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

Posted on July 31st 2017 (over 2 years)

Guido Kroemer, MD, PhD, is a professor at the Faculty of Medicine of the University of Paris Descartes. He serves in a leadership capacity at multiple research and medical institutes in Paris, including the Medical Research Council (INSERM), the Gustave Roussy Comprehensive Cancer Center, the Cordeliers Research Center, and the Hôpital Européen George Pompidou. He is also an adjunct professor at the Karolinska Institute, Stockholm, Sweden.

Dr. Kroemer is an expert in immunology, cancer biology, aging, and autophagy. He is one of the most cited authors in the field of cell biology and was the most cited cell biologist for the period between 2007 and 2013. He is best known for identifying the key role that permeabilization of mitochondrial membranes plays in programmed cell death.

His work has elucidated the intricate mechanisms involved in mitochondrial cell death control, the molecular pathways associated with cell death inhibition, and the role that cancer cell death plays in inducing immune function. In fact, he demonstrated that the therapeutic success of anticancer chemotherapy is mediated by the immune response against stressed and dying tumor cells. His groundbreaking work has been recognized in numerous awards from organizations in the fields of science, medicine, pharmacology, and cancer research.

Dr. Kroemer completed his medical degree and postdoctoral training at the Collège de France, Nogent-sur-Marne. He completed his doctoral degree in molecular biology from the Autonomous University of Madrid.

Autophagy is a highly conserved adaptive response to stress. During autophagy, a spectacular event in cell biology that is observable under a microscope, the cell gathers unnecessary or dysfunctional cellular components such as protein aggregates, pathogens, or damaged organelles into vesicles and delivers them to lysosomes for destruction, releasing proteins, lipids, carbohydrates, and nucleic acids for energy and re-use. The primary goal of autophagy is the maintenance of homeostasis in the face of changing cellular conditions and stress.

Autophagy activation relies on nutrient sensing

Integral to the mechanisms that regulate autophagy is nutrient sensing. In particular, the cell responds to changes in cellular levels of acetyl CoA, an end product of nutrient metabolism. Acetyl CoA acetylates or deacetylates key proteins involved in autophagy (such as mTOR and AMP kinase), thereby serving as a common regulator for the many pathways that lead to autophagy induction or inhibition.

Alterations in nutrient status that regulate autophagy

Starvation and fasting

In the fed state, the body synthesizes essential cellular components from readily available macromolecules and stockpiles the surplus. In the fasted state, however, cellular reductions in acetyl CoA switch on homeostatic mechanisms that mobilize those stockpiles via autophagy. Although the duration of nutrient deprivation necessary to induce autophagy varies among mammals, when mice or human volunteers experience starvation, autophagy can be observed on the whole-body level.

Prolonged fasting – a period of voluntary starvation that typically exceeds 48 hours – sets off a wide range of metabolic events, including the activation of cellular and systemic cleanup programs such as apoptosis and autophagy. Many people may find the prolonged fast too onerous, but the fasting-mimicking diet, an approach that recapitulates many of the same effects of prolonged fasting with a hyper-low calorie, low protein, higher fat diet stretched out over a longer interval of five days, may offer a more palatable strategy for activating autophagy.

Calorie restriction mimetics

Another strategy for modulating acetyl CoA levels involves intake of caloric restriction mimetics, compounds that “trick” cells into inducing autophagy even in the setting of sufficient nutrient levels. Examples of caloric restriction mimetics include resveratrol and spermidine, two dietary compounds present in red wine and cheese, respectively.

Exercise

The many health benefits associated with exercise are well known and include extension of lifespan and protection against cardiovascular diseases, diabetes, cancer and neurodegenerative diseases. Some of these benefits may be due to the fact that exercise induces autophagy in the brain and several organs involved in metabolism, including the liver, pancreas, adipose tissue, and muscles.The greatest benefits are observed with endurance training, which induces autophagy in mice, mediating the deleterious effects of diabetes and obesity.

Autophagy and mitochondrial health

Defective and aging mitochondria contribute to metabolic dysfunction and disease. Mitophagy, the selective degradation of dysfunctional mitochondria, helps ensure that the body’s cells are metabolically efficient. These old or defective mitochondria self-identify as dysfunctional, offering themselves for mitophagy, like martyrs on behalf of the cell. Mitophagy ultimately serves as a trigger for mitochondrial biogenesis, the process by which new mitochondria are produced. Failures in mitophagy are associated with several chronic diseases, including cardiovascular disease, kidney disease, and Alzheimer’s disease.

Autophagy and neurological health

Parkinson's disease, a neurodegenerative disorder characterized by mitochondrial dysfunction and energy deficits in dopaminergic neurons in the brain, may be due in part to mitophagy failure. A growing body of evidence suggests that mitophagy is compromised in Parkinson's disease and promotes the accumulation of dysfunctional mitochondria. Impaired mitophagy likely contributes to the aggregation of misfolded proteins, which in turn impairs mitochondrial homeostasis.

Autophagy as a critical trigger for immunosurveillance

Autophagy plays a role in triggering mechanisms of immunosurveillance by facilitating the release of ATP from dying cells, which attract the attention of myeloid cells via a special class of receptor known as purinergic receptors. Activation of this important system of immunosurveillance is a predictor of long-term efficacy of chemotherapy and may help to explain the complex relationship of autophagy with cancer, wherein the initial suppression of autophagy may help prevent attracting undue attention from the immune system, but may later facilitate ongoing transformation. In later stage cancer, autophagy may be reactivated to help cells in their pursuit to continue gaining a foothold in the otherwise hostile tumor microenvironment of the body.

In this episode, Dr. Kroemer describes the complex process of autophagy and how it influences many aspects of health and disease, including cancer, neurodegenerative disease, and aging, and how modulation of autophagy may represent a promising therapeutic approach for extending human lifespan and healthspan.

Learn more about autophagy in this topic article from FMF.

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.

Learn more about Dr. Guido Kroemer

TL;DR

Fasting Autophagy

Nutrient deprivation → ↑ Protein Deacetylation (↓ cytosolic Acetyl CoA) + ↓ mTOR + ↑ AMP Kinase → Autophagy

Hydroxy Citrate Autophagy

↓ ATP citrate lyase activity → ↓ Protein Acetylation → Autophagy

Spermidine Autophagy

↓ Acetyltransferase activity (especially EP300) → ↓ Protein Acetylation → Autophagy

Resveratrol Autophagy

↑ Detacetylase activity (especially SIRT1) → ↓ Protein Acetylation → Autophagy

... and... more generally...

↑ Protein Deacetylation → Autophagy

The relationship between cancer and autophagy is complex...

↓ tumor suppressor gene activity → ↓ autophagy → survival of pre-malignant cells → ↑ autophagy as a malignant adaptation​​​​​​​

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