#038 Dr. Guido Kroemer on Autophagy, Caloric Restriction Mimetics, Fasting & Protein Acetylation
Dr. Guido Kroemer, a professor at the University of Paris Descartes and expert in autophagy, discusses how nutrient deprivation, exercise, and specific "fasting mimetics" like spermidine and resveratrol activate autophagy, a crucial cellular clean-up process for health and disease prevention.
Deep Dive Analysis
13 Topic Outline
Introduction to Autophagy and its Cellular Regulation
Defining Autophagy: Process, Purpose, and Stress Adaptation
Nutrient Deprivation as a Physiological Inducer of Autophagy
Acetyl-CoA's Role in Protein Acetylation and Autophagy Activation
Challenges and Potential Biomarkers for Measuring Autophagy in Humans
Fasting Duration for Autophagy: Rodent vs. Human Differences
Exercise-Induced Autophagy and its Anti-Diabetic Effects
Specific Autophagy Types: Mitophagy, Pexophagy, Virophagy, and Ribophagy
Mitophagy: Selective Degradation of Damaged Mitochondria and Biogenesis
Autophagy's Role in Preventing and Treating Neurodegenerative Diseases
Autophagy's Dual Role in Cancer: Suppression, Reactivation, and Immune Response
Fasting Mimetics: Hydroxycitrate, Spermidine, and Resveratrol Mechanisms
Personal Fasting Practices and Coffee's Autophagy-Inducing Properties
7 Key Concepts
Autophagy
A cellular self-digestion process where portions of the cytoplasm, including organelles, protein aggregates, bacteria, or viruses, are sequestered by an autophagosome and then digested by lysosomes. Its primary goal is adaptation to stress and prevention of cell death by recycling material and degrading macromolecules.
mTOR Pathway
A cellular pathway activated by IGF-1 and protein consumption, particularly essential amino acids, involved in protein synthesis, cell growth, and proliferation. Autophagy is induced when mTOR activity decreases, often due to nutrient restriction.
AMP Kinase (AMPK)
A cellular pathway activated when ATP levels decrease, typically in a fasted state. It regulates cellular energy by inhibiting fatty acid and triglyceride synthesis while activating fatty acid uptake and beta-oxidation, and its activation is associated with autophagy induction.
Cytosolic Acetyl-CoA Pool
A central metabolite whose concentration in the cell's cytosol directly influences protein acetylation levels. Reductions in glucose, amino acids, or fatty acids decrease this pool, leading to protein deacetylation and a multi-pronged induction of autophagy.
Autophagosome
A mouth-like structure that forms within the cell to sequester portions of the cytoplasm, including damaged organelles, protein aggregates, or pathogens. Once closed, it fuses with a lysosome for digestion.
Mitophagy
A specific type of macro-autophagy focused on the selective degradation of damaged or suboptimal mitochondria. Dysfunctional mitochondria, marked by decreased transmembrane potential, signal for their engulfment and destruction, which is coupled with mitochondrial biogenesis.
Fasting Mimetics
Compounds that induce similar biochemical changes in cells as starvation or caloric restriction, primarily by stimulating deacetylation reactions to activate autophagy. Examples include hydroxycitrate, spermidine, and resveratrol, which act through different molecular targets but converge on protein deacetylation.
9 Questions Answered
Autophagy is a cellular self-digestion process that cleans up damaged cellular components, including organelles, protein aggregates, and pathogens. It is crucial for adapting to stress, preventing cell death, and plays a significant role in counteracting aging processes and cancer development.
Autophagy is primarily activated by three energy-linked signals: a decrease in the cytosolic acetyl-CoA pool (indicating low glucose and fatty acids), a decrease in mTOR and IGF-1 activity (indicating low amino acids), and activation of AMP kinase (indicating low cellular energy/ATP).
The cytosolic pool of acetyl-CoA directly determines the level of protein acetylation. A reduction in acetyl-CoA due to nutrient deprivation leads to widespread protein deacetylation, which is a highly efficient common pathway for stimulating autophagy.
While rodents show robust autophagy after 48 hours of fasting, humans typically require a longer fast, such as three to four days, to observe significant autophagy induction in circulating leukocytes. The impact of shorter intermittent fasts (e.g., 14-16 hours) on human autophagy is not yet well-established.
Exercise, particularly endurance training, is known to induce autophagy in skeletal muscle in humans and in mice. In mice, this exercise-induced autophagy mediates anti-obesity and anti-diabetic effects, though specific tissue-level effects in humans are less studied.
Mitophagy selectively degrades damaged or dysfunctional mitochondria, which are then replaced by new, healthy ones. This process is vital for maintaining an efficient bioenergetic metabolism, preventing the accumulation of reactive oxygen species, and plays a significant role in preventing neurodegenerative diseases like Parkinson's.
Autophagy has a complex, dual role in cancer: early in oncogenesis, its suppression can promote genomic instability and malignant transformation. Later, cancer cells may reactivate autophagy to survive stress. Importantly, autophagy is also required for chemotherapy to elicit a long-term anti-cancer immune response.
Fasting mimetics (or caloric restriction mimetics) are compounds like hydroxycitrate, spermidine, and resveratrol that biochemically mimic starvation to induce autophagy. They achieve this by inhibiting acetyl-CoA generation, inhibiting protein acetyltransferases, or activating deacetylases, all leading to protein deacetylation.
Yes, studies in mice have shown that both caffeinated and decaffeinated coffee can induce autophagy, likely due to polyphenols, and this effect can be observed within approximately four hours, independent of caffeine.
17 Actionable Insights
1. Prolonged Fast for Autophagy
Engage in a prolonged fast of three to five days (water, coffee/tea without sugar/milk) for robust autophagy induction. This duration has been shown to cause “massive induction of autophagy” in human circulating leukocytes and can lead to cell regeneration.
2. Practice Intermittent Fasting
Implement intermittent fasting regimens, such as eating within an 8-10 hour window daily or fasting completely for one day followed by normal nutrition. In mice, this approach extended lifespan similarly to caloric restriction and helped manage weight.
3. Induce Autophagy with Exercise
Incorporate regular exercise, including aerobic, eccentric, and concentric types, into your routine. Exercise is known to induce autophagy in skeletal muscle in humans and mediates anti-obesity and anti-diabetic effects dependent on autophagy in mice.
4. Consume Coffee for Autophagy
Drink coffee, whether caffeinated or decaffeinated, as its polyphenols can magnificently induce autophagy. Regular coffee consumption has also been linked to a reduction in cardiovascular and neurodegenerative diseases.
5. Restrict Protein to Reduce mTOR
Limit your protein intake to reduce the activation of IGF-1 and mTOR. This reduction is associated with the induction of autophagy, a process important for cellular cleanup.
6. Eat Spermidine-Rich Foods
Increase your intake of spermidine by consuming foods like natto, durian fruit, fermented cheese (from non-pasteurized sources), and certain vegetables. Spermidine is a natural compound that can induce autophagy.
7. Manipulate Gut Microbiome
Explore ways to manipulate your gut microbiome, potentially via specific probiotics, to increase its production of polyamines like spermidine. This manipulation may help reduce colon cancer development and aging.
8. Utilize Fasting Mimetics
Consider using specific fasting mimetics like hydroxycitrate, spermidine, and resveratrol. These compounds can induce autophagy by modulating key signaling pathways, potentially mimicking the benefits of fasting and caloric restriction.
9. Inhibit Acetyl-CoA Generation
Use hydroxycitrate or other pharmacological compounds that inhibit ATP citrate lyase. This action depletes acetyl-CoA, leading to deacetylation and autophagy, mimicking caloric restriction.
10. Utilize Spermidine or C6
Consider using spermidine (a natural compound) or C6 (a pharmacological compound) as specific inhibitors of EP300. These compounds cause deacetylation and autophagy, mimicking caloric restriction.
11. Consume Resveratrol
Consume resveratrol, found in red wine, as it activates deacetylases. This activation causes hypoacetylation and autophagy, mimicking caloric restriction.
12. One Meal a Day (OMAD) Routine
Adopt a one-meal-a-day pattern, specifically having dinner with cheese and wine, as personally practiced by Dr. Cromer. This combines spermidine (from cheese) and resveratrol (from wine) for a synergistic effect on autophagy.
13. Five-Day Fast Twice Yearly
Practice a five-day prolonged fast twice a year, as personally done by Dr. Cromer. This is a more intense fasting regimen for potential health benefits.
14. Limit Glucose During Infection
When experiencing a bacterial infection, avoid force-feeding or increasing glucose levels. Not eating during infection is a protective mechanism that helps avoid excessive inflammation and can prevent the infection from becoming lethal.
15. Stimulate Autophagy for Neuroprotection
Stimulate general autophagy through methods like starvation or biochemical mimetics. This is a theoretical strategy to increase autophagic turnover and reduce toxic protein aggregates associated with neurodegenerative diseases.
16. Combine CR Mimetics with Chemo
For cancer treatment, combine chemotherapy with caloric restriction mimetics such as spermidine, hydroxycitrate, and resveratrol. This combination can enhance the anti-cancer immune response, making the therapy more durable and effective.
17. Enhance Learning with Video
If you find the scientific concepts challenging, watch the accompanying video on YouTube. The video provides definitions of scientific terms and figures, serving as a good resource for learning more about autophagy.
6 Key Quotes
Autophagy is a means of adaptation to stress and a technique of the cell to avoid cell death.
Dr. Guido Kroemer
The primary goal of autophagy is adaptation to changing conditions and adaptation to external stress and, at the end, avoidance of the unverentaged demise of the cell.
Dr. Guido Kroemer
The organelle, in a way, offers itself, it proclaims its sacrifice by autophagy.
Dr. Guido Kroemer
Chemotherapy is not just killing the cancer cells as if we used an antibiotic that specifically paralyzes the metabolism of bacteria. Now, it is true that chemotherapy induces cancer cell death, but the important point is that chemotherapy must provoke this cell death in a way that it later leads to an immune response.
Dr. Guido Kroemer
So one can also consider that this may be more amusing to have, if I was a mouse, I would probably prefer the intermittent regimen because it means satisfaction during one day and dissatisfaction on the other day, but not permanent dissatisfaction.
Dr. Guido Kroemer
Most cardiovascular and neurodegenerative diseases are actually reduced in heavy coffee drinkers as an independent link between lifestyle and pathology.
Dr. Guido Kroemer
1 Protocols
Dr. Guido Kroemer's Personal Fasting and Dietary Regimen
Dr. Guido Kroemer- Eat only one meal per day, typically dinner.
- Include cheese and wine in dinner for spermidine and resveratrol content.
- Practice a 5-day prolonged fast twice per year.
- Engage in regular exercise.
- Drink coffee throughout the day when not eating.