#70 - David Sinclair, Ph.D.: How cellular reprogramming could slow our aging clock (and the latest research on NAD)
David Sinclair, Ph.D., a Professor in the Department of Genetics at Harvard Medical School, returns to discuss his book "Lifespan: Why We Age - and Why We Don't Have To." The conversation delves into the Information Theory of Aging, epigenetics, sirtuins, NAD, and potential longevity compounds, including David's personal regimen.
Deep Dive Analysis
16 Topic Outline
Introduction to 'Lifespan' and the Information Theory of Aging
Claude Shannon's Information Theory and its Relevance to Aging
Sirtuin Genes as Silent Information Regulators
Epigenetic Modifications and DNA Methylation in Cellular Identity
The Horvath Clock: Measuring Biological Age and its Predictability
Impact of Lifestyle on the Epigenetic Clock
Cellular Reprogramming with Yamanaka Factors for Age Reversal
Restoring Vision in Mice through Partial Reprogramming Gene Therapy
Challenges and Future of Systemic Reprogramming in Humans
Senescent Cells: 'Zombie Cells' and Their Contribution to Aging
David Sinclair's Updated Metformin Usage
Resveratrol: Efficacy, Mechanism, and Personal Use
NAD Precursors (NR, NMN) and Sirtuin Activation
Current Research and Debates on NAD Boosters
Development of Next-Generation NAD Booster Prodrugs
David Sinclair's Artistic Work in 'Lifespan'
10 Key Concepts
Information Theory of Aging
This theory posits that aging is primarily caused by the loss of epigenetic information in cells, leading to a breakdown of cellular identity and function, rather than solely genetic mutations. This loss is akin to noise accumulating in a signal, making it harder for cells to read their original genetic program.
Silent Information Regulator (SIR) Genes
These are genes, like sirtuins, that control other genes by switching them on and off, primarily keeping them silent to maintain cellular health and division. When cells are stressed (e.g., by DNA breaks), SIR proteins leave their silent regions to repair damage, and their failure to fully return can lead to epigenetic noise and loss of cellular identity over time.
DNA Methylation
A deep layer of epigenetic modification where chemical methyl groups are added to DNA, effectively marking specific genes to be silent for long periods. This precise pattern is crucial for defining cell types and is altered predictably with age, forming the basis of biological age clocks.
Waddington's Landscape
A metaphor describing how an embryonic cell differentiates into various stable cell types (e.g., nerve, skin) by metaphorically rolling down a hill into specific valleys. In aging, this landscape is thought to erode, causing cells to lose their stable identity and migrate into less defined, dysfunctional states.
Horvath Clock
A highly accurate biological clock that measures an individual's biological age by analyzing specific DNA methylation patterns across hundreds of sites in the genome. It can predict lifespan and is influenced by lifestyle factors, reflecting the rate at which a person is aging rather than just their chronological age.
Yamanaka Factors
A set of specific genes (originally four: Oct4, Sox2, Klf4, c-Myc) that, when expressed, can reprogram adult cells back into induced pluripotent stem cells (iPSCs). These factors are now being used in partial reprogramming to reverse cellular age without fully dedifferentiating cells.
Partial Reprogramming
A technique using a subset of Yamanaka factors (e.g., three factors excluding the oncogene c-Myc) to reset the epigenetic clock and restore youthful gene expression patterns in cells. This aims to reverse aging and restore function without causing cells to lose their specific identity or become cancerous.
Senescent Cells
Often called 'zombie cells,' these are cells that have stopped dividing due to stress or damage (like telomere erosion or DNA breaks) but do not die. Instead, they remain in tissues, secreting inflammatory and stress-inducing chemicals that disrupt the epigenome and accelerate aging in surrounding healthy cells.
NAD (Nicotinamide Adenine Dinucleotide)
A crucial molecule in the body required for countless chemical reactions and essential for life. It also acts as a signaling molecule, particularly for sirtuins, which need NAD as fuel for their activity in DNA repair and epigenetic regulation. NAD levels decline with age.
NR (Nicotinamide Riboside) and NMN (Nicotinamide Mononucleotide)
These are precursors to NAD that can be taken as supplements to boost NAD levels in cells. NR is converted to NMN, then to NAD. They are studied for their potential to activate sirtuins and confer health benefits associated with increased NAD, especially in distressed or older organisms.
8 Questions Answered
Shannon's theory describes how to preserve information despite noise. In aging, cells lose epigenetic information due to 'noise' from constant DNA repair, leading to a breakdown of cellular identity, which Sinclair terms the Information Theory of Aging.
The Horvath clock measures biological age by analyzing specific DNA methylation patterns, which change predictably over time. It is highly accurate, capable of estimating chronological age with 95% accuracy in human blood samples and predicting lifespan.
Yes, lifestyle factors such as exercise and calorie restriction can slow down the epigenetic clock, while smoking or lack of exercise can accelerate it, indicating that the clock reflects the rate of aging, not just chronological age.
Early evidence from mouse studies suggests that partial cellular reprogramming using specific Yamanaka factors can reset the epigenetic clock, making cells functionally younger without causing them to lose their identity or become cancerous.
Senescent cells are 'zombie cells' that stop dividing but don't die, instead secreting chemicals that stress surrounding healthy cells. They are thought to be a protective mechanism against cancer but accumulate with age, contributing to tissue dysfunction and accelerating aging.
NAD is a crucial molecule that acts as fuel for sirtuins, which are protective enzymes involved in DNA repair and epigenetic regulation. Maintaining optimal NAD levels is believed to support sirtuin activity and potentially slow down aging processes.
NR and NMN are precursors that can raise NAD levels in mice and, in recent human studies, have shown to increase NAD in muscle cells. However, debates continue regarding optimal dosing, absorption efficiency, and whether these increases translate to significant health or longevity benefits in healthy humans.
Metformin inhibits mitochondrial function, which can stimulate the body to produce more mitochondria as a compensatory response. However, taking it on days of intense exercise might blunt the body's natural adaptive response to build up mitochondria, potentially reducing some exercise benefits.
18 Actionable Insights
1. Slow Epigenetic Aging
Engage in regular exercise and calorie restriction, and avoid smoking, as these actions are known to slow down your biological (epigenetic) clock.
2. Fast to Boost NAD
Practice fasting (e.g., for a couple of days) to increase NAD levels, which helps sirtuins repair DNA and maintain gene silencing, thereby slowing the aging clock.
3. Pulse Biological Stress
Apply biological stressors (like exercise or certain supplements) in a pulsatile manner, allowing the body adequate time to recover and adapt, rather than continuous exposure.
4. Pulse Rapamycin Dosing
If taking rapamycin, use a pulsatile dosing schedule rather than daily, and avoid taking it around exercise to prevent blunting muscle growth and healing.
5. Time Metformin with Exercise
If taking metformin, avoid taking it on days of intense exercise and potentially the day after, to allow your body to recover and build up mitochondria without inhibition.
6. Metformin for Inactive Periods
Consider taking metformin during periods of inactivity, such as long trips with limited exercise, and lay off it when you are regularly exercising.
7. NAD Boosters for Unhealthy
If you are metabolically unhealthy, obese, or have a disease, NAD boosters (like NR or NMN) may offer more significant benefits by replenishing lost NAD levels.
8. Avoid High-Dose Nicotinamide
Avoid taking high doses of nicotinamide (NAM) unless for specific medical reasons (e.g., cancer), as it can inhibit sirtuins, which are enzymes you want to keep active for longevity.
9. Prefer NR/NMN over Niacin
If your goal is to effectively raise NAD levels, consider taking nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN) rather than high doses of niacin (vitamin B3), as NR/NMN are more effective in mice.
10. Consider Higher NR Dose
A recent human study used 1000mg of oral NR (four times the typical supplement dose) to successfully raise NAD levels in muscle, suggesting a higher dose might be needed for systemic effects.
11. Take Resveratrol with Fat
If taking resveratrol, consume it with a fatty meal (e.g., yogurt) to potentially enhance its absorption and effectiveness.
12. Resveratrol for Unhealthy Diet
Consider resveratrol supplementation if consuming a Western diet, as it has been shown to extend the lifespan of mice on such a diet.
13. Consider Daily Resveratrol
David Sinclair takes 1 gram of resveratrol every morning, noting it’s a high dose but seems fine for him and he keeps it constant in his regimen.
14. Monitor Biological Age
Consider getting your DNA methylome (Horvath clock) measured every 6-12 months to track your biological aging rate and assess the directional correctness of your lifestyle interventions.
15. Find DNA Methylation Service
Search for companies online that offer DNA methylation age testing to determine your biological age.
16. Read “Lifespan” Book
Read David Sinclair’s book “Lifespan” for a deep, technical understanding of the information theory of aging and related concepts.
17. Stay Informed on Science
Actively follow podcasts and other reliable sources to stay informed about the cutting edge of scientific research, allowing you to make informed personal decisions about health interventions.
18. Support Podcast for Value
If you value the content, consider supporting the podcast via a monthly subscription to gain access to exclusive show notes, AMA episodes, and deals on products Peter loves.
7 Key Quotes
SIR is an acronym for Silent Information Regulator.
David Sinclair
This is a gene that controls other genes. It switches them on and off. Its main job is to keep genes silent, and that allows cells to be dividing, be healthy.
David Sinclair
Your birth certificate just tells you when you're born. This clock tells you how fast you're aging.
David Sinclair
Theoretically, this is as close as we've come to finding a way to actually live for thousands of years.
David Sinclair
Every month that we stay alive, we get an extra week of life. That's how technology is going currently.
David Sinclair
If you've got a tumor somewhere in your body, we've detected it. Go have that killed before it grows. That's going to be 20 years ahead of what we can do now for patients.
David Sinclair
There is so much smoke out there that you have to believe there's a fire, but I just don't know where it is.
Peter Attia
1 Protocols
David Sinclair's Metformin Usage Protocol
David Sinclair- Avoid taking metformin on days of intense exercise to allow the body to recover and build up mitochondria.
- Take metformin on days of long trips (e.g., planes, trains) when not exercising, as a time to 'rebuild your body'.
- Avoid taking metformin when the stomach feels 'out of whack' or after a big meal, due to potential stomach discomfort.