What to Eat & When to Eat for Longevity | Lifespan with Dr. David Sinclair #2
In a Nutshell
Eat less often through time-restricted feeding (e.g., 16-20 hour fasts, one meal a day) to activate sirtuins, AMPK, mTOR inhibition, and autophagy, mimicking calorie restriction's lifespan-extending effects seen across species, including humans via fasting studies and blue zone diets. Prioritize plant-based eating (Mediterranean, Okinawan, pesco-vegetarian) low in sugar, fructose, and branched-chain amino acids from red meat to avoid glucose spikes, glycation, and defense shutdowns while leveraging xenohormetic polyphenols from stressed plants like organic veggies, olive oil, and Pinot noir. Track biomarkers with tools like Inside Tracker and CGMs to personalize, aiming for stable low glucose, leanness (waist-to-height 0.5), and reversed biological age for longevity.
These notes were generated by AI and may contain inaccuracies.
Welcome to the Lifespan Podcast, discussing the science of aging and how to be healthier at any stage of life. David Sinclair is a professor at Harvard Medical School researching the biology of aging and co-director of the Center for the Biology of Aging. Joined by co-host and co-author Matthew LaPlante. This is episode two, covering when to eat and what to eat within 24-hour periods and over a year to maximize wellness, appearance, and longevity. David shares protocols developed over 20 years. Episode one covers fundamental biology.
Levels: App that syncs with a continuous glucose monitor they provide, interprets glucose data. David joined as advisor. Monitors blood glucose to see food impacts. White rice and grapes spike his blood sugar; potatoes do not. Stable blood glucose important for daily mental/physical energy and long-term health. Try at levels.link/sinclair to skip 150,000-person waitlist.
Athletic Greens: All-in-one daily greens supplement with 75 vitamins, minerals, whole food ingredients, adaptogens for recovery, probiotics, prebiotics, digestive enzymes for gut health, vitamin C, zinc citrate for immune support. David drinks it mornings, especially when traveling. Try at athleticgreens.com/sinclair for five free travel packs + year's supply of vitamin D3 and K2. Vitamin D3 for immune system; K2 keeps calcium out of arteries into bones.
Inside Tracker: Personalized nutrition platform analyzing blood and DNA data for health goals. David has used for over a decade, chairs scientific advisory board. Best blood/DNA analysis; easy blood draw at clinic or home (10-15 minutes). Presents analysis with graphs, diet/lifestyle recommendations to improve biomarkers. Inner age test compares biological to chronological age, suggests improvements. Try at insidetracker.com/sinclair for 25% off using code Sinclair.
One starting place for health advice: eat less often. Biggest impact on longevity from science discussed.
Eat less often. Those three words, eat less often.
Not necessarily fewer calories, though that can happen naturally. David now does one meal a day, shed weight, maintains with larger dinner to avoid malnutrition. Packing calories into shorter period means less calories inevitably, but key is period of not eating boosting body's defenses against aging. Works at any weight; lab showed obese mice tricked into thinking fasted live as long as skinny mice. Optimal body weights exist; excess weight accelerates aging clock. Waist-to-height ratio optimal at 0.5 for humans. Leaner people live longer, but not necessary for fasting benefits. Eating less often causes weight loss as side effect; David lost 15 pounds since pandemic start, looks/feels better. Eases into lifestyle for decades longer life.
Most fasting research on model organisms, but universal effects seen.
Most reliable way to extend lifespan of any animal or yeast: restrict calories. Works on yeast, spider, fish, worm, pet Labradors. 2002 study: 25% calorie reduction lengthened Labrador lifespan from 12 to 14 years (1.8 years extension).
David went to MIT in 90s to figure out how calorie restriction works to bottle it. Now at that point; pills + diet give additive doubling effect. Supplements in another episode. Focus: maximize when/what to eat. Saves money; recommends cheap foods.
Studied yeast (used for bread/beer, microscopic). Named them like pets, followed lifespans, spent 14-16 hours/day, removed daughters to count divisions. Reducing glucose from 2% (25 divisions) to 0.5% (25% concentration) extended to over 30 divisions. Triggers genetic pathway, not just glucose hurting cell. Sirtuins (5 in yeast, 7 in humans) respond to low energy, other stresses (high heat, low amino acids, high salt) via hormetic effects (what doesn't kill makes stronger). Sirtuins do DNA repair, stabilize epigenome.
Low energy activates PNC-1 gene (human equivalent NAMPT), makes NAD fuel for sirtuins. In caloric restriction/fasting, more NAD boosts sirtuins for protection.
This led to NAD boosters (NR, NMN) from David's lab, plus resveratrol/other plant molecules (2000s craze). Mimic low glucose; deleting sirtuins abolishes calorie restriction benefits. Low glucose activates natural defense state inherited over billions of years.
Glucose doesn't hurt you, it's that the low glucose is activating the natural defense state of that cell.
Glucose is bad, but not for thought reason.
mTOR (mammalian target of rapamycin): registers amino acids. Big protein meal (steak) activates to build things (e.g., muscle), but not for longevity. Downregulating mTOR extends life via autophagy (recycles old proteins into fresh ones when hungry). Inhibiting mTOR/stimulating autophagy extends fly/mice lifespan dramatically (30%).
AMPK (AMP-activated protein kinase): responds to low energy, rises when hungry. Makes more mitochondria (lost with age; gained with exercise). Mitochondria metabolize food, make energy. Activating AMPK gives more energy, fights aging.
Much research in model organisms; human studies fewer/smaller, take time/expensive. Provide references for informed decisions on diets/lifestyles/meds/supplements.
Sirtuins, mTOR, AMPK signal tough times, trigger metabolic shift to defense state.
Clinical studies (e.g., 2-year placebo-controlled NAD booster trials at Harvard). Self-experimentation (anecdotal, guides trials; ~1% US population not waiting). Evidence modulating defenses extends human longevity.
Low-dose intermittent rapamycin (mTOR inhibitor) mimics fasting, boosts immunity, gives fasting-like biochemical changes predicting longevity.
Metformin (diabetes drug, activates AMPK): in tens of thousands with type 2 diabetes, slows diseases of aging.
Fasting/drugs mimicking it important for long-term health/wellness.
Population evidence: Jains in India (most over-70s in good health vs. other groups, even vegetarians). Christians fast; Muslims do Ramadan. Not coincidences; activates three longevity defenses (sirtuins, mTOR, AMPK). Feel/look better, disease resistant, may cure diseases.
Baylor College of Medicine study (published last year): dawn-to-sunset fasting 4 weeks improved blood pressure, reduced BMI/weight circumference, upregulated DNA repair proteins.
Dozens of studies: fasting benefits obese (weight loss + defenses, insulin sensitivity, lower glucose) and normal weight. Benefits type 1 diabetes, multiple sclerosis, cancer (esp. fasting + chemotherapy double benefit). Mimics like metformin help (e.g., prescribed for prostate cancer).
When seeing multiple disease states affected, aging is the upstream factor being targeted. The three defense components in the cell—autophagy, sirtuins, AMPK—protect the body not just from aging but fight diseases in young people, middle-aged, genetic diseases. Macular degeneration has been shown to be slowed and even reversed by fasting.
Fasting and calorie restriction discussed broadly; online recommendations vary widely and are confusing. Recommendations must consider individual factors: lifestyle, tolerance for pain and hunger, sex (female or male), microbiome. Try different approaches; if one doesn't work, try another. Use Inside Tracker to measure biomarkers for objective feedback on whether exercise, diet, or eating timing is working. Speaker has optimized diet over 30 years by measuring, not guessing. Analogy: wouldn't drive a car without a dashboard; bodies are more important.
Fasting Mimicking Diet (FMD)
Valter Longo (UCLA colleague) proponent of fasting mimicking diet, lowers mTOR activity, low in branched-chain amino acids (BCAAs). Mimics fasting effects through food; body perceives adversity (running out of food). Plants have fewer BCAAs, responds to low amino acid input. FMD helps cancer patients survive and recover from chemotherapy quicker.
Extended Fasting
Intermittent fasting or just fasting: periods longer than a day (some do 3 days, up to a week max to avoid muscle loss). Does deep cleanse, turns on autophagy for recycling proteins. Beyond 3 days, switches to chaperone-mediated autophagy (deep cleanse).
Time-Restricted Feeding (TRF)
Speaker practices time-restricted feeding: at least 16 hours not eating (or very little), 8-hour eating window. Skip breakfast or dinner (prefer skipping breakfast, late lunch). Leverages sleep (easy no-eating period), add hours before/after. Skipping lunch less helpful. Speaker skips breakfast (habit since teenager), has tea/coffee, minimal yogurt (couple spoons) to mix supplements—burns off in 15 minutes. Eats largish dinner (specific foods discussed later). Gives >20 hours without external glucose. Body adapts in weeks via gluconeogenesis (liver generates glucose), overcomes hunger.
Initially hungry, nervous; push through at least 2-3 weeks. Liver learns to produce steady glucose, avoids spikes/crashes leading to hunger.
Ramp up: skip one meal first, then two. Avoid reactive hypoglycemia from carbs (toast, orange juice): insulin spike sucks glucose, causes crash, ghrelin release, hunger. Now speaker has steady glucose from wake-up to dinner: focused, no brain fog/shakiness. Wish started in 20s.
Measure with continuous glucose monitors (sponsor Levels): stick on arm, tracks glucose. Identifies foods causing spikes/crashes (white rice, toast, grapes bad; potatoes okay). Optimizes diet to avoid post-meal crashes. Responses vary by genetics, microbiome.
Jim Nelson's mouse study: similar strains (Black 6, white) crossed for genetic diversity (~100 strains). Standard calorie restriction (~35% less than ad libitum): half strains lived longer, third of remainder lived shorter. Genetics matter; some more sensitive. Test on self, measure.
We're all lab rats experimenting.
Critics say no self-experimentation or CGMs; counter: then ban bathroom scales.
Speaker experiments openly, adjusts over time (starts/stops). Made mistakes: wrong foods, too much eating, poor Inside Tracker results.
All fasting types beneficial. Trouble when unprepared (e.g., skip lunch without mindset). Trick: fill with fluids (constant coffee, tea, hot water) eliminates hunger. If needed, nibble nuts (protein rapidly reduces hunger). Cardiologist John Day: handful of nuts, wait 20 minutes, hunger gone.
Protein and hunger: Stephen Simpson (Australia) studied locusts—low protein triggers swarming, cannibalism. Mice on low protein get aggressive. Don't go too low.
Speaker's routine: trained liver for steady sugar; liquids if hungry, nuts if very hungry. Got 20-year-old body back, never going back. Initial hunger expected, but worth it.
IFAN: Intermittent Fasting with Adequate Nutrition (not starvation). Athletic Greens provides nutrients (speaker drinks in morning).
Sugar biggest killer, especially fructose (causes fatty liver, diabetes in animals). Glucose spikes bad for three reasons:
- Glycation: glucose attaches to proteins (caramelized body parts), lowers longevity, causes type 2 diabetes, cardiovascular disease.
- Shuts off defenses (AMPK, sirtuins).
- Causes brain fog.
Keep glucose low/consistent: no glommed proteins, defenses on, no fog. Gave up dessert at 40 (steals occasionally—doesn't count). Not draconian; occasional okay, not nightly.
Avoid super high protein: activates mTOR constantly, prevents autophagy. Carnivore diets: short-term gains (feel better, build muscle) if athlete/bulking, but long-term no evidence for longevity (counter-evidence). Populations with low meat live longest. Inhibits mTOR, sirtuins.
Aminos essential (from plants/animals). Speaker recently vegetarian (not vegan yet—may be better). Plants mostly protein (less bioavailable—body works harder, activates defenses, burns energy).
Effects of Meat
Digest meat: stomach acid breaks to aminos, microbiome uses some, rest to blood. Key: leucine, isoleucine, valine (BCAAs)—sense protein via mTOR. High BCAAs (esp. leucine) activate mTOR: build muscle, repair cells (feel great). But mTOR better at autophagy for longevity.
Autophagy good (no debate): recycles modified proteins (e.g., Alzheimer's accumulation in brain/all tissues). Reversible by fasting or low BCAAs.
Advice: eat meat if wanted, but focus plant-based more often for mTOR downregulation periods.
Primarily plant-based diets include vegan, Mediterranean, Okinawan, and lacto-ovo vegetarian. These can be grouped as blue zone diets.
Large study by Adventist Health Group (2013) calculated hazard ratios for mortality based on diets in thousands of people. Hazard ratio ranges from 0 to 1; lower means reduced chance of dying (e.g., 0.80 = 20% less chance daily).
- Non-vegetarians: 1.0
- Semi-vegetarians: 0.92
- Lacto-ovo vegetarians: 0.91 (9-10% reduction)
- Vegans: 0.85 (15% reduction)
- Pesco-vegetarians (little fish): 0.81 (19% reduction); fish oils likely beneficial.
This is all-cause mortality. Diets also reduce biological aging per studies using aging clocks.
One-year study on mostly vegetarian diet. Exciting two-year study (recent, mostly women): Mediterranean diet + exercise reduced biological age.
- Diet: limit alcohol (red wine fine), little fish, olive oil as fat, mostly plants.
- Exercise: walking, weightlifting.
- Fourier study from Geovanna Masala's lab at Italian Cancer Institute.
Reducing biological aging cuts diseases at source, as diseases stem from aging. Mediterranean diet + fasting slows/reverses biological age.
"It's possible by changing your diet to reverse your biological age."
Okinawan diet (mostly carbs like rice, better with brown rice to avoid glucose spike): Chinese/Japanese vegetables (organic, fresh, green, vitamins), soy, little fish. Sinclair followed it (Wilcox brothers' 2000s book), looked/felt great until kids led to pizza.
Okinawans (island of Japan) arguably longest-lived; also have social structure, exercise (work into 90s/100s). Lifestyle optimal for longevity. Okinawans moving to Hawaii don't live as long.
Blue zones: communities worldwide with long-lived people share diet, exercise, social structure. Criticism (Dr. Harriet Hall) on age data accuracy, but records validated (Dan Buettner); out of hundreds, one error (111 vs. 107).
Areas with right foods + exercise + social live longer. Even yeast live longer on modified/time-restricted diets. Not controversial.
Xenohormesis (coined by Sinclair + Konrad Howitz mid-2000s): explains why plant molecules benefit us. Prompted by 2003 Nature paper (co-published) finding 20 polyphenols activate Sirt1 (top sirtuin).
Polyphenols (resveratrol in red wine, piceatannol, fisetin, quercetin) activate/inhibit pathways for health/longevity precisely.
"That cannot be coincidence... no way that could just happen randomly."
Humans sense stressed plants as food shortage warning (plants wilt, dehydrated). Stressed plants produce more resveratrol, quercetin, piceatannol (e.g., low water/nutrients, preyed by caterpillars).
All plants have sirtuin genes, make polyphenols to survive stress. Modern farming grows fast, unstressed plants (profitable but low beneficial molecules).
Choose: organic, field-grown (no pesticides, most stressed), local, colorful (plant defenses). Intentionally stressed: red wine (dehydrated/fungus vines taste better, more color). Stress-sensitive grapes like Pinot noir have most resveratrol.
- Eat less often: skip one meal/day, no snacking.
- Avoid sugary drinks/foods; use artificial/natural sweeteners (e.g., Stevia).
- Reduce meat (data shows benefits, especially less red/processed to prevent cancer, longevity).
- Red meat: branched-chain amino acids block mTOR benefits; TMA → TMAO (toxic, accelerates cardiovascular disease/cancer).
- Occasional steak fine; limit nitrates/preserved meats.
- Push to plant-based/focused: veggies, occasional red wine, lots olive oil (oleic acid activates sirtuins).
- Mediterranean diet easiest in West, biggest impact; Sinclair lived on it >10 years.
Mediterranean vs. Western diet studies (2000 + 5 more): under 80, reduces mortality 31%.
Never too late (even elderly). Lean better than fat in old age (nursing homes: skinny little women survive, not obese men).
Eat veggies (stressed for xenohormetic effect). Meal order: sugar/carbs last to reduce glucose spike (dessert end fine; starting spikes glucose).
Candy/snacks make lethargic post-crash.
Food industry pushes constant eating (breakfast best, snacks, never hungry). Obesity epidemic in kids sets epigenome for feast (not famine), accelerates aging now + diseases in 20-30 years.
Obesity = accelerated aging.
Parents: teach kids hunger OK occasionally; no constant food/snacks. Evolved for metabolic winter (cold, hungry 100k-6M years ago); now AC/heated homes + constant food suboptimal.
Need occasional hunger/cold for bodies to fight disease, ultimate health, longevity.
Exercise, cold therapy, etc., create adversity states activating longevity genes. Best combos emerging.
Keep David Sinclair in your library
Save the videos and channels worth coming back to, and find them again in one place.
