Autophagy Wins the 2016 Nobel Prize in Physiology or Medicine
Some of the greatest advances in healthy longevity research have been discovering and understanding nutrient-sensing pathways. When the body is depleted of energy and/or nutrients, it turns on an ancient protective mechanism called autophagy. The cells of your body switch from using food as an energy source to using junk (aggregated proteins and damaged organelles) in the cell for energy. Clearing out the junk, as well as many other processes such as DNA repair, the release of potent antioxidants has obvious benefits. This process is so important that it garnered Yoshinori Ohsumi, Ph.D., the Nobel Prize in 2016. He discovered many of the mechanisms of autophagy.
“Autophagy is an ancient pathway in which parts of eukaryotic cells are self-digested within the lysosome or vacuole. This process has been studied for the past seven decades; however, we are only beginning to gain a molecular understanding of the key steps required for autophagy. Originally characterized as a hormonal and starvation response, we now know that autophagy has a much broader role in biology, including organellar remodeling, protein and organelle quality control, prevention of genotoxic stress, tumor suppression, pathogen elimination, regulation of immunity and inflammation, maternal DNA inheritance, metabolism, and cellular survival. Although autophagy is usually a degradative pathway, it also participates in biosynthetic and secretory processes. Given that autophagy has a fundamental role in many essential cellular functions, it is not surprising that autophagic dysfunction is associated with a wide range of human diseases. Genetic studies in various fungi, particularly Saccharomyces cerevisiae, provided the key initial breakthrough that led to an explosion of research on the basic mechanisms and the physiological connections of autophagy to health and disease. The Nobel Committee has recognized this breakthrough by the awarding of the 2016 Nobel Prize in Physiology or Medicine for research in autophagy.”
“These key early findings established the existence of autophagy in mammalian cells; its regulation by nutrient status, nutrient-sensing hormones, kinases, and phosphatases; its potential for selective cargo degradation; and its increase in certain stress and developmental conditions. Remarkably, a review article by de Duve and Wattiaux in 1966 (16) presaged much of what we know today about the functions of autophagy. These included a role in ‘nutrition under unfavorable conditions of food supply through piecemeal self-digestion,’ ‘cellular differentiation and metamorphosis,’ ‘intracellular scavenging as part of the self-rejuvenation of long-lived cells,’ and the ‘self-clearance of dead cells.’ However, there was one major problem—how could this (or other) functionality of autophagy be proved by morphological observations? Herein lies the basis for the importance of describing the conserved genetic machinery of autophagy in yeast.”
mTOR Regulation of Autophagy
A chance finding on Easter Island, also known as Rapa Nui, has changed the field of healthy longevity. A substance called Rapamycin was found in the soil and was originally used as an anti-cancer and an anti-fungal drug. During testing on mice, it was observed that this newly discovered substance dramatically extended their life expectancy. This initiated many years of diligent research. What has been discovered is that mTOR (mechanistic target of rapamycin) is a key factor in metabolic health. It controls the intracellular switch from anabolism to catabolism and back to anabolism. This works through a complex set of nutritional, biochemical, genetic and epigenetic signals in conjunction with other pathways (growth hormone axis and PKA). You will be hearing more about this amazing research. The article cited below discusses the basics and how this mechanism is conserved, from the most basic forms of life on our planet to human beings.
“Nutrient starvation induces autophagy in eukaryotic cells through inhibition of TOR (target of rapamycin), an evolutionarily-conserved protein kinase. TOR, as a central regulator of cell growth, plays a key role at the interface of the pathways that coordinately regulate the balance between cell growth and autophagy in response to nutritional status, growth factor and stress signals. Although TOR has been known as a key regulator of autophagy for more than a decade, the underlying regulatory mechanisms have not been clearly understood. This review discusses the recent advances in understanding of the mechanism by which TOR regulates autophagy with focus on mammalian TOR (mTOR) and its regulation of the autophagy machinery.”
The Ras/cAMP-dependent Protein Kinase Signaling Pathway
Regulates an Early Step of the Autophagy Process in Saccharomyces cerevisiae*
mTOR, mentioned above, has many interactions in the cell and with extracellular cues as well. One of its main sensing pathways is the result of the depletion of protein (leucine). There is another signaling pathway that senses nutrient deprivation and energy depletion. The Ras/PKA (cAMP-dependent protein kinase) signaling pathway plays an important role in regulating the entry into the resting state and the subsequent survival of cells. When the cell has a limited supply of the nutrients (glucose) to make energy in the form of ATP, it will initiate autophagy through this pathway. This is crucial for cell survival. This article is not for the faint-hearted but gives an excellent description of the crucial healthy longevity pathway.
“When faced with nutrient deprivation, Saccharomyces cerevisiae cells enter into a nondividing resting state, known as stationary phase. The Ras/PKA (cAMP-dependent protein kinase) signaling pathway plays an important role in regulating the entry into this resting state and the subsequent survival of stationary phase cells. The survival of these resting cells is also dependent upon autophagy, a membrane trafficking pathway that is induced upon nutrient deprivation. Autophagy is responsible for targeting bulk protein and other cytoplasmic constituents to the vacuolar compartment for their ultimate degradation. The data presented here demonstrate that the Ras/PKA signaling pathway inhibits an early step in autophagy because mutants with elevated levels of Ras/PKA activity fail to accumulate transport intermediates normally associated with this process. Quantitative assays indicate that these increased levels of Ras/PKA signaling activity result in an essentially complete block to autophagy. Interestingly, Ras/PKA activity also inhibited a related process, the cytoplasm to vacuole targeting (Cvt) pathway that is responsible for the delivery of a subset of vacuolar proteins in growing cells. These data therefore indicate that the Ras/PKA signaling pathway is not regulating a switch between the autophagy and Cvt modes of transport. Instead, it is more likely that this signaling pathway is controlling an activity that is required during the early stages of both of these membrane trafficking pathways. Finally, the data suggest that at least a portion of the Ras/PKA effects on stationary phase survival are the result of the regulation of autophagy activity by this signaling pathway.”
Fasting-mimicking Diet Promotes Ngn3-driven β-cell Regeneration to Reverse Diabetes
Stem Cell Regeneration
Replacing tires is an important and convenient part of car maintenance. You would never abuse your current tires based on this convenience, but it is nice to know. This article explores the possibility of replacing your internal tires rather than limping along with the old ones. Specific nutrient strategies have been proven to stimulate stem cells which regenerate organs. This is not science fiction; you can rebuild your immune system and other body organs by stimulating stem cell production. This article explores this concept in the context of regenerating the pancreas of diabetics. These findings offer amazing insights into healthy longevity.
“Stem cell-based therapies can potentially reverse organ dysfunction and diseases but the removal of impaired tissue and reactivation of the program leading to organ regeneration pose major challenges. In mice, a four-day fasting mimicking diet (FMD) induces a step-wise expression of Sox17 and Pdx-1, resembling that observed during pancreatic development, followed by Ngn3-driven generation of insulin-producing β-cells. FMD cycles restore insulin secretion and glucose homeostasis in both a type 2 and type 1 diabetes mouse models. In human type 1 diabetes pancreatic islets, fasting conditions reduce PKA and mTOR activity and induce Sox2 and Ngn3 expression and insulin production. The effects of the FMD are reversed by IGF-1 treatment and recapitulated by PKA and mTOR inhibition. These results indicate that a FMD promotes the reprogramming of pancreatic cells to restore insulin generation in islets from T1D patients and reverse both T1D and T2D phenotypes in mouse models.”