Friday, May 7, 2021
Mitochondrial Health

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



Dr. Guido Kroemer is a professor at the University of Paris Descartes and an expert in immunology, cancer biology, aging, and autophagy. He is one of the most highly cited authors in the field of cell biology and was the most highly cited cell biologist for the period between 2007 and 2013. Especially notable among his contributions: he was the first to discover that the permeabilization of mitochondrial membranes is a concrete step towards apoptotic cell death.

This episode is decidedly focused on autophagy, an important cellular program that is inducible by dietary fasting and has broad implications for aging and cancer. Autophagy discussion includes:
• 00:04:44 – How the 3 main signals that activate autophagy all involve nutrient sensing.
• 00:16:30 – The role of different types of fasting and nutrient deprivation in autophagy.
• 00:24:35 – How different types of exercise can induce autophagy.
• 00:32:04 – How a specific type of autophagy called mitophagy keeps mitochondria healthy.
• 00:33:07 – How autophagy has been shown to slow cellular aging.
• 00:35:13 – How autophagy prevents neurodegenerative diseases by clearing away protein aggregates.
• 00:44:04 – The role of autophagy in cancer as a possible double-edged sword.
• 00:50:27 – How certain compounds known as caloric restriction mimetics (or fasting mimetics) including resveratrol, spermidine, hydroxycitrate can induce autophagy by tricking the cell through the modulation of one or more of the 3 main autophagy signaling pathways.

Chapters:
00:00:00 – Introduction
00:00:25 – What is autophagy
00:06:13 – Acetyl-CoA
00:12:37 – Measuring autophagy
00:16:29 – Inducing autophagy
00:24:26 – Exercise
00:26:52 – Types of autophagy
00:35:11 – Neurodegenerative diseases
00:39:52 – Sickness response
00:41:42 – Cancer
00:50:22 – Fasting mimetics
00:59:17 – Kroemer’s healthy habits

▶︎ Dr. Kroemer’s Lab Website
http://www.kroemerlab.com/

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41 thoughts on “Dr. Guido Kroemer on Autophagy, Caloric Restriction Mimetics, Fasting & Protein Acetylation
  1. TIMELINE…
    00:03:22 – How genetically inhibiting autophagy actually increases cellular sensitivity to death and how this was counterintuitive because autophagy was thought, at one time, as a type of activity predominantly concerned with actually initiating cell death.
    00:04:44 – The external signals causing autophagy.
    00:05:29 – The role of growth factors in transporting nutrients from the outside world into the intracellular space.
    00:05:48 – Autophagy as a process that destroys bioenergetic macromolecular reserves including proteins, lipids, and nucleic acids to generate energy.
    00:06:28 – How declines in the ATP (energetic) status of the cell trigger autophagy by increasing the activity of a pathway known as AMP Kinase.
    00:06:36 – How reductions in the cytosolic pool of acetyl-CoA as a consequence of reductions in glycolysis, amino acid catabolism, or beta-oxidation, ultimately result in the de-acetylation of hundreds of cellular proteins involved in autophagy. Nutrient deprivation → ↑ Protein Deacetylation (↓ cytosolic Acetyl CoA) + ↓ mTOR + ↑ AMP Kinase → Autophagy
    00:09:37 – The role of the inhibition of mTOR and activation of AMP Kinase in cellular autophagy. mTOR is a pathway robustly activated by IGF-1 and associated with increases in cell growth, proliferation, motility and protein synthesis. AMP Kinase, on the other hand, is a pathway important in regulating cellular energy homeostasis by inhibiting synthesis of fatty acids and triglycerides and activating fatty acid uptake and beta-oxidation in the liver.
    00:09:37 – The indirect relationship between protein acetylation status (and cytosolic acetyl CoA availability) and the suppression of mTOR and activation of AMP Kinase in cellular autophagy.
    00:10:23 – The possibility of using selective nutrient restriction as an autophagy-inducer instead of more generalized nutrient deprivation or fasting.
    00:11:11 – Cytoplasmic protein deacetylation as a potential surrogate marker for fasting-induced autophagy (still undergoing validation) but possibly not other forms of autophagy, such as the kind pharmacologically induced by interaction with a protein involved in vesicle-trafficking processes called Beclin 1.
    00:12:53 – How a protein called LC3 associate with structures called autophagosomes to facilitate autophagy in response to deacetylation it undergoes. Note: this sirt1-mediated deacetylation of LC3 is induced as an important response to cell starvation.
    00:14:22 – The special flow cytometry needed in order to measure some of the proteins associated with the activation of autophagosomes in autophagy.
    00:15:04 – The desirability of being able to know and test whether or not your fasting is triggering robust autophagy or not.
    00:16:30 – The minimum amount of fasting necessary to activate autophagy.
    00:16:56 – Whether or not time-restricted eating or 16:8 intermittent fasting reliably induces autophagy in any of our tissues.
    00:17:57 – The important differences between prolonged fasting in humans and the rodent animal models used in studies.
    00:19:03 – The ~12-hour half-life of IGF-1 and whether or not that has any implications for the potential of autophagy in shorter duration fasts.
    00:20:12 – The effects of long-term caloric restriction on markers of cellular autophagy in humans.
    00:21:32 – The effect of an every-other-day eating pattern in rodents and how this pattern actually mimics the longevity producing effects of caloric restriction but with the advantage of stabilizing long-term at a more normal body weight. (Note: Dr. Kroemer is quick to point out that this type of intermittent fasting is more dramatic than it would be in humans because of differences in metabolism… the animals actually experience a 10% oscillation in body weight from this pattern!)
    00:24:35 – The effect of exercise (especially endurance exercise) on autophagy in muscle tissue.
    00:25:08 – The role of autophagy as a mediator of the anti-obesity and anti-diabetic effects of endurance exercise.
    00:26:58 – The differences between macroautophagy, microautophagy, and chaperone-mediated autophagy.
    00:28:03 – The difference between autophagy that is dictated by demand (nutrient stress) versus autophagy that occurs as the need arises to recycle damaged organelles.
    00:28:40 – How damaged organelles change the composition of their surfaces in order to decorate them with signals for the stimulation of their engulfment by the autophagosome.
    00:29:07 – The many, many names autophagy has when we are talking about it in the context of specific macromolecular structures and organelles (e.g. mitophagy for mitochondria, pexophagy for peroxisomes, reticulophagy for endoplasmic reticulum, ribophagy for ribosomes, and virophagy for viruses).
    00:29:35 – How autophagy from nutrient deprivation still prefers to first recycle organelles that have been slightly marked… in other words, that are already aged or slightly damaged.
    00:31:15 – How mitochondrial use ubiquitination, a process which occurs when these organelles begin to lose their membrane potential, in order to signal damage and to ensure preferential targeting by the autophagic machinery. ↓ mitochondrial transmembrane potential → ↑ ubiquitination → ↑ mitophagy
    00:32:42 – The coordinated manner in which mitophagy and mitochondrial biogenesis act together in a closed feedback loop in order to preserve mitochondrial quality while preserving the total pool of functioning mitochondria.
    00:33:34 – The changes that can occur in total mitochondrial pool as cells adapt to take on new metabolic profiles through a mitophagy-mediated process. This can occur as cells differentiate into new cell types that are specialized for glycolytic energy generation.
    00:35:13 – The role autophagy plays in the prevention of neurodegenerative diseases caused by protein aggregates.
    00:37:18 – How autosomal recessive mutations (where both parents must contribute a defective gene for PD to arise in the offspring) in a kinase protein called PINK1 disrupts its ability to recruit a protein called Parkin that mediates the targeting of mitochondria for mitophagy. ↓ PINK1’s kinase activity → ↓ parkin recruitment → ↓ mitophagy → ↑ accumulation of damaged mitochondria
    00:38:01 – Mitochondrial membrane permeabilization as a death signal due to the release of dangerous proteins contained in the mitochondria.
    00:39:05 – Dr. Valter Longo’s research demonstrating a cycle of prolonged fasting followed by a refeeding can recycle 28% of the white blood cells, and reduce the severity of an autoimmune disease (multiple sclerosis).
    00:39:52 – The evolutionarily-conserved sickness response (food avoidance) as a way of beneficially altering immune responses through through altered metabolism and autophagy.
    00:41:02 – The surprising increase in lethality that happens when mice are force fed (glucose in this case) while exhibiting sickness response from a bacterial challenge.
    00:42:27 – The effects of an anti-malarial known as chloroquine which has some cytotoxic effects in cancer cells, but is actually (surprisingly) an inhibitor of autophagy.
    00:43:12 – Studies of the lysosomal disrupter and anti-malarial chloroquine in combination with chemotherapy in the treatment of cancer.
    00:44:04 – The differential roles autophagy plays in the progression of cancer in pre-malignant cells, when it is suppressed, versus in malignant cells, when it is sometimes used as an adaptation helpful to the survival of malignant cells experiencing environmental stress. ↓ tumor suppressor gene activity → ↓ autophagy → survival of pre-malignant cells → ↑ autophagy as a malignant adaptation
    00:44:49 – How inhibition of autophagy by itself is sufficient to induce oncogenesis, particularly in leukemia.
    00:48:10 – How cells undergoing autophagy can release ATP into the extracellular space where it can function as a signal that recruits and activates immune cells against tumor antigens through the activities of purinergic receptors. ↑ autophagy → ↑ extracellular ATP → activation of purinergic receptor-mediated immunosurveillance
    00:48:49 – The importance of the triggering of this immunosurveilance system as part of the cell death associated with chemotherapy.
    00:50:27 – The class of compounds known as “caloric restriction mimetics” that affect autophagy by perturbing various pathways in such a way as to reductions in cytosolic acetyl CoA and protein deacetylation in a manner similar to nutrient deprivation. Examples include: hydroxycitrate (inhibits ATP citrate lyase), spermidine (inhibits Ep300, a protein acetyltransferase), and resveratrol (activates deacetylases).
    00:55:27 – How intestinal bacteria may produce as much as 1/3rd of the body’s spermidine and how this production rate can be manipulated by probiotic and dietary interventions.
    00:56:17 – How the ability of caloric restriction mimetics (CRMs) to induce a type of autophagy that provokes immunosurveillance potentially offers an opportunity for synergy when used in combination with chemotherapeutic agents in the treatment of cancer.
    00:56:56 – How the inhibition of autophagy in malignant cells or destruction of the extracellular ATP released by cells undergoing autophagy is able to abolish the favorable interaction between caloric restriction mimetic drugs and chemotherapy.
    00:58:02 – The tendency for dietary consumption of caloric restriction mimetics, particularly hydroxy citrate, to induce autophagy and reduce weight gain in mice fed an obesogenic diet.
    00:59:17 – Dr. Kroemer’s personal intermittent and prolonged fasting practices and his habit of consuming foods that may contain some natural quantities of caloric restriction mimicking compounds.
    01:01:40 – The autophagy-enhancing effect of coffee (with and without caffeine).

  2. Its very difficult for me to cognitively induce or restrict mitosis on trillions of my cells. How they heck am I to now induce all the different types of autophagy? I won't have time to eat anything, now or later. By the time I get this figured out, the next phase of published research will contradict all this.
    Call me when they make a pill

  3. Indeed a very enlightening explapnation of very complex subject. now I begin to understand why in some occasions we tend lose appetite or avoid foods when we are not well.

  4. This was an amazing presentation!! It really helped connect the dots on how these mechanisms can dictate the outcomes in health and disease. I would certainly be interested in your thoughts on his personal regimen of prolonged fasting, exercise and diet. You are doing a great service to all of us.

  5. Top 10, or even 5 here Rhonda, this was an exceptional interview! There is beauty in science, you know how to waltz with intellects and match them step for step. There were so many "connect the dots" moments for me in this one, I'm sharing it far and wide, and coming back for the encore. Bravo, and many thanks to Guido for coming on, he clearly appreciated your considerate, intelligent interview style. So grateful for your work, thank you.

  6. I found this interview extremely interesting, esp., about the importance of autophagy in using the immune system in the long term suppression of a cancer.

  7. Hi Dr Patrick

    I was wondering what you think of the 'Snake Diet' which includes an intermittent fasting lifestyle. Is it safe to drink water with these ingredients while fasting? Will true autophagy occur? The creator of the diet says you lose too many electrolytes while fasting for longer periods like 48,72, or more hours. He says you need to replace lost salts and potassium while fasting or you will feel shaky.

    'SNAKE JUICE' Water RECIPE

    Per 2 Liter H20:
    (Evian bottled water recommended because of PH)

    *drink less than 2L per day of the bottled water mixture*

    Potassium Chloride Powder = 2 tsp
    (4700 mg) —(No Salt brand or Windsor salt free)
    Himalayan Pink Salt = 1 tsp
    (2,000 mg/L)
    Organic lemon Juice – 8 Tbs per day
    Organic apple cider vinegar – 4 Tbs per day

  8. in her new book how to starve cancer jane maclland says autophagy can be a fuel for cancer and needs to be stopped as it acts as fuel for the cancer cell at certain  periods of the process. The cancer cell uses autophagy when arginine  is deprived it used glutimine

  9. Japanese scientiste Yoshinori Ohsumi has descovered the autophagy/self-eating or destruction, and he has obtained Nobel prize for that descovery which consist on how cells recycle their content.

  10. As usual when scientific info is dummed down through the media for mass population key facts are missed/misinterpreted. This benefits those who exploit this lack of understanding and sell books, do talks/videos etc for profit and promote themselves as ‘experts’ but few actually check their credentials or sources cited (if any).

  11. Thank you so much! So much time you must have spent putting all of this together. Pro tip:I watch this on my phone and tablet at the same time so I can pause the pictures and articles. Probably because I’m slow and need more autophagy in my life.

  12. Fascinating and very important info! When protein management becomes dysregulated thanks to oxidative stress and insulin resistance you get everything from Kidney Stones to Alzheimers to Cataracts! A proper diet that's free of processed carbs should allow us to age much more gracefully with fewer complications.

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