Lysosomes Mediate Benefits of Intermittent Fasting in Cardiometabolic Disease: The Janitor Is the Undercover Boss

Abstract

Adaptive responses that counter starvation have evolved over millennia to permit organismal survival, including changes at the level of individual organelles, cells, tissues, and organ systems. In the past century, a shift has occurred away from disease caused by insufficient nutrient supply toward overnutrition, leading to obesity and diabetes, atherosclerosis, and cardiometabolic disease. The burden of these diseases has spurred interest in fasting strategies that harness physiological responses to starvation, thus limiting tissue injury during metabolic stress. Insights gained from animal and human studies suggest that intermittent fasting and chronic caloric restriction extend lifespan, decrease risk factors for cardiometabolic and inflammatory disease, limit tissue injury during myocardial stress, and activate a cardioprotective metabolic program. Acute fasting activates autophagy, an intricately orchestrated lysosomal degradative process that sequesters cellular constituents for degradation, and is critical for cardiac homeostasis during fasting. Lysosomes are dynamic cellular organelles that function as incinerators to permit autophagy, as well as degradation of extracellular material internalized by endocytosis, macropinocytosis, and phagocytosis. The last decade has witnessed an explosion of knowledge that has shaped our understanding of lysosomes as central regulators of cellular metabolism and the fasting response. Intriguingly, lysosomes also store nutrients for release during starvation; and function as a nutrient sensing organelle to couple activation of mammalian target of rapamycin to nutrient availability. This article reviews the evidence for how the lysosome, in the guise of a janitor, may be the "undercover boss" directing cellular processes for beneficial effects of intermittent fasting and restoring homeostasis during feast and famine. © 2018 American Physiological Society. Compr Physiol 8:1639-1667, 2018.

Early Time-Restricted Feeding Improves 24-Hour Glucose Levels and Affects Markers of the Circadian Clock, Aging, and Autophagy in Humans

“…Increasing autophagy may have anti-aging or rejuvenating effects. Although no previous studies examining TRF as a meal timing intervention have investigated autophagy in either animals or humans, other studies on intermittent fasting conclude that several of the benefits of intermittent fasting are mediated through enhanced autophagy [69,70]. By comparison, we observed no changes in the expression of the four antioxidant genes measured.…”

Come Together: Protein Assemblies, Aggregates and the Sarcostat at the Heart of Cardiac Myocyte Homeostasis

“…In addition to the unusually large energetic apparatus, essential for powering the contractile machinery, cardiac myocytes, like yeast, require a complex proteostatic system. Unlike the dominant role of the proteasome in other cell types, cardiac myocyte lysosome function, like the vacuole in bacteria, plants and yeast, plays a major role in integrating metabolism (Mani et al, 2018) with both synthetic and degradation machinery for the contractile proteins. Thus, lysosome dysfunction results in metabolic derangement, as well as, proteotoxicity.…”

Lysosome impairment as a trigger for inflammation in obesity: The proof is in the fat.

“…This phenotype was attenuated by pharmacologic inhibition of IP3R1 and Fyn, indicating that CD36/ Fyn/IP3R1 signaling plays a role in increasing lysosomal Ca 2+ content and pH impairment. These experiments provide evidence to support the contention that obesity provokes acquired lysosome dysfunction and, in turn, inflammation, which can be therapeutically targeted in cardio-metabolic disease (reviewed in [2]).…”