Exercise, Heat, Cold & Other Stressors for Longevity | Lifespan with Dr. David Sinclair #3

Exercise, Heat, Cold & Other Stressors for Longevity | Lifespan with Dr. David Sinclair #3

Introducing Episode Three: Exercise Hot Cold (00:00:00)

  • The Lifespan podcast is hosted by Dr. David Sinclair, a genetics professor at Harvard, and Matthew LaPlante, his co-author and cohost.
  • The episode explores adversity mimetics, which are practices that can improve health and longevity.
  • They briefly touch upon the previous episode’s topic of iron and its relevance to aging.

A Pernicious Element Called Iron (Fe) (00:01:01) and A Quick Primer on Free Radicals (00:02:46)

  • Excess iron in the body is associated with accelerated aging.
  • Iron is essential for oxygen transport in hemoglobin, but high levels can be harmful.
  • Too much iron, especially ferrous iron, leads to free radical production, damaging tissues and causing senescent cell accumulation.
  • Three main types of free radicals are superoxide molecules, superoxide anion, and hydrogen peroxide.
  • High iron levels turn hydrogen peroxide into hydroxyl radicals, damaging DNA, RNA, lipids, and proteins.
  • People with the HFE gene mutation are more susceptible to iron overload.
  • Regular blood tests can help monitor iron levels, with blood donation being a potential remedy for those with hemochromatosis.

Review of Dietary Takeaways (00:05:42)

  • Dr. Sinclair recommends a plant-based diet and eating less frequently to turn on defensive genes against aging.
  • The three main defense mechanisms against aging are mTOR, AMPK, and sirtuins.
  • They argue for a diet and lifestyle that activates these protective genes through perceived adversity, such as fasting and exercising.

Biological Adversity and the Survival Circuit (00:09:32)

  • Adversity mimetics are practices that mimic biological adversity, known to enhance lifespan and health span.
  • The idea of a survival circuit was introduced, based on Cynthia Kenyon's 1990s research on longevity genes in worms.
  • Longevity genes like the DAF-2 insulin receptor and sirtuins were found to control the aging process.
  • These longevity genes activate survival and stress resistance pathways in response to environmental adversity.

Survival Sensors and Communicators (00:13:24)

  • mTOR, AMPK, and Sirtuins are cellular sensors that monitor environmental conditions such as amino acid levels, energy availability, and NAD levels, respectively.
  • Insulin acts as a cellular communicator that signals the presence of sugar in the body, telling cells to absorb and use it.
  • Adversity in human history activated these longevity defenses as a response to stress from being cold, hungry, or threatened by predators.
  • Modern comfort stifles these longevity defenses, leading to health issues.
  • Intermittent fasting with adequate nutrition (IFAN) can activate these defenses without negative consequences.
  • Bodies can be 'tricked' into a survival state, improving metabolism, alertness, and defense against diseases, despite the availability of food.

Get Off Your Butt and Exercise Protects against Disease and Mortality (00:17:25) (00:19:40)

  • Physical activity, such as standing, walking, or running, induces beneficial stress on the body.
  • Sitting leads to muscle atrophy, reduced hormone levels, and potential health issues.
  • Standing desks and other means of avoiding prolonged sitting can prevent these problems.
  • Regular exercise prevents diseases like cancer and cardiovascular disease, with up to a 23% and 30% reduction in risk, respectively.
  • All-cause mortality and aging are reduced by 27% with regular exercise.
  • Biological aging clocks, like the Horvath clock, can measure the effect of exercise on slowing the aging process.

Daily Step Count and Walking After Eating (00:21:17)

  • All exercise is beneficial; the 10,000 steps a day goal is a general guideline, with notable health benefits starting at 4,000-6,000 steps.
  • Walking after a meal can help regulate glucose levels and improve blood circulation.

Exercise Activates AMPK and Creates More Mitochondria (00:22:33)

  • Exercise activates AMPK, which senses low energy levels in the cell and leads to the creation of more mitochondria, providing long-term health benefits beyond the exercise period.
  • Both low-level and vigorous exercises are important, with vigorous exercise defined by increased breathing and heart rates.

Vigorous Exercise, Hypoxia, and the Electron Transport Chain (00:24:03)

  • Vigorous exercise induces hypoxia, which translates to low oxygen levels beneficial for health.
  • Hypoxia activates HIF-1alpha, triggering genes responsible for new blood vessel growth and enhancing mitochondria.
  • During vigorous exercise, lack of oxygen leads to free radical generation, specifically superoxide radicals.
  • Electrons in the mitochondria are normally used in the electron transport chain to produce ATP.
  • Reduced oxygen levels cause these electrons to create free radicals, leading to cell damage - a process called mitohormesis.
  • Mitohormesis can stimulate the production of more mitochondria and improve energy levels over time.
  • Vigorous exercise increases mitochondria and blood vessel count, which diminish as we age, but there are ways to reverse this process through exercise and other interventions.

Exercise Increases Glucose Sensitivity and Stimulates Blood Vessel Formation (00:28:19)

  • A small amount of stress, like exercise, improves bodily functions, such as increasing insulin sensitivity and blood vessel formation.
  • As people age, muscles and brains become less sensitive to insulin due to cellular identity loss and decreased GLUT4 transporter proteins.
  • Glucose inability to enter cells leads to type 2 diabetes and cardiovascular disease from blood vessel lining damage.
  • Exercise stimulates the production of VEGF, promoting new blood vessel growth in response to muscular activity.
  • PGC-1alpha, a transcription factor, boosts VEGF production, which then causes endothelial cells to create new capillaries.
  • Aging impairs this VEGF response, even with exercise, but NAD production activated through exercise can restore muscle youthfulness and stimulate blood vessel growth.

The Epigenome and Biological Age are Impacted by Exercise (00:32:13)

  • Exercise impacts the epigenome, which regulates gene activity.
  • A healthy lifestyle and exercise can make an individual's epigenetic age younger according to biological clocks like the Horvath clock or the proteomic clock.
  • GDF15, a protein that changes over time, is a marker for biological age.
  • Studies indicate that aerobically active individuals are epigenetically younger by about five and a half years compared to sedentary people.
  • Biological age can predict mortality, but about 80% of future health is modifiable, suggesting lifestyle choices can significantly affect aging.

How to Measure your Biological Age (00:36:43)

  • Biological age can be measured through blood tests or DNA tests, with services offered by companies like InsideTracker.
  • A methodology developed at Dr. Sinclair's lab could reduce the cost of biological age testing to under a dollar.

Exercise Recommendations (00:37:31)

  • Exercise does not have to be running; any physical activity that increases heart rate and breathing is beneficial.
  • The World Health Organization and Mayo Clinic recommend at least 75 minutes of vigorous exercise weekly.
  • Even with a busy or unhealthy lifestyle, 10 minutes a day of elevated heart rate exercise is achievable.

Wearables and Individualized Health Tracking (00:39:28)

  • Monitoring fitness parameters like resting heart rate can be done through wearables like fitness rings or watches.
  • Modern bio monitors can track numerous health metrics many times a second, potentially predicting medical conditions.
  • Long-term health tracking enables individuals to optimize their health and provide valuable data during medical consultations.
  • Advances in wearable technology are integrating more with exercise and health management.

The Importance of Weight Training (00:43:14)

  • Weight training is an enjoyable form of exercise that is beneficial for maintaining hormone levels, posture, muscle mass, and bone strength.
  • Engaging in weight training regularly helps counteract the natural loss of muscle mass that occurs with aging, approximately 1% per year.
  • Adequate muscle mass and flexibility, especially around the waist, reduce the likelihood of breaking bones during falls, which can be as severe as having metastatic cancer in terms of mortality rates.
  • Building and maintaining muscle through weight training can naturally boost testosterone levels more effectively than topical applications or injections.

Physical Activity and Senescent Cells (00:46:08)

  • Senescent cells, or "zombie cells," secrete harmful chemicals and contribute to aging and disease.
  • A study indicated that a 12-week exercise program can decrease the number of senescent cells.
  • Exercise, lifestyle choices, certain supplements, and drugs can either slow the formation or eliminate senescent cells from the body.

Exercise Wrap-up and Takeaways (00:48:01)

  • Low-level exercise such as walking, even below the often suggested 10,000 steps, is beneficial.
  • High-intensity exercise a few times a week is important for vascular health and mitochondrial function.
  • Muscle-building exercises are essential for maintaining hormone levels and overall health. They're simple to do and can be performed at home without a gym.
  • The overarching goal of exercise is to trigger longevity genes through adversity mimetics, which promote longevity.

Hyperbaric Oxygen Therapy (HBOT) (00:49:47)

  • Hyperbaric oxygen therapy (HBOT) is acknowledged as an adversity mimetic akin to exercise, impacting cellular and genetic levels.
  • Wound healing benefits from increased oxygen, with theories suggesting hormesis or better tissue growth from enhanced oxygen supply.
  • HBOT involves a pressurized environment which boosts oxygen intake; it's used by the military and is becoming popular for treating neurological disorders and aging.
  • A study in Israel showed HBOT could reverse telomere shortening, potentially slowing aging and extending life, with impressive results in mice and humans.
  • Data indicated HBOT reduced Alzheimer's plaques and tangles in mice and improved dementia and Parkinson's in humans.
  • Human studies suggested increases in cognitive performance, telomere length, T helper cells, and reductions in senescent cells.
  • The theory behind HBOT's effectiveness posits it may work similarly to the benefits derived from hypoxia during exercise, involving HIF-1alpha protein and a mitohormesis response.
  • The Israeli study protocol included 60 sessions lasting 90 minutes each, showing reversals in aging markers and a decrease in senescent immune cells.
  • HBOT's accessibility is improving as it becomes more popular, with the potential to mimic exercise benefits for those unable to perform physical activity.


  • HBOT is an emerging and promising therapy for longevity and health, offering benefits similar to physical exercise and the potential for cognitive improvements and anti-aging effects. The treatment is scalable, and research is ongoing to fully understand its mechanisms and applications.

Cold Therapy (00:57:24)

  • Cold therapy is a form of stress that triggers the production of brown or beige fat, beneficial for metabolic health.
  • Brown fat, also found in adults, burns white fat and secretes health-promoting proteins.
  • The gene PRDM16 is crucial for converting white fat to brown; its absence leads to health problems like diabetes and cardiovascular disease in mice.
  • Being cold has been shown to have longevity benefits in various organisms, including an increased lifespan observed in cold-stressed dwarf mice, albeit due to an unintended cold environment.
  • Mitochondrial uncoupling proteins (UCPs) in brown fat can reduce free radical production and have been associated with longer lifespans in different species.
  • Cold therapy, also known as cryotherapy, induces shivering and stimulates brown fat production, which may have lasting health benefits.
  • Establishing cold-resistant brown fat reserves at a younger age is recommended, as older mice are less efficient at producing it.

Applying Heat (01:03:50)

  • Heat stress, like sauna use, prompts the body to activate heat shock proteins (HSPs), aiding in protein folding and stimulating pathways for new blood vessels and more mitochondria.
  • Regular sauna sessions are associated with a lower rate of cardiovascular disease and related mortality, but optimal sauna usage guidelines are not well-established.
  • Both extreme heat and cold treatments are seen as ways to shock the body for potential health benefits, termed adversity mimetics.
  • No conclusive evidence shows that excessive sauna use is harmful, but medical consultation is recommended.
  • Alternatives like hot showers can simulate the effects of sauna for those without access to one.
  • Infrared saunas are believed to penetrate the skin and may reverse aspects of skin aging and improve hair growth.

Adversity Mimetics Produce Endorphins (01:07:04)

  • Endorphins are released when engaging in vigorous exercise, cryotherapy, or heat therapy, providing a sense of well-being.
  • A physical indication that beneficial longevity protocols are working is the release of endorphins at the neurological level, concurrent with the activation of cellular defense pathways.
  • The pleasurable effects from endorphin release after these stress-inducing activities suggest that the body is responding positively to the induced adversity.

A Basic Protocol for Mimicking Adversity (01:08:07)

  • Individuals can vary in their response to protocols for exercise, cold, heat, and hyperbaric exposure.
  • A recommended routine involves cycling through heat and cold exposure about five times in one day of the week, potentially even daily.
  • Exercise is essential and previously discussed.
  • Cold exposure can be achieved with cold showers or baths at home if gym access is limited.
  • Hyperbaric oxygen therapy is likened to exercise and hypoxia at the molecular level but is less accessible due to cost and availability.
  • Safety is important, and extreme exercises like underwater weight training are not recommended for the general public.

Next Week’s Episode: Molecules and Supplements (01:10:04)

  • Future discussions will cover exciting developments in longevity, including the use of molecules and supplements to mimic the benefits of physical and environmental stressors.
  • The next episode will delve into how pills and injections can simulate the stress of exercise and other adversities that contribute to longevity.
  • There is anticipation that this topic will garner high interest and possibly be one of the most downloaded episodes.

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