How did David Sinclair get involved in aging research?

David's interest in aging began at age four when he realized mortality. He pursued a PhD in molecular biology and yeast genetics, then joined Lenny Guarente's lab at MIT, which was pioneering the discovery of genes that controlled aging in yeast cells, particularly sirtuins.

What is the connection between NAD+ and sirtuins?

NAD+ is a crucial co-factor required for sirtuin activity. While previously thought to be constant, NAD+ levels fluctuate and decline with age. Raising NAD+ levels, often through precursors like NMN or NR, can activate sirtuins, leading to potential health and longevity benefits.

How effective is Resveratrol for human longevity?

Resveratrol, a sirtuin activator, showed promise in increasing lifespan in mice, especially those on a high-fat diet or when combined with caloric restriction. However, its poor solubility and low bioavailability in typical human diets mean it likely isn't potent enough on its own in realistic doses to significantly extend human lifespan, though it might offer cardiovascular benefits.

Why does David Sinclair take Resveratrol and Metformin?

David Sinclair takes Resveratrol and Metformin (among other molecules) as part of his personal experimentation. He reasons that while neither is definitively proven for human longevity, both have shown potential benefits in animal models, and he perceives a low risk of harm, particularly with Metformin at a low dose, considering their known additive effects on longevity pathways like AMPK.

What is the difference between Nicotinamide Riboside (NR) and Nicotinamide Mononucleotide (NMN)?

NR is converted into NMN in the body, which is then converted into NAD+. Both effectively raise NAD+ levels in human cells, though there's an academic debate on whether NMN is directly transported into cells like NR. NMN is generally found to be more stable than NR in lab conditions.

Are commercial NAD+ precursor supplements endorsed by David Sinclair?

David Sinclair explicitly states that he does not endorse any specific over-the-counter NAD+ precursor products. He mentions that his name is often used without his permission on various supplements, and he cautions listeners that any product claiming his endorsement for retail sale is doing so falsely.

How can NAD+ precursors help with female infertility?

NAD+ precursors, like NMN, show promise in treating female infertility by improving egg quality. Research suggests that increased NAD+ levels in the ovary and egg can regulate proteins like Bobr1 (a kinase important for spindle quality), thereby reducing aneuploidy and improving fertilization rates and healthy offspring outcomes.

What is David Sinclair's unifying theory of aging related to epigenetics?

Sinclair proposes that while the digital information of our genome (DNA) remains largely intact with age, the analog epigenetic information (gene expression patterns) gets corrupted over time. DNA damage distracts sirtuins from their silencing role to repair, causing them to not reliably return, leading to a loss of cell identity and function, analogous to a 'scratched CD'.

What is the most pressing human experiment needed in longevity research?

The most crucial human experiment involves a large-scale clinical trial with approximately 5,000 people, likely starting in their 70s, to test common longevity interventions like Metformin or NAD+ precursors. This would aim to demonstrate a change in the hazard ratio or mortality rate within 3-4 years, providing definitive evidence of their human health and lifespan benefits.

Key Moments

#27 – David Sinclair, Ph.D.: Slowing aging – sirtuins, NAD, and the epigenetics of aging

Peter Attia MD

People & Blogs4 min read102 min video

Jan 6, 2020|28,602 views|621|28

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Key Moments

TL;DR

David Sinclair discusses slowing aging via sirtuins, NAD+, and epigenetics, exploring research and potential interventions.

Key Insights

Sirtuins play a crucial role in aging, involved in DNA repair and gene silencing, and are conserved across species.

NAD+ levels decline with age and are essential for sirtuin activity; precursors like NMN and NR are being investigated.

Caloric restriction, sirtuins, and NAD+ pathways are ancient survival mechanisms that also impact longevity.

Resveratrol, an early sirtuin activator, showed promise but has limitations in potency and bioavailability.

Epigenetic drift, visualized as a 'scratched CD,' is a unifying theory for aging, where cells lose identity and function.

Newer synthetic molecules and combination therapies (e.g., NAD+ precursors with sirtuin activators) show greater promise.

Research in areas like female infertility offers a measurable, near-term application of NAD+ biology.

While supplements like NMN are available, Sinclair emphasizes the importance of rigorous scientific validation and clinical trials.

THE DISCOVERY AND MECHANISM OF SIRTUINS

Dr. David Sinclair's research journey began with a fascination for aging, leading him to study yeast genetics at MIT under Lenny Guarente. His work centered on sirtuins, a class of proteins originally known for gene silencing. He discovered their critical role in DNA repair, especially in response to DNA breaks, and established their involvement in aging. Sirtuins, surprisingly conserved across diverse life forms, are HDACs (histone deacetylases) but also target non-histone proteins, influencing signaling and metabolism. Their function is fundamentally linked to cellular stress responses and maintaining genomic stability.

NAD+ AS A KEY REGULATOR OF AGING

A pivotal discovery revealed that sirtuins are dependent on NAD+ to function. NAD+ levels naturally decline with age, impacting sirtuin activity. This insight shifted focus towards NAD+ metabolism as a major factor in aging. While NAD+ is crucial for hundreds of cellular processes, including respiration, its specific role in regulating aging pathways became a key area of investigation. The research highlighted that NAD+ levels fluctuate, particularly within cellular compartments like the mitochondria, and maintaining these levels is vital for cellular survival and repair.

FROM CALORIC RESTRICTION TO IN VIVO ACTIVATORS

Early research linked caloric restriction (CR) to increased lifespan, with sirtuins identified as necessary mediators of these benefits. Sinclair's lab demonstrated that overexpressing sirtuins could mimic aspects of CR. This led to the search for molecules that could activate sirtuins externally. Resveratrol, a plant-derived compound found in grapes, emerged as an early, though imperfect, sirtuin activator. Initial studies in yeast, worms, and flies showed lifespan extension dependent on sirtuins, followed by more significant findings in mice, particularly those on high-fat diets.

RESVERATROL AND THE CHALLENGE OF SYNTHETIC ANALOGS

The discovery of resveratrol's potential sparked considerable public interest, but its limitations became apparent. Resveratrol has poor solubility and bioavailability, requiring high doses, and its effects can be complex, activating other pathways like AMPK at higher concentrations. Subsequent efforts focused on developing more potent and bioavailable synthetic analogs. While resveratrol provided proof-of-concept and allowed for early human studies (often at very high doses), it ultimately paved the way for next-generation molecules with improved pharmaceutical properties, showing promise even in normal aging mice.

THE EPIGENETIC THEORY OF AGING

Sinclair proposes a unifying theory of aging: the loss of epigenetic information. He compares the genome to a digital CD, which remains intact, while the epigenetic information is like the analog signal that gets scratched over time. This 'epigenetic drift' causes cells to lose their identity and function correctly, leading to the hallmarks of aging. This concept is visualized by Waddington's landscape, where cells normally settle into specific valleys; aging causes them to 'jump' out of these valleys, disrupting cellular identity and function. This theory suggests that aging isn't about losing essential genes but about losing the correct program for gene expression.

NAD+ PRECURSORS AND FUTURE DIRECTIONS

Current research heavily focuses on NAD+ precursors like NMN and NR, which can be taken orally and converted to NAD+ within the body. While there's debate about the exact transport mechanisms, evidence suggests these molecules effectively raise NAD+ levels. Companies are developing improved precursors with better bioavailability. Beyond general longevity, these NAD+ boosting strategies show specific promise in areas like improving fertility by enhancing mitochondrial function and chromosome quality in eggs. The field is moving towards combination therapies, potentially integrating NAD+ precursors with sirtuin activators or other longevity pathways to achieve additive or synergistic effects.

CLINICAL TRIALS AND THE PATH FORWARD

Translating these findings into tangible human benefits requires rigorous clinical trials. Sinclair highlights the ongoing efforts to conduct large-scale, well-controlled studies to assess the impact of interventions on healthspan and mortality. He advocates for a multi-pronged approach, testing various drugs and combinations across different age groups. The availability of advanced technologies like NMR spectroscopy, along with gene-editing tools, accelerates the ability to test hypotheses in animal models and inform human trials. The ultimate goal is to develop safe and effective ways to intervene in the aging process, not just for extending lifespan but for improving quality of life.

Mentioned in This Episode

●Supplements

●Products

●Companies

●Organizations

●Drugs & Medications

●Concepts

●People Referenced

Common Questions

Sirtuins are a class of molecules that play a protective role in responding to energy and nutrients. They are involved in gene silencing and DNA repair, and their proper function is crucial for healthy aging. Disruptions in sirtuin activity due to DNA damage can lead to a loss of proper gene expression patterns, contributing to aging phenotypes.

Topics

Calorie Restriction Health & Longevity Neuroscience & the Brain Science & Mathematics Drug Discovery DNA Repair Female Fertility Medicine & Clinical NAD+ Metabolism Sirtuin Activation Epigenetics Of Aging

Mentioned in this video

Organizations

Harvard Medical School

David Sinclair is 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.

Massachusetts Institute of Technology

David Sinclair joined Lenny Guarente's lab at MIT for his postdoctoral research, a pivotal step in his career in aging research.

University of New South Wales

David Sinclair completed his PhD in molecular genetics at the University of New South Wales in Sydney, Australia.

Helen Hay Whitney Foundation

A prestigious foundation that provided funding for David Sinclair to pursue his postdoctoral research, despite initially being told he couldn't apply as a foreigner.

Supplements

Resveratrol

A molecule that stimulates sirtuins, found in grapes and wine, which gained fame for promoting longevity phenotypes in animal models, though the 'French paradox' connection is a 'spoiler alert, not true'.

Nicotinamide Riboside

NR is a one-step precursor to NAD+ and is packaged with pterostilbene in some over-the-counter products, shown to raise NAD+ levels in the body and cells.

Quercetin

Another plant molecule, found in fruits and onions, discovered by Conrad Howitz at Biomol to activate sirtuin-1 activity in humans, similar in structure to resveratrol.

NAD

A molecule and its precursors, specifically NMN, are discussed for their role in stimulating sirtuins and their potential in life extension, although the efficacy of oral administration is debated.

NMN

A precursor to NAD+ being explored as a supplement for its potential in life extension, with various companies now selling it.

Pi-C-channel

One of the first plant molecules discovered by Conrad Howitz at Biomol to activate sirtuin-1 activity in humans, similar in structure to resveratrol.

Pterostilbene

Essentially resveratrol with some methyl groups on it, a 'more novel, sexier version' that some companies include with NR, described as potentially more active by Lenny Guarente.

Companies

ChromaDex

Another company that sells NAD+ precursors as supplements, mentioned in the context of competition in the NAD+ supplement market.

Lifespan Biosciences

A parent company that encompasses a family of eight companies collaborating on different aspects of aging, sharing resources and knowledge to conquer aging through various approaches, including NAD+ biology.

Jumpstart Fertility

A company based in Massachusetts and Australia, exploring the significant positive effects of NAD+ precursor molecules on female infertility or low fertility, with planned publications and clinical trials.

Metro Biotech

A company in Massachusetts working on developing improved NAD+ precursor molecules with better bioavailability, stability, and efficacy, which are moving into clinical trials.

Drugs & Medications

Metformin

A widely used anti-diabetic drug that also impacts longevity pathways, often taken by David Sinclair and his colleagues in low doses due to its additive effects with other longevity molecules.

Simvastatin

A statin drug that was part of some ITPs (Interventions Testing Program) at NIA, alongside rapamycin and resveratrol, though its inclusion was questioned by Peter Attia.

People

Leonard Guarente

David Sinclair's mentor at MIT and a pioneer in yeast genetics and aging research, who discovered a mutation that led to the sirtuin story.

Matt Kaeberlein

An incoming graduate student in Lenny Guarente's lab who performed the experiment showing that overexpressing the sirtuin gene in yeast cells extended their lifespan.

Peter Attia

The host of the podcast, Peter Attia, who interviews David Sinclair about his work in aging, sirtuins, and NAD+.

Brian Kennedy

Worked in Lenny Guarente's lab and was involved in finding genes that controlled aging in yeast cells, and discovered the 'sir2' gene.

Doug Melton

A super smart and tough guy, king of endocrinology and stem cells at Harvard, who interviewed David Sinclair for his postdoc position.

David Sabatini

A mutual friend who introduced Peter Attia and David Sinclair, famous for his work on mTOR.

Cynthia Kenyon

The discovery of the daf-2 mutation in C. elegans, a nematode worm, by Cynthia Kenyon, coincided with initial work on sirtuins and longevity genes.

Rob Zipkin

The brilliant CEO of Biomol and a chemist, who recognized the structural similarity between the discovered sirtuin-activating molecules and resveratrol, leading to its investigation.

Peter Medawar

A brilliant scientist from the 1950s who, along with others, speculated on antagonistic pleiotropy, suggesting that traits beneficial in youth can become detrimental in old age.

Concepts

Sirtuins

A class of molecules pioneering David Sinclair's field of aging research, known for their role in gene silencing, DNA repair, and response to energy and nutrients.

Products

Elysium Health Basis

A supplement containing NAD+ precursors, discussed as a high-quality, over-the-counter option, with Nobel laureates involved and a commitment to quality.