What are the main signals that trigger autophagy?

The primary signals for autophagy are nutrient deprivation, such as starvation or lack of essential nutrients like amino acids and glucose. Stress signals, including low ATP levels and oxidative stress, also play a role.

Can protein deacetylation be used as a biomarker for autophagy?

Protein deacetylation is strongly associated with autophagy induction, particularly a reduction in cytosolic acetyl-CoA. However, it's not a perfect surrogate, as autophagy can be induced pharmacologically without significant deacetylation.

How can autophagy be measured in humans in a clinical setting?

Currently, measuring autophagy in humans is challenging. One method involves analyzing the redistribution of the LC3 protein in circulating leukocytes via immunofluorescence, but this requires specialized equipment and further validation.

What is the minimum fasting time required to induce autophagy in humans?

For circulating leukocytes, significant autophagy induction has been observed after 3-4 days of complete fasting. Evidence for shorter fasting periods, like 16 hours, inducing systemic autophagy in humans is still lacking.

Does exercise induce autophagy, and is it enhanced in a fasted state?

Exercise, particularly endurance training, is known to induce autophagy in skeletal muscle. While exercise can induce autophagy even without fasting, the synergy of exercising in a fasted state is still under investigation, with preliminary evidence in mice suggesting potential benefits.

What is the difference between macroautophagy and microautophagy?

Macroautophagy is the most studied form, involving autophagosomes. Microautophagy involves direct engulfment of cytoplasmic components by the lysosome. There are also specialized forms like mitophagy (for mitochondria) and pexophagy (for peroxisomes).

How does impaired autophagy contribute to neurodegenerative diseases like Alzheimer's and Parkinson's?

These diseases are often linked to the accumulation of toxic protein aggregates or defects in the autophagy-lysosome system. Enhancing autophagy turnover is a theoretical strategy to treat these conditions by clearing these aggregates.

Is it beneficial to inhibit autophagy for cancer treatment?

The role of autophagy in cancer is complex. While early oncogenesis may involve autophagy suppression, cancer cells often reactivate it for survival. Inhibiting it can make cells more vulnerable to therapies, but it's also crucial for anti-cancer immune responses.

What are caloric restriction mimetics?

These are compounds like spermidine, hydroxycitrate, and resveratrol that mimic the cellular effects of fasting or caloric restriction, inducing autophagy through mechanisms such as protein deacetylation.

How can spermidine be obtained?

Spermidine can be found in foods containing cell nuclei, such as natto and fermented products. It is also produced by gut microbiota, and its levels can potentially be increased through probiotics.

Does drinking coffee induce autophagy?

Studies in mice show that polyphenols in coffee, independent of caffeine, can magnificently induce autophagy, suggesting potential health benefits related to cardiovascular and neurodegenerative disease prevention.

Dr. Guido Kroemer on Autophagy, Caloric Restriction Mimetics, Fasting & Protein Acetylation

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Education4 min read66 min video

Jul 31, 2017|364,654 views|6,874|477

caloric restriction mimetics autophagy fasting protein acetylation acetyl-CoA cancer macroautophagy microautophagy prolonged fasting AMP Kinase mTOR LC3

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Key Moments

TL;DR

Autophagy cleans cells, adapting to stress and preventing disease. Fasting & mimetics enhance it, impacting cancer & aging.

Key Insights

Autophagy is a cellular process for recycling damaged components, crucial for adaptation to stress and cell survival.

Nutrient deprivation, particularly hunger, is a primary inducer of autophagy, mediated by sensing pathways like mTOR and AMP kinase.

Protein acetylation plays a key role in regulating autophagy, with reduced acetylation often stimulating the process.

Fasting, especially prolonged, can induce autophagy, though the precise minimum duration in humans remains under investigation.

Specific types of autophagy, such as mitophagy, target and degrade damaged mitochondria, crucial for preventing neurodegenerative diseases.

Autophagy is implicated in cancer, acting as a double-edged sword: it can suppress early oncogenesis but also aid cancer cell survival under stress.

THE MECHANISM AND PURPOSE OF AUTOPHAGY

Autophagy, meaning 'self-eating,' is a fundamental cellular process where the cell sequesters and digests its own damaged components, like organelles and protein aggregates. This process, visible under microscopy, involves the formation of autophagosomes that fuse with lysosomes. The primary goal is not self-destruction, but rather adaptation to stress, resource recycling, and maintaining cellular homeostasis, ultimately preventing cell death.

SIGNALS THAT TRIGGER AUTOPHAGY

Autophagy is predominantly triggered by cellular stress, with nutrient deprivation being a key physiological inducer. This includes the absence of nutrients, growth factors, or oxygen. These signals activate internal sensing pathways, such as reduced ATP levels activating AMP kinase and amino acid scarcity inhibiting mTOR. A crucial biochemical link is the cytosolic acetyl-CoA pool, which directly influences protein acetylation, a major regulator of autophagy initiation.

AUTOPHAGY AND METABOLIC REGULATION

The process of autophagy is tightly linked to cellular metabolism. Reduced nutrient availability leads to a decrease in acetyl-CoA, resulting in protein deacetylation. This deacetylation activates key pathways that promote autophagy. Interestingly, this common regulatory mechanism through acetylation integrates signals from various nutrient sensing pathways, providing an efficient way to stimulate the autophagic machinery in response to diverse metabolic stresses.

INVESTIGATING AUTOPHAGY IN HUMANS AND ANIMALS

While fasting in mice can induce autophagy relatively quickly, determining the precise minimum fasting duration for significant autophagy induction in humans is challenging. Studies on circulating leukocytes suggest a need for several days of fasting. Research into calorie restriction mimetics, like spermidine and resveratrol, shows promise in inducing autophagy pharmacologically, offering alternative avenues for therapeutic intervention.

SPECIFIC TYPES OF AUTOPHAGY AND THEIR ROLES

Beyond general macroautophagy, specialized forms exist, such as mitophagy, which targets damaged mitochondria. Dysfunctional mitochondria can release reactive oxygen species and trigger apoptosis. Mitophagy is essential for clearing these defective organelles, promoting mitochondrial biogenesis and maintaining cellular energy production. This selective organelle turnover is crucial for preventing age-related diseases and is also involved in developmental metabolic reprogramming.

AUTOPHAGY IN NEURODEGENERATION AND AGING

Autophagy plays a critical role in combating neurodegenerative diseases, which often stem from the accumulation of toxic protein aggregates or defects in cellular clearance machinery. Enhancing autophagy can help clear these aggregates, such as amyloid-beta and alpha-synuclein, offering a potential therapeutic strategy. By removing damaged mitochondria and protein clumps, autophagy contributes to slowing the aging process and maintaining cellular health.

THE COMPLEX ROLE OF AUTOPHAGY IN CANCER

Autophagy's role in cancer is complex. Initially, its suppression can promote oncogenesis by increasing genomic instability. However, established cancer cells often reactivate autophagy to survive the stressful microenvironment, including nutrient scarcity and therapeutic insults. While some drugs inhibiting autophagy are used in cancer treatment, their efficacy is often debated, and the process's interaction with the immune system is also crucial for long-term therapeutic success.

AUTOPHAGY, IMMUNITY, AND CANCER THERAPY

Interestingly, autophagy can enhance anti-cancer immunity by facilitating the release of extracellular ATP, which signals to immune cells. Chemotherapy, when combined with autophagy induction, can lead to more durable anti-cancer effects by stimulating this immune response. This highlights a synergistic potential between autophagy-inducing interventions, including fasting mimetics, and immunotherapies for cancer treatment.

FASTING MIMETICS AND DIETARY INTERVENTIONS

Caloric restriction mimetics, such as hydroxycitrate, resveratrol, and spermidine, aim to replicate the benefits of fasting and caloric restriction. These compounds can induce protein deacetylation and stimulate autophagy. Spermidine, found in fermented foods, has shown promise in extending lifespan in animal models and may help mitigate weight gain even on a high-fat diet, potentially through autophagy-dependent mechanisms.

PERSONAL PRACTICES AND FUTURE DIRECTIONS

Dr. Kroemer practices intermittent fasting (one meal a day) and incorporates foods rich in spermidine and resveratrol. He also undertakes periodic prolonged fasts. Coffee polyphenols have also been shown to induce autophagy. Future research directions include further elucidating the molecular details of these processes, establishing optimal therapeutic interventions in humans, and exploring the synergistic effects of autophagy induction with existing treatments.

Mentioned in This Episode

●Supplements

●Products

●Software & Apps

●Tools

●Organizations

●Concepts

●People Referenced

Common Questions

Autophagy is a cellular process where the cell digests its own components, like damaged organelles and protein aggregates, to recycle materials and generate energy. It involves the formation of an autophagosome, which fuses with a lysosome for degradation.

Topics

Cellular Recycling Protein Acetylation Neurodegenerative Diseases Hydroxycitrate Immune Response

Mentioned in this video

conceptneurodegenerative diseases

Diseases like Alzheimer's and Parkinson's are often caused by toxic protein aggregates or deficiencies in autophagy machinery, making autophagy stimulation a potential therapeutic strategy.

softwarePINK1/Parkin pathway

A pathway crucial for marking damaged mitochondria for removal via mitophagy, implicated in Parkinson's disease.

supplementreactive oxygen species

Byproducts of mitochondrial dysfunction that can cause cellular damage and are increased when mitophagy is inhibited.

conceptimmune surveillance

The process by which the immune system identifies and eliminates abnormal or pre-malignant cells, which cancer cells must evade to survive. Autophagy plays a role in facilitating this evasion.

conceptoncogenesis

The process by which normal cells are transformed into cancer cells, which can involve initial suppression of autophagy that is later reactivated for survival.

conceptCaloric Restriction Mimetics

Substances that induce similar biochemical changes to starvation or fasting, promoting autophagy by mechanisms like inhibiting ATP citrate lyase, acetyltransferases, or activating sirtuins.

organizationUniversity of Paris Descartes

The academic institution where Dr. Guido Kroemer is a professor.

softwareLC3

A protein marker used to study autophagy. Its redistribution from a diffuse pattern to a punctate pattern indicates autophagosome formation and is used as a biomarker for autophagy.

softwareATP citrate lyase

An enzyme that generates cytosolic acetyl-CoA, inhibiting it with compounds like hydroxycitrate reduces acetyl-CoA levels, leading to protein deacetylation and autophagy.

conceptaging

A process associated with the accumulation of damage and defective components within cells, which autophagy helps to mitigate.

conceptEsophageal cancer

While mentioned briefly at the start as a field Dr. Kroemer publishes in, it is not a primary topic of discussion regarding autophagy in this specific segment.

drugChloroquine

An antimalarial drug and lysosomal inhibitor that was initially thought to inhibit autophagy in cancer treatment, but its mechanism is broader than just autophagy inhibition.

supplementHydroxycitrate

A compound that inhibits ATP citrate lyase, reducing cytosolic acetyl-CoA and promoting protein deacetylation and autophagy. It is a caloric restriction mimetic.

conceptsickness response

A conserved reaction to bacterial infection where organisms reduce activity and food intake, which can involve autophagy induction to avoid excessive inflammation.

softwareEP300

A protein acetyltransferase that plays a significant role in autophagy regulation. Inhibitors like Brahmadine can cause deacetylation and induce autophagy.

organizationCalorie Restriction Society

A group of individuals practicing calorie restriction, which was referenced in the context of a study measuring autophagy biomarkers in muscle biopsies.

conceptPexophagy

A specialized form of autophagy targeting peroxisomes for degradation.

conceptleukemia

A type of cancer where inhibition of autophagy is noted to be sufficient to cause oncogenesis.

supplementBrahmadine

A natural compound that inhibits EP300, leading to deacetylation and autophagy induction. It is a type of caloric restriction mimetic.

softwareKroemer lab website

The website for Dr. Guido Kroemer's research laboratory, where people can find more information about his work.