What to Eat & When to Eat for Longevity | Lifespan with Dr. David Sinclair #2

Introducing Episode Two: What to Eat & When to Eat for Longevity (00:00:00)

• Lifespan Podcast discusses the science of aging and ways to be healthier, hosted by Dr. David Sinclair, an aging research professor at Harvard Medical School.
• Episode two focuses on dietary timing and choices over a 24-hour period and throughout the year to optimize wellness and longevity.
• Dr. Sinclair shares his own protocols and findings from 20 years of research.

A Starting Place for Longevity: Eat Less Often (00:04:36)

• The key to longevity is to eat less often; this doesn't necessarily mean fewer calories but leads to calorie reduction as a side effect.
• Eating less often activates the body's defenses against aging, relevant to any weight, although optimal body weights and waist to height ratios (approximately 0.5) are associated with increased longevity.
• Eating less often tends to naturally result in weight loss and improved health.

Caloric Restriction is an Evolutionarily Conserved Anti-Aging Strategy (00:08:04)

• Caloric restriction is universally the most reliable way to extend lifespan across organisms from yeast to dogs.
• Studies show that animals live longer when their caloric intake is restricted.
• While supplementation can complement a diet focused on longevity, it is not a substitute for dietary control.

Dietary Longevity Strategies are Accessible (and Save Money) (00:09:52)

• Dietary strategies for longevity are cost-effective, as they can save money on food expenses.
• The recommended foods for longevity are relatively inexpensive.
• Research on yeast shows that caloric restriction can expand lifespan by activating certain genetic pathways.

A Low Energy State Triggers a Genetic Pathway Involving Sirtuin Activation (00:11:39)

• A low-energy state from caloric restriction activates a set of genes called sirtuins, increasing lifespan.
• Sirtuins are part of a genetic response to low energy and other stressors, improving DNA repair and stabilizing the epigenome.
• The sirtuin pathway gets boosted during caloric restriction, leading to improved longevity mechanisms at a cellular level.

NAD+ is Elevated by a Low Energy State (00:13:10)

• Low energy activates the PNC-1 gene in yeast and its human equivalent NAMPT, which produces NAD, fueling sirtuins to repair DNA and stabilize the epigenome.
• NAD levels in the human body increase when hungry, triggering protective actions of sirtuins.
• The discovery led to the development of NAD boosters, including the red wine molecule resveratrol and NAD precursor supplements such as NR and NMN.
• Yeasts with artificially activated PNC-1 or NAD boosters have increased longevity, while yeast without sirtuin genes don't benefit from caloric restriction.
• Low glucose activates cells' natural defenses, a process inherited from ancient organisms.

Fasting, mTOR, and AMPK (00:15:23)

• The activity of sirtuins is increased during fasting, impacting longevity-related mTOR and AMPK genes similarly.
• mTOR, activated by protein consumption, promotes cellular growth and the building of muscle but inhibits longevity when overactive.
• Reduced mTOR activity engages autophagy, recycling proteins, and extending lifespan dramatically in studies on flies and mice.
• AMPK is elevated in a state of hunger, stimulating the production of mitochondria that are vital for metabolism and producing energy.
• This process combats aging and increases energy and wellness.

Data in Humans vs. Model Organisms (00:17:37)

• Much longevity research comes from model organisms due to the challenges associated with human studies, including smaller sample sizes and longer durations required.
• Clinical studies, including double-blind trials with NAD boosters, are ongoing and provide scientific validity.
• Existing evidence for humans suggests that activating body defenses extends longevity, evident in the effects of rapamycin and metformin.
• Rapamycin appears to mimic fasting and boost immunity, while metformin, a diabetes drug, has been associated with delayed aging-related diseases.

Evidence that Fasting is a Pro-longevity Intervention in Humans (00:21:24)

• Observations from populations and cultural traditions that have practiced fasting suggest its benefits on health and longevity.
• Studies on populations like the genes in India show a higher number of healthy older individuals.
• A study from Baylor College of Medicine revealed fasting improves blood pressure, lowers BMI, and increases DNA repair proteins.
• Periods of fasting not only aid in weight loss but also activate the body's defenses in both obese and regular-weight individuals.
• Published research indicates various health improvements related to fasting, which viewers can find in the show notes.

Evidence that Fasting can Attenuate Human Disease (00:24:00)

• Fasting shows potential benefits against diseases such as type 1 diabetes, multiple sclerosis, and even cancer, especially when combined with chemotherapy.
• Prescription of metformin is increasing for cancer patients, as studies show benefits from fasting or fasting-mimicking molecules.
• The impact of fasting is thought to affect the upstream processes of aging and activate cellular defense mechanisms that fight a range of diseases, including macular degeneration.

Different Fasting Regimens (00:25:11)

• Fasting regimens differ widely and should be individualized based on lifestyle, tolerance, sex, and microbiome.
• It's crucial to measure the effects of diet changes using tools like Inside Tracker to optimize health over time.
• The fasting mimicking diet by Valter Longo lowers mTOR activity, is low in certain amino acids, and improves cancer patients' survival and recovery.
• Intermittent fasting (fasting longer than a day or up to a week) induces autophagy, especially after three days.
• Time-restricted feeding involves fasting for 16 hours or more and is a method practiced by Dr. David Sinclair, usually skipping breakfast and lunch and enjoying a large dinner.

Focus on Time-restricted Feeding (≥ 16 Hours of Fasting) (00:29:42)

• Aim for at least 16 hours of fasting each day and eat during an 8-hour window.
• Sleep counts as part of the fasting period.
• Skipping breakfast is an effective strategy, and the body can adapt to this routine over a few weeks.
• The process of gluconeogenesis in the liver compensates for lack of food intake, and helps prevent hunger spikes and crashes associated with eating.
• It's beneficial to gradually skip meals to avoid reactive hypoglycemia caused by sugar and insulin spikes from processed carbohydrate-heavy meals.

Continuous Glucose Monitors (00:33:26)

• Continuous glucose monitors (CGMs), such as those provided by Levels, allow individuals to track and manage glucose spikes and crashes.
• Personal experience with CGMs can help optimize diet by identifying foods that cause unhealthy blood sugar fluctuations.

Genetics Influence How an Intervention Affects Aging (00:34:24)

• Individual responses to dietary interventions can vary due to different genes and lifestyles.
• A mouse study by Jim Nelson showed that genetic diversity affects the response to caloric restriction, with varying effects on lifespan.
• Approximately half the mouse strains lived longer, while about a third lived shorter under caloric restriction.
• This suggests that caloric restriction doesn't always work and depends on genetics.
• Some mice and likely humans are more sensitive to certain diets.
• Individual trial and error with self-monitoring can help determine the best dietary approach.

A Trick for Fasting: Filling your Body with Fluids (00:36:51) and Intermittent Fasting with Adequate Nutrition (IFAN) (00:38:44)

• Dr. Sinclair struggled with fasting until discovering that staying hydrated with coffee, tea, and water curbs hunger.
• Consuming nuts can also quickly reduce hunger.
• Training the liver to produce sugar can eliminate feelings of hunger.
• The goal is not starvation but intermittent fasting with adequate nutrition (IFAN) to avoid harm.
• Proper nutrition is essential during fasting to prevent negative health effects.
• Athletic Greens is mentioned as a source of nutrients during fasting.

Things to Avoid: Excess Sugar and Protein (00:40:00)

• Consuming sugar and high levels of protein should be minimized.
• Sugar, particularly glucose and fructose, can lead to fatty liver disease and diabetes.
• High sugar levels deactivate protective mechanisms against disease and aging.
• Reducing sugar intake supports the body's defenses and minimizes disease risk.
• Excess protein can inhibit autophagy and negatively impact longevity.
• While proteins are necessary, they can be obtained from plant sources, which may be more beneficial.
• Dr. Sinclair has adopted a vegetarian diet and believes it could be advantageous for longevity.

Branched Amino Acids, Red Meat, and mTOR (00:45:16)

• Consumption of red meat leads to digestion into amino acids, particularly branched-chain amino acids like leucine, isoleucine, and valine.
• These amino acids activate the protein complex mTOR, which signals the body to build muscle and repair cells.
• Excessive activation of mTOR inhibits autophagy—a beneficial cellular recycling process that helps prevent the accumulation of old proteins related to aging and diseases like Alzheimer's.
• To promote longevity, it is beneficial to periodically reduce intake of branched-chain amino acids, allowing mTOR downregulation and autophagy.

Plant-Based Diets Protect Against Aging (00:47:53)

• Vegetarian and vegan diets, including Pesco vegetarianism (which includes fish), have been associated with lower all-cause mortality and a reduced hazard ratio for death.
• The Mediterranean diet, particularly when combined with exercise, has been shown to slow biological aging and potentially even reverse it.
• Eating the right foods and fasting can slow the ticking of the biological clock and reduce the incidence of diseases typically caused by aging.
• Plant-based diets with limited meat intake are effective in reducing biological aging.

The Okinawa Diet and Blue Zones (00:51:44)

• The Okinawa diet, which is plant-based with soy and some fish, is associated with longevity and was beneficial to health when personally adopted.
• Okinawans, who live on an island in Japan, have one of the longest life expectancies, attributed to their diet, social structure, and consistent exercise.
• Blue Zones are areas around the world where people live longer due to a combination of diet, exercise, and social aspects, despite some critiques about the accuracy of age data in these populations.
• Lifestyle factors in addition to diet play a significant role in longevity, and this concept is supported even in simple organisms like yeast.

Xenohormesis (00:54:16)

• Xenohormesis is the concept that eating plants which have experienced stress can benefit health and longevity due to their polyphenols like resveratrol.
• The idea suggests that humans evolved mechanisms to sense the stress in plants, which indicates environmental challenges and scarcity of food.
• Stressed plants produce more beneficial polyphenols such as quercetin, fisetin, and piceatannol, known to activate and inhibit certain proteins and pathways associated with health.
• Typically, plants grown organically, without pesticides, and in challenging conditions are likely to be more stressed and have higher levels of these molecules.
• Specifically stressed grape varieties like Pinot noir used in red wine production have high levels of resveratrol, a beneficial polyphenol.

Main Takeaways (00:58:16)

• Key actions to take for longevity include eating less often, avoiding snacking and sugary drinks, reducing meat intake, and favoring plant-based diets.
• The consumption of red and processed meats, associated with adverse health effects, should be minimized.
• The Mediterranean diet is recommended due to its balance and association with reduced mortality, even for older individuals.
• Dietary changes are never too late and can have significant benefits, even in later life.
• Meal order matters; sugar should be consumed at the end of meals to minimize blood sugar spikes.
• The prevalent habit of constant eating, especially in children, can prematurely age the epigenome and accelerate the onset of age-related diseases.

Obesity, Eating Habits, and Aging (01:04:12)

• The current food environment promotes constant eating, leading to an obesity epidemic and rapid aging in children.
• Being overweight turns off survival programs, accelerating aging and predisposing individuals to age-related diseases.
• Parents are advised to instill healthier eating habits in children, including familiarity with occasional hunger.

Metabolic Winter Hypothesis (01:05:54)

• The Metabolic Winter Hypothesis posits that human health and longevity are optimized under conditions of occasional hunger and cold, similar to ancestral environments.
• Modern lifestyles with constant food availability and temperature control run counter to these conditions, leading to metabolic and health challenges.
• Introducing elements of a 'metabolic winter' such as periodic hunger and exposure to cold can be beneficial.

Preview for Episode 3: Beneficial Stress (01:06:44)

• Episode 3 will discuss methods to induce stress in the body, similar to fasting and certain diets.
• Topics include exercise and cold therapy, which activate longevity genes.
• The episode will explore the combination of these methods for optimal longevity benefits.