Dr. David Sinclair: The Biology of Slowing & Reversing Aging | Huberman Lab Podcast #52

Dr. David Sinclair, a professor of genetics at Harvard Medical School, focuses on understanding the biology of aging and developing interventions to slow or reverse its effects. His research explores cellular and molecular pathways that contribute to aging and identifies points of intervention through behavioral, nutritional, and pharmaceutical approaches. Dr. Sinclair believes that aging is not an inevitable consequence but rather a treatable disease. He has published numerous research articles and a bestselling book titled "Lifespan: Why We Age And Why We Don't Have To." Dr. Sinclair is actively involved in public education about the biology of aging and will be launching a podcast called "Lifespan" to further discuss interventions in the aging process. The video discusses various interventions and behaviors that can slow down and reverse aging, including fasting, exercise, supplementation with compounds like resveratrol and NMN, and maintaining hormone levels. It also emphasizes the importance of public science education and accurate information dissemination. Dr. Sinclair has developed a biological age test that provides personalized recommendations for lifestyle changes and interventions to slow down the aging process.

Dr. David Sinclair, Harvard Medical School

Dr. David Sinclair is a professor of genetics at Harvard Medical School.
He focuses on understanding the biology of aging and developing interventions to slow or reverse its effects.
His research explores cellular and molecular pathways that contribute to aging.
He identifies points of intervention through behavioral, nutritional, and pharmaceutical approaches.
Dr. Sinclair believes that aging is a treatable disease, not an inevitable consequence.
He has published numerous research articles and a bestselling book titled "Lifespan: Why We Age And Why We Don't Have To."
Dr. Sinclair is actively involved in public education about the biology of aging.
He will be launching a podcast called "Lifespan" to further discuss interventions in the aging process.

“Aging as a Disease” vs. Longevity & Anti-Aging

The difference between longevity, anti-aging, and aging as a disease is as follows:

Longevity and anti-aging focus on increasing lifespan and slowing down the aging process.
Aging as a disease challenges the traditional definition of disease and views aging itself as a disease.
Aging is considered the primary cause of diseases such as heart disease and Alzheimer's.

The concept of "aging as a disease" is discussed in the video, emphasizing the importance of addressing aging itself rather than just treating the diseases that arise from it. Slowing down the aging process can prevent age-related diseases, and reversing aging may lead to the disappearance of these diseases.

What Causes Aging? The Epigenome

The epigenome, which controls gene expression, is a major cause of aging. It deteriorates over time, leading to cells not functioning properly. Changes in the epigenome can result in cells losing their identity and forgetting their function, leading to diseases. These changes can be measured and used to predict lifespan.

Key points:

Aging is caused by the deterioration of the epigenome, which controls gene expression.
Damage to the epigenome results in cells not functioning properly.
Disruptions in the epigenome can lead to cells losing their identity and function, causing diseases.
Changes in the epigenome can be measured and used to predict lifespan.

Cosmetic Aging

Cosmetic aging is characterized by outward signs of aging like graying hair, wrinkling skin, and drooping face. This is associated with DNA damage and the appearance of the skin can indicate overall aging. Centenarian families tend to live longer and look younger than their age. An AI system can accurately predict someone's age by analyzing their face.

Development Never Stops, Horvath Clock

Development never stops and your entire life is one long developmental arc.

The early stages of infancy and puberty are rapid stages of aging.
The epigenome undergoes changes during these stages, which can be measured using Horvath's clock.
Horvath's clock predicts biological age, which can be different from chronological age.
There is a significant increase in age based on this clock during the first few years of life, followed by linear aging throughout the rest of life.
The genes that contribute to aging are often the same genes involved in early development.
These genes are susceptible to damage, such as broken chromosomes and DNA breaks.

Dr. David Sinclair discusses the biology of slowing and reversing aging.

The unwinding of DNA loops accelerates aging, observed in mice.
Controlling aging in a forward direction can induce aging characteristics such as bent spine kyphosis, gray hair, and organ deterioration.
Massive cell damage or stress can also accelerate the aging process.

Puberty Rate as a Determinant of Aging Rate

Puberty rate can predict aging rate, with slower development during puberty associated with longer and healthier lives. Growth hormone, which is pro-aging, may play a role in this relationship. Animals with low growth hormone levels, like dwarfs, tend to live longer. Smaller individuals also have longer lifespans. Individuals with dwarf mutations in South America are protected against diseases of aging, indicating a link between growth and aging processes.

Fasting, Hunger & Food Choices

Fasting, Hunger & Food Choices:

Fasting and controlling blood sugar and insulin levels can positively impact aging.
Hunger can be beneficial and constant consumption of food throughout the day is not ideal for longevity.
Animals that do not eat constantly live longer and healthier lives.
Longevity genes can be activated by low levels of insulin and insulin-like growth factor.
Constant feeding prevents these longevity genes from being switched on, leading to faster aging.
Fasting increases sensitivity to insulin and prevents type two diabetes.
The subjective experience of hunger may play a role in these processes.
Eating within a specific time window may be more important than what you eat.
Skipping a meal a day, preferably at the beginning or end of the day, is recommended.
Intermittent fasting involves skipping breakfast and consuming only liquids throughout the day.
Regulating blood sugar levels naturally helps maintain focus throughout the day.
Avoiding sugar and simple carbohydrates improves dental health and breath.
Everyone is different and what works for one person may not work for others.
The benefits of fasting and the importance of sleep are briefly mentioned.

Fasting Schedules, Long Fasts, (Macro)Autophagy

Fasting schedules and long fasts, such as 48-72 hours or even up to three days, can trigger autophagy, a process that cleanses the body of old and misfolded proteins. This process has been shown to increase longevity in mice. However, it can be challenging to go longer than 24 hours without eating due to a busy lifestyle.

Caffeine, Electrolytes

The ingestion of electrolytes and caffeine is discussed in the transcript snippets. Some people find relief from lightheadedness and shakiness during fasting by adding sodium, potassium, or magnesium to their water. However, the speaker personally does not feel the need to do so and drinks tea and coffee without negative effects. Tea and coffee already contain beneficial components, but supplementing with electrolytes may be helpful after heavy drinking. The mechanistic question is not addressed in the given snippets.

Some people add electrolytes to their water to relieve lightheadedness and shakiness during fasting.
The speaker drinks tea and coffee without negative effects and does not supplement with electrolytes.
Tea and coffee already contain beneficial components.
Electrolyte supplementation may be helpful after heavy drinking.

Blood Glucose & the Sirtuins; mTOR

Keeping blood sugar low for a period of time can trigger pro-longevity and anti-aging mechanisms. This is because blood glucose levels are linked to the activation of longevity genes, such as sirtuins, and the mTOR pathway. These pathways communicate with each other and can be influenced by factors like sugar, insulin, and amino acids.

Fasting can activate sirtuins and down-regulate mTOR.
This leads to improved insulin sensitivity, increased energy, and cellular repair.
These pathways are crucial for promoting longevity.

Amino Acids: Leucine, “Pulsing”

The concept of "pulsing" amino acids, particularly leucine, is discussed in relation to its effects on vitality, fitness, and aging. Dr. David Sinclair follows a protocol of pulsing, involving fasting, exercise, and strategic timing of supplement intake, to build muscle without excessive growth. The discussion explores the idea that alternating between periods of restriction and nourishment may have a positive impact on cellular processes, particularly involving mTOR and sirtuins. Pulsing amino acids like resveratrol has been shown to protect against the negative effects of a high-fat diet and extend lifespan in mice.

Metformin, Berberine

Metformin and berberine are both substances that affect the AMPK and mTOR pathways, regulating metabolism and aging. Metformin is commonly used to treat type 2 diabetes and has potential anti-aging effects. It is associated with increased longevity and protection against diseases like cancer, heart disease, and dementia. Some people take it daily, while others take it every other day. Metformin reduces stamina and inhibits energy production, resulting in fewer reps during exercise. However, muscles built while taking Metformin have the same strength and lower inflammation.

Berberine, derived from Tree Barco, works similarly to Metformin and can improve metabolism and insulin sensitivity. It has been effective in rats, mice, and humans. However, a study on worms suggested it may reduce lifespan, but human trials have shown it to be safe. It is important to consult a doctor before considering Metformin or berberine as alternatives.

Resveratrol, Wine

Resveratrol, a compound found in red wine, has potential anti-aging effects. However, obtaining sufficient resveratrol through red wine consumption is impractical. Therefore, a resveratrol supplement is recommended, with a daily dosage of 1000 milligrams. It is important to choose a pure supplement that is light gray or white in color. Resveratrol should be ingested with a fatty substance like olive oil or yogurt to enhance absorption. Taking resveratrol with food increases its levels in the blood. The recommended protocol is to take resveratrol once a day in the morning, accompanied by a fatty substance.

What Breaks a Fast?

The answer depends on factors such as the previous night's meal and individual health conditions.
The body operates based on glucose, AMPK, and mTOR, not a specific "breaking the fast" switch.
Enjoying life is important, and small additions like coffee with a little milk and yogurt may not negatively affect longevity pathways.
Optimal fasting practices may vary for each individual.
Taking a gradual approach to fasting is important, rather than quitting cold turkey.
Forgiving oneself for occasional slip-ups is crucial.
Gradually reducing meal frequency, starting with skipping breakfast and gradually reducing lunch, is recommended.
Strict diets should not be attempted right away.

Resveratrol, NAD, NMN, NR; Dosage, Timing

Resveratrol, NMN, NR, and NAD are molecules that impact the sirtuin pathway, which controls aging and the epigenome. These molecules can naturally boost the activity of sirtuins, which are genes that produce proteins that take care of the body. Exercise and fasting can also activate sirtuins. Resveratrol is an activator of sirtuins and acts as an accelerator pedal, revving up the system.

Key points:

Resveratrol, NMN, NR, and NAD impact the sirtuin pathway, which controls aging and the epigenome.
Sirtuins are genes that produce proteins that take care of the body.
Exercise and fasting can activate sirtuins.
Resveratrol acts as an accelerator pedal, boosting the activity of sirtuins.

NAD (nicotinamide adenine dinucleotide) is a crucial molecule in the body that is used for various chemical reactions. However, NAD levels decline with age and obesity, and an enzyme called CD38 further depletes NAD. To address this, a precursor to NAD called NMN can be taken, which the body uses to produce NAD. Clinical trials have shown that taking NMN for about two weeks can double NAD levels in the blood. Another option is taking NR, which is used to make NAD.

Key points:

NAD is a crucial molecule in the body used for various chemical reactions.
NAD levels decline with age and obesity, and CD38 further depletes NAD.
NMN is a precursor to NAD and can be taken to increase NAD levels.
Clinical trials have shown that NMN can double NAD levels in the blood.
NR is another option to increase NAD levels.

Resveratrol, NAD, NMN, and NR are compounds that have been studied for their potential to slow down and reverse aging. NR is made from vitamin B3 and can be found in milk and other foods, but taking vitamin B3 alone does not effectively increase NAD levels. NMN contains all the necessary components to make NAD and has shown positive effects on blood flow and energy in mouse studies. When it comes to dosage, a gram of NMN is recommended, but individual needs may vary.

Key points:

Resveratrol, NAD, NMN, and NR have potential anti-aging effects.
NR is made from vitamin B3 and can be found in milk and other foods.
NMN contains all the necessary components to make NAD and has positive effects on blood flow and energy.
A gram of NMN is recommended, but individual needs may vary.

Dr. David Sinclair advises taking NMN at a gram or two grams daily to increase NAD levels. He recommends purchasing NMN from well-established companies with high levels of quality control and good manufacturing practices. Dr. Sinclair personally takes a gram of NMN in the morning along with other supplements like resveratrol.

Key points:

Dr. David Sinclair advises taking a gram or two grams of NMN daily to increase NAD levels.
Purchase NMN from well-established companies with high levels of quality control and good manufacturing practices.
Dr. Sinclair personally takes a gram of NMN in the morning along with other supplements.

Taking NMN in the morning can help reset the body's clock when traveling. It is suggested that taking the protocol for at least two weeks may increase NAD levels and potentially improve energy and focus. However, measuring insulin sensitivity requires a glucose monitor.

Key points:

Taking NMN in the morning can help reset the body's clock when traveling.
Taking the protocol for at least two weeks may increase NAD levels and potentially improve energy and focus.
Measuring insulin sensitivity requires a glucose monitor.

Resveratrol, NAD, NMN, and NR are being studied for their potential to slow down and reverse aging. Clinical trials are being conducted to determine their effects on energy, vitality, and focus. Anecdotal evidence suggests that these supplements can improve endurance and overall well-being. Athletes have reported increased performance, and individuals taking NMN have experienced positive effects. Further research is being conducted to validate these claims.

Key points:

Resveratrol, NAD, NMN, and NR are being studied for their potential anti-aging effects.
Clinical trials are being conducted to determine their effects on energy, vitality, and focus.
Anecdotal evidence suggests that these supplements can improve endurance and overall well-being.
Further research is being conducted to validate these claims.

In conclusion, Resveratrol, NMN, NR, and NAD are molecules that impact the sirtuin pathway and have potential anti-aging effects. NMN and NR can increase NAD levels, which decline with age and obesity. Taking NMN in the morning may help reset the body's clock, and a gram or two grams of NMN is recommended daily. Resveratrol acts as an accelerator pedal for sirtuins. Further research and clinical trials are being conducted to validate the effects of these compounds on energy, vitality, and focus.

Are Artificial Sweeteners Bad for Us?

Artificial sweeteners, such as Stevia, sucralose, and aspartame, may disrupt the gut microbiome, but the negative effects of Stevia are uncertain. However, the perception of sweet taste has minimal impact on longevity pathways. Consuming artificial sweeteners in moderation or during fasting is unlikely to significantly affect health compared to high-sugar meals or sugary sodas. Stevia, a naturally sourced product, is preferred as there is no strong evidence suggesting harm. It is important to approach media coverage of artificial sweeteners with skepticism and consider the credentials of science journalists.

Iron Load & Aging

Excess iron can accelerate aging by increasing senescent cells and inflammation, potentially leading to cancer. Taking excess iron as a supplement may also accelerate aging. It is important to track individuals over time to determine their normal iron levels.

Key points:

Excess iron can increase senescent cells and inflammation, contributing to aging and cancer.
Taking excess iron as a supplement can also accelerate aging.
Personalized medicine is important for optimal health, considering individual variations in iron levels.
Even with slightly low hemoglobin and ferritin levels, individuals can still have high energy levels and overall well-being.
Long-term tracking of individuals is crucial to determine what works best for them, rather than relying solely on average values.

Blood Work Analysis

Blood work analysis is crucial for gaining informative insights and tracking multiple measurements over time. It goes beyond categorizing results as red, yellow, or green and emphasizes understanding the molecules and markers on the blood work charts. Having a decade or more of data is valuable for a comprehensive understanding. Access to blood work data can help identify changes in cholesterol levels and inflammatory markers. While insurance companies may not cover the cost, blood work analysis is not overly expensive and can be paid out of pocket. It is important to have a conversation with a doctor to request a comprehensive blood test and to use companies like InsideTracker for analysis. Sharing blood work results with a doctor is recommended, and specific tests like blood sugar levels, HbA1c, and CRP should be considered. For further inquiries, an email and phone number are provided.

C-Reactive Protein, Cholesterol: Serum & Dietary

C-Reactive Protein (CRP) is a marker for cardiovascular inflammation and predictor of longevity. High levels of CRP indicate increased mortality and future heart attack risk. Lower CRP by switching to a healthier diet, eating fewer calories, and consuming more vegetables. Anti-inflammatory drugs can also help. Measure high sensitive hCRP levels, as normal blood sugar levels may not indicate high CRP. The relationship between serum cholesterol, dietary cholesterol, and longevity is complex. Impact of LDL levels on mortality and role of dietary cholesterol in determining cholesterol levels are not fully understood. Anorexics can have high LDL cholesterol levels due to their bodies manufacturing it. Personal experience with cholesterol and statin medication. Despite concerns, statins have successfully managed high cholesterol levels. Recent research suggests dietary cholesterol has minimal impact on blood cholesterol levels. Foods like eggs and butter can be consumed without significant concern. Majority of cholesterol is synthesized internally rather than absorbed from the gut, challenging previous dietary guidelines.

Amino Acids, Plants, Antioxidants

The profound aspect of the topic is the role of plants, amino acids, and antioxidants in slowing and reversing aging.

Key points:

Plants are highly nutritious and provide essential vitamins and nutrients.
Stressed plants produce xenohormetic molecules that can benefit health and promote longevity.
Consuming plants that have undergone stress activates sirtuin genes, which are involved in our own defense mechanisms.
Supplements like resveratrol and quercetin mimic plant molecules and activate sirtuins.
Antioxidants are beneficial in moderation for immune system and mitochondrial function.
Aging involves more than just free radical damage, such as disruptions in the epigenome and misfolding of proteins.
To truly benefit from antioxidants, it is necessary to activate the body's natural defenses and address other factors.
Resveratrol was initially thought to be beneficial due to its antioxidant properties but later found to have broader effects on lifespan.
Amino acids can extend the lifespan of yeast cells through the activation of sirtuins.
Resveratrol activates yeast's defenses against aging, not through its antioxidant activity but by turning on these defenses.
Understanding the mechanisms behind processes is important for studying cellular aging.

Behaviors That Extend Lifespan, Testosterone, Estrogen

Aerobic exercise raises NAD levels and sirtuin gene expression in mice and rats, but optimal exercise for these effects in humans is unclear. Maintaining muscle mass through exercise is important for hormone levels, especially for older males experiencing testosterone decline. Some males in their '80s and '90s have testosterone levels equivalent to younger adults, suggesting age-related decline is not always necessary. Dr. David Sinclair shares his personal experience of testosterone levels decreasing and then increasing after becoming complacent. He was able to lower his biological age from 58 to 31 using certain protocols. Fasting and caloric restriction can delay infertility in female mice and potentially slow down aging in the reproductive system. Extreme weight loss is not necessary for preserving fertility. Old mice given NMN rejuvenated their fertility, challenging the belief that female mammals run out of eggs. Sensory deprivation can reopen the critical period of neuroplasticity and reactivate it. Both fertility and neuroplasticity are associated with youth. Dr. David Sinclair discusses the biology of slowing and reversing aging, focusing on behaviors that extend lifespan and the role of testosterone and estrogen.

Neuroplasticity & Neural Repair

Neuroplasticity and neural repair have shown promising results in aging research, with the ability to reverse the age of cells and rejuvenate the body. Recent studies have restored vision in blind mice by reversing the age of neurons in the eye. Human clinical trials are expected to begin in 2022. Gene therapy using a virus and specific genes can reverse aging in the eye, resulting in restored vision. Antibiotics have potential for slowing down and reversing aging. Affordable at-home tumor detection technology is lacking, but a cheaper colon cancer test involving a stool sample is close in accuracy to a colonoscopy.

Ice Baths, Cold Showers, “Metabolic Winter”

Cold exposure, such as ice baths and cold showers, promotes thermoregulation and increases energy expenditure. The "Metabolic Winter Hypothesis" suggests that our constant warmth contributes to obesity. Dr. David Sinclair emphasizes the importance of challenging our system to thermoregulate by sleeping cool and dressing lightly. He used to do ice baths regularly with his son and plans to resume.

Obesity & How It Accelerates Aging, GnRH

Obesity & How It Accelerates Aging, GnRH:

Obesity reduces NAD levels and accelerates aging by increasing the number of senescent cells in fat tissue, which release inflammatory molecules. The exact mechanism involves glucose response and sirtuin gene activation. Leptin does not interact with the sirtuin pathway.

Obesity affects the hypothalamus, which controls the body's age. Leptin triggers early puberty but may cause reproductive issues later. SIRT1 gene and inhibiting inflammation in the hypothalamus extend lifespan in mice. GnRH, released by hypothalamic neurons, controls fertility and is influenced by environmental and dietary conditions. Research on factors triggering GnRH release is crucial.

Methylation, Methylene Blue, Cigarettes

Methylene blue, typically used for cleaning fish tanks, is ingested by some people for unclear reasons. It may extend the lifespan of lower organisms and interfere with mitochondrial activity, but more research is needed to understand its effects and safety.

Methylation is a process that affects the epigenome and can be influenced by factors like smoking and lack of exercise. Measuring biological age is crucial to determine the effectiveness of interventions on aging. Anecdotal evidence suggests age reversal is possible through certain interventions. A device that measures various health aspects in real-time, such as body temperature, movement, heart rate variability, voice, and sleep, can provide personalized healthcare.

The video discusses the biology of slowing and reversing aging. Methylation, which affects gene expression and is influenced by lifestyle factors, is mentioned. Methylene blue, a compound with potential anti-aging properties, is also discussed. The harmful effects of cigarettes on aging and health are emphasized, highlighting the importance of lifestyle choices for longevity.

X-Rays

Exposure to x-rays carries potential risks and precautions, including cumulative effects. Unnecessary exposure, such as from airport scanners, should be avoided. Opting for a pat-down is suggested. While one or two dental x-rays may not be harmful, limiting exposure is advised. The use of lead coats during dental x-rays indicates potential risks. Regular x-rays in dental technology may not be necessary if teeth are in perfect health and cavity-free. Concerns about x-rays and dental technology have been raised by physicist Richard Feynman.

Public Science Education, Personal Health

The most profound aspect of the topic of public science education and personal health is the importance of scientists and experts engaging in public discourse and providing accurate information to the public.

Key points:

There is a gap in understanding and an overwhelming amount of misinformation available in public science education.
Experts who are both knowledgeable and effective communicators are crucial in providing accurate information to the public.
In the past, scientists who communicated with the public were often seen negatively, but there is now a need for voices of reason and trusted facts.
The popularity of podcasts like Andrew Huberman's demonstrates the demand for accessible and relatable explanations and protocols.
There is an increased thirst for knowledge and an openness from the general public towards health practices.
Individuals believe they can control their stress levels, sleep, cholesterol, and even lifespan.
Dr. David Sinclair emphasizes the importance of scientists being able to communicate directly with the public and present information accurately.
He commends Andrew Huberman for his work in spreading the message of public science education and personal health.
Dr. Sinclair has opened a survey email/website for people to access in addition to his book and social media presence.

The Sinclair Test You Can Take: www.doctorsinclair.com

Dr. David Sinclair has developed a biological age test that measures an individual's health and rates of aging. The test aims to be accessible to everyone and involves a simple mouth swab. It provides personalized recommendations for lifestyle changes and interventions to slow down the aging process. Those who successfully reduce their biological age may receive a negative birthday card from Dr. Sinclair.

Key points:

Dr. David Sinclair has developed a biological age test
The test measures an individual's health and rates of aging
It aims to be accessible to everyone
The test involves a simple mouth swab
It provides personalized recommendations for lifestyle changes and interventions
Those who successfully reduce their biological age may receive a negative birthday card from Dr. Sinclair.