December 27, 2021 • 2hr 7min

Dr. David Sinclair: The Biology of Slowing & Reversing Aging

Huberman Lab

In this episode, Dr. Andrew Huberman interviews Dr. David Sinclair, professor of genetics at Harvard Medical School and a leading researcher on aging and longevity. They discuss the biology of aging, Dr. Sinclair's view of aging as a treatable disease, and both behavioral and supplementation strategies to slow or reverse aspects of aging. Dr. Sinclair explains his research on sirtuins and NAD - key regulators of aging - and how interventions like fasting, exercise, and compounds like resveratrol and NMN can activate longevity pathways. They explore cutting-edge topics like measuring biological age, reprogramming cells to a more youthful state, and the future of anti-aging therapies.

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Key Takeaways

Aging is a disease that can be slowed or reversed, not an inevitable natural process
The epigenome - the systems controlling which genes are switched on/off - is the main driver of aging
Fasting and calorie restriction activate longevity pathways and genes like sirtuins
NAD levels decline with age but can be boosted with precursors like NMN to slow aging
Exercise, cold exposure, and plant compounds like resveratrol can activate longevity pathways
Measuring biomarkers like DNA methylation can track biological age and effects of interventions
Gene therapies to reset the epigenome show promise for reversing aging in animal studies

Introduction

In this episode, Dr. Andrew Huberman interviews Dr. David Sinclair, professor of genetics at Harvard Medical School and a leading researcher on aging and longevity. They discuss the biology of aging, Dr. Sinclair's view of aging as a treatable disease, and both behavioral and supplementation strategies to slow or reverse aspects of aging.

Dr. Sinclair explains his research on sirtuins and NAD - key regulators of aging - and how interventions like fasting, exercise, and compounds like resveratrol and NMN can activate longevity pathways. They explore cutting-edge topics like measuring biological age, reprogramming cells to a more youthful state, and the future of anti-aging therapies.

Topics Discussed

Aging as a Disease (7:55)

Dr. Sinclair argues that aging should be viewed as a disease that can be treated, not an inevitable natural process:

Aging meets the definition of a disease - deterioration in health that can lead to death
It's only not classified as a disease because it affects >50% of the population
Aging is the root cause of most major diseases like heart disease and Alzheimer's
Treating aging itself, rather than individual diseases, is a more effective approach

"If we didn't get old and our bodies stayed youthful, we would not get those diseases. And actually, what we're showing in my lab is if you turn the clock back in tissues, those diseases go away." - Dr. David Sinclair

The Epigenome and Information Theory of Aging (10:38)

Dr. Sinclair explains his view that aging results from a loss of epigenetic information:

The epigenome controls which genes are switched on/off in cells
Over time, this epigenetic information gets corrupted, like scratches on a DVD
This leads to the wrong genes being expressed, causing aging and disease
The epigenome, not just DNA mutations, is the primary driver of aging

"Aging is a loss of information in the same way that when you xerox something a thousand times, you'll lose that information." - Dr. David Sinclair

Fasting and Calorie Restriction (23:00)

They discuss how fasting and calorie restriction activate longevity pathways:

Skipping meals, especially breakfast or dinner, can provide longevity benefits
Dr. Sinclair practices time-restricted eating, consuming food in a 2-hour window
Fasting lowers insulin and activates sirtuins and other longevity genes
3+ day fasts can trigger deeper cellular cleansing processes

"If there's one thing I could say, if I would say, definitely try to skip a meal a day, that's the best thing." - Dr. David Sinclair

Resveratrol, NAD, and NMN Supplementation (50:29)

Dr. Sinclair shares his supplement regimen and the science behind it:

Takes 1 gram resveratrol and 1 gram NMN daily
Resveratrol activates sirtuins; NMN boosts NAD levels
NAD levels decline with age but are crucial for sirtuin function
NMN can double NAD levels in humans within 2 weeks
Takes supplements in the morning with olive oil or yogurt

"I know from measuring dozens of human beings that if you take NMN for the time period that I do, I've been taking it for years. But if you take it for about two weeks, you'll double, on average, double your NAD levels in the blood." - Dr. David Sinclair

Exercise and Muscle Preservation (1:33:45)

They discuss the importance of exercise, especially for maintaining muscle mass:

Maintaining muscle mass is crucial for hormone levels and longevity
Both aerobic and resistance exercise activate longevity pathways
Exercise increases NAD levels and activates sirtuins
Dr. Sinclair aims for strong, functional muscles rather than large muscles

"I base my exercise on the scientific literature, which has shown that maintaining muscle mass is very important for a number of reasons." - Dr. David Sinclair

Cold Exposure and Hormesis (1:46:19)

They explore how cold exposure and other mild stressors can promote longevity:

Cold exposure activates longevity pathways and brown fat
Dr. Sinclair sleeps cool and dresses lightly to challenge thermoregulation
Mild stressors like cold, heat, and exercise trigger beneficial adaptations
The "metabolic winter" hypothesis - we evolved to experience periods of cold/scarcity

"I've got this hypothesis with Ray Cronise. We published what's called the metabolic winter hypothesis, which is few tens of thousands of years ago, we were either hungry or cold or both, and we rarely experience that now." - Dr. David Sinclair

Measuring Biological Age (1:15:05)

Dr. Sinclair discusses the importance of tracking biomarkers of aging:

DNA methylation patterns can measure biological vs chronological age
Tracking biomarkers over time is crucial to optimize interventions
Key markers: blood sugar, HbA1c, CRP, cholesterol ratios
Dr. Sinclair is developing an at-home biological age test

"If you don't measure something, you can't optimize it. And so this is the biological age test. We've developed it. It's a simple mouth swab." - Dr. David Sinclair

Reprogramming Cells to Reverse Aging (1:40:35)

They discuss cutting-edge research on resetting the epigenome to reverse aging:

Dr. Sinclair's lab showed vision restoration in mice by resetting retinal cells
Uses gene therapy to reactivate youthful epigenetic patterns
Human trials for vision restoration planned for 2022/2023
Working on systemic rejuvenation via pills to reset the epigenome

"We're going to be testing the treatment on monkeys, just for safety reasons. And then the first patient should be done sometime in 2022, early 2023, and we're going to try to recover blindness." - Dr. David Sinclair

Public Science Education (1:59:00)

They discuss the importance of scientists communicating directly with the public:

Podcasts and social media allow experts to share cutting-edge science
The pandemic highlighted the need for trusted scientific voices
Universities are becoming more supportive of public engagement
Dr. Sinclair is launching his own podcast on aging research

"Finally people like you are allowed by our universities to talk to the public. I used to do it with a real threat to my survival." - Dr. David Sinclair

Conclusion

This wide-ranging conversation covered the cutting-edge science of aging and practical strategies to slow or reverse aspects of aging. Key takeaways include viewing aging as a treatable condition, the central role of the epigenome, and how interventions like fasting, exercise, and supplements can activate longevity pathways. Dr. Sinclair's research on reprogramming cells shows the potential to reset biological age, with human trials on the horizon. Overall, the episode provides an optimistic view that aging is more plastic than previously thought, with many opportunities to extend healthspan through both lifestyle choices and emerging therapies.