Longevity Biologist Reveals Shocking Truth About Fasting, Autophagy & Longevity - Dr. Kaeberlein

What’s truly crazy, once you read The Silent War on Health you realize how blinded you were, but it’s never too late. That book has serious knowledge.

Cliff notes: Circadian Timing and Fasting: Timing of eating impacts fasting and caloric restriction effectiveness due to circadian rhythms. Eating out-of-sync with circadian rhythms may diminish some benefits of fasting and caloric restriction. Fasting, mTOR, and AMPK: Fasting inhibits mTOR and activates AMPK, shifting metabolism differently depending on tissue type, duration of the fast, and individual responses. Long fasts (multiple days) significantly affect hormones and growth signaling and could lead to muscle and bone loss. Short-term fasting (e.g., 16 hours) doesn’t cause these negative effects. mTOR and Longevity: mTOR acts as a "gatekeeper," sensing nutrient availability to signal growth and reproduction. Lower mTOR signaling (from fasting or caloric restriction) is associated with stress resistance, slowing aging, and potentially increasing lifespan. Rapamycin, a specific inhibitor of mTOR Complex 1, clearly extends lifespan in animal models, but it's still unclear if mTOR inhibition alone fully explains longevity benefits from fasting and caloric restriction. Complexity in mTOR Activation: mTOR activation isn't universally good or bad; muscle growth requires localized mTOR activation in muscle tissue, even if fasting globally inhibits mTOR. Exercise and fasting may simultaneously send conflicting signals (exercise increases muscle mTOR signaling; fasting suppresses systemic mTOR signaling). The net result depends on duration and context (e.g., chronic fasting vs. acute fasting). Inflammation, Fasting, and Muscle Growth: Chronic inflammation (common with aging) negatively impacts muscle growth. Fasting (and rapamycin) reduces chronic inflammation, potentially enhancing muscle growth indirectly. Fasting may briefly reduce inflammation, but this benefit might be lost if fasting ends with overeating, causing inflammation spikes. Caloric Restriction vs. Fasting for Longevity: Animal studies consistently show that caloric restriction dramatically increases lifespan (up to ~60%) in rodents, but fasting alone (without caloric restriction) doesn't consistently provide longevity benefits. Circadian timing matters: Eating aligned with circadian rhythms enhances caloric restriction benefits. Autophagy: Autophagy recycles cellular components and mitochondria, stimulated by both fasting and rapamycin through mTOR inhibition. Exercise boosts autophagy more effectively than fasting, and the autophagy stimulated by fasting might vary significantly across tissues. It's challenging to precisely measure autophagy and differentiate beneficial versus pathological forms, as current biomarkers are indirect. Practical Takeaways: Short-term fasting, combined strategically with exercise, likely beneficially affects inflammation, insulin sensitivity, and metabolic health without significant muscle loss. Chronic, prolonged fasting or excessive caloric restriction may negatively affect muscle growth, recovery, libido, and general well-being. Summary (Bottom Line): Fasting, caloric restriction, mTOR, and autophagy are interconnected processes that influence aging, health, and longevity. Short-term or strategic fasting, combined with nutrient timing, exercise, and caloric balance, provides health and potential anti-aging benefits. However, it's nuanced—chronic fasting may have detrimental effects. The key factor for longevity (in animal studies) appears to be caloric restriction rather than fasting alone.

The discussion revolves around the complex interplay between fasting, circadian rhythms, caloric restriction, and their effects on cellular mechanisms like mTOR (mechanistic Target of Rapamycin) and AMPK (AMP-activated protein kinase), which are linked to longevity and metabolic health. Key points include: 1. **Circadian Rhythms and Fasting**: The timing of fasting relative to circadian rhythms is crucial. Mice that eat opposite their circadian rhythm while calorically restricted lose some benefits of caloric restriction, indicating that when you eat matters. 2. **Fasting and Cellular Mechanisms**: Fasting inhibits mTOR and activates AMPK, shifting metabolism in ways that depend on cell or tissue type. The effects vary based on the duration of fasting, with longer fasts leading to more pronounced systemic effects like muscle loss and reduced bone density. 3. **Longevity and Caloric Restriction**: Caloric restriction and fasting share overlapping benefits, but the exact mechanisms driving longevity are unclear. Inhibiting mTOR, which fasting does, is sufficient to slow aging and increase lifespan, but it's not proven to be the sole reason for the benefits of fasting or caloric restriction. 4. **Intermittent Fasting vs. Time-Restricted Eating**: Intermittent fasting (24-hour fasts) and time-restricted eating (eating within a shorter daily window) have distinct biological effects. Intermittent fasting may have anti-inflammatory benefits that persist beyond the fasting period, especially if overeating is avoided during refeeding. 5. **Exercise and Fasting**: Exercise can activate mTOR in muscles, potentially counteracting the mTOR inhibition from fasting. The net effect on muscle growth and metabolism is complex and likely varies by individual. 6. **Autophagy**: Fasting boosts autophagy, a cellular recycling process, primarily through mTOR inhibition. Autophagy is linked to longevity, particularly in model organisms like nematode worms, but its role in mice and humans is less clear. 7. **Inflammation and Refeeding**: Fasting reduces inflammation, but refeeding, especially with unhealthy foods, can spike inflammation and negate some benefits. The type of food consumed after fasting matters. 8. **Practical Takeaways**: Fasting can be a powerful tool for weight management and metabolic health, but its effects are highly individual. Short-term fasting is generally safe, but long-term fasting or chronic underfeeding can impair muscle growth and recovery. Overall, the conversation highlights the nuanced and multifaceted effects of fasting on health and longevity, emphasizing that while fasting has potential benefits, its impact depends on factors like timing, duration, and individual health goals.

I fasted 3 times for 21 days (no food, took water, salt, baking soda, "no" salt and coffee). I felt great. Still gain muscle easily. I was overweight, so wasn't "starving." A digestive issue I've had my whole life is absolutely gone. I also felt great, alert, focussed. Also all joint pain and sciatica gone. Moles and scars disappeared. I just recently did a 31 day fast. Hair grew fast during this time and I was walking 6 miles a day (again, I'm not thin). Previously (21 days) I gained weight back. This time I gained about 5 lbs (water assuming) but am noticing feeling "stable." Planning on next fast being longer (i seem to be insulin resistant), so plan to continue until glucose is at a healthy number and stable).

I believe that results speak. I have been intermittent fasting for 6 years. 16:8. Results? I have lost 75lbs and kept it off. My testosterone has spiked. My muscle mass has increased. I have much more energy. Libido is off the charts. My blood pressure is down. Strong muscle strength and endurance. My doctor after my last physical said "Keep doing what you are doing" - That's good enough for me.

Eating healthy, exercising, and reducing stress are the keys to a prolonged life.

You ask about insulin and he deflects the question by talking about inflammation instead. But he loves talking about caloric restriction when Dr. Jason Fung showed it's not a good way to try to lose weight and keep it off. Insulin plays a key role and the calorie model doesn't apply to biology, it's a physics model. People don't want to give it up though.

I fasted 20 hours or longer daily years ago. Very effective to regulate my BG bringing it back to normal (insulin sensitive)all my arthritis swollen snuggles shrunk significantly, no pain and no hunger and no cravings. But i got too skinny and hardly get my weight back. Someone online informed me to do resistance training with bands and eat lots more protein. I followed what he said. i got a normal weight back, muscles clearly showed, and i dropped my fast 14 to 18 hours depending my mood, but every day after my exercise routine. My snuggles are swollen back again. Clearly short fast doesn't impact arthritis and inflammation but long fast at least 20+ hours or omad.I give up. Human body is very conflicted. You cannot get all perfectly. Health videos we watch on YouTube are conflicted too. One day it says something, the next month it says a totally different thing.

I’ve found that fasting and time restricted eating have two real health benefits. First, I have found that regular time restricted eating really helps strengthen my circadian rhythm. Second, I have become really fat adapted. Having a body that regularly goes into ketosis seems to have helped me stay really healthy.

The real secret to longevity is mental state. Most centenarians lived care free lives and didn't worry about all this. Poor mental health promotes poor physical health. Social media promotes poor mental health. Cultivate a calm mind. These interventions are free and will improve both physical and mental health and anyone can do them. The Full Breath by James Francis.