
Do not trust over-the-counter supplements that claim to be endorsed by David Sinclair, as he does not endorse any products.
8. Store NAD Precursors Cold
Store NAD precursors like NMN and NR in the freezer to maintain their stability and extend their shelf life.
9. Scrutinize NAD Precursor Claims
Recognize that claims of significant performance improvement from NAD precursors (NR/NMN) are currently anecdotal and lack placebo-controlled evidence, requiring caution.
10. Understand NAD Measurement Complexity
Understand that measuring NAD precursor effects is complex; blood levels don’t necessarily reflect tissue uptake or activity, and advanced studies are ongoing to clarify distribution.
11. Cultivate Grit and Determination
Develop massive determination and grit, as demonstrated by David Sinclair’s career path, to overcome challenges and achieve ambitious life goals.
12. Advocate for Longevity Trials
Advocate for or support large-scale human clinical trials (e.g., 5,000 people in their 70s for 3-4 years) to definitively assess the impact of longevity drugs on mortality rates.
13. Read David Sinclair’s Book
Look for David Sinclair’s book, expected in late summer/early fall 2019, for a comprehensive understanding of aging, his universal hypothesis, and societal implications.
14. Sign Up For Weekly Email
Head to PeterTiaMD.com to sign up for Peter Attia’s weekly email list for updates on longevity, science, performance, and sleep.
15. Follow David Sinclair Online
Follow David Sinclair on Twitter (@DavidASinclair) or LinkedIn to communicate and stay updated on his work.
7 Key Quotes
I've been interested in aging since I was four, since I realized that everybody and everything around me is going to die.
David Sinclair
You don't evolve death genes.
David Sinclair
Aging is actually not that difficult to be able to control. And that's because our models are very good.
David Sinclair
The sirtuins evolved, we believe, what are we talking about, three and a half billion years ago in the first life forms... And their job is to sense stress, biological stress in the environment... and allow that organism to hunker down and survive, stop mating, stop breeding.
David Sinclair
The genome is digital information... it's very robust. And so what we've actually come to discover is that the genome is fairly intact in old people and old animals... But the other part of information that you inherit from your parents is the epigenetic information... And that is analog information... analog information doesn't last very long.
David Sinclair
I've seen things you wouldn't believe.
David Sinclair
It's not a question of if anymore. It's a when it's going to happen.
David Sinclair