The Role of Mitochondrial Plasticity for Intermittent Fasting Mediated Longevity

Abstract

Aging is the single greatest risk factor for most chronic diseases that plague modern society. Research in the past two decades has demonstrated that dietary interventions can be utilized to modulate the rate of biological aging and these pathways can be targeted to promote health and longevity. Dietary restriction (DR) is the most well-studied and conserved method of in- creasing lifespan in many organisms, but it has associated negative side-effects and low rates of compliance in humans. Intermittent Fasting (IF), the modulation of the timing of eating with prolonged periods of fasting, is an alternative intervention shown to promote healthy aging, independent of reduced overall caloric intake. IF leads to lifespan extension in multiple model organisms and evidence is beginning to suggest that these mechanisms may be partially distinct from those of traditional chronic dietary restriction (DR). In my dissertation research, I show that mitochondrial dynamics are integral to IF-mediated longevity, and interestingly these requirements are different than those for chronic DR. Specifically, the ability of mitochondrial networks to remodel in response to feeding and fasting, what I define as mitochondrial plasticity, is necessary for IF-longevity. IF-longevity is abolished in C. elegans that have adynamic mitochondrial networks, but astonishingly mitochondrial plasticity is dispensable for DR-mediated longevity. Using an inducible system of mitochondrial fusion and fission expression, I show that synthetic manipulation of mitochondrial plasticity mimics IF at the level of mitochondrial morphology, and this is sufficient to extend lifespan in C. elegans. Finally, by comparing the effects of fasting on transcription that only occur specifically in wild type animals and not drp-1;fzo-1 double mutant animals that lack mitochondrial plasticity, I show that rewiring of metabolism is an important and potentially causal mechanism coupling IF to longevity. Together my data suggest that mitochondrial plasticity and metabolic flexibility are key mechanisms of longevity mediated by intermittent fasting. Key words: Intermittent Fasting, Mitochondrial Dynamics, Mitochondrial Plasticity, Metabolic Flexibility, C. elegans, Longevity, Aging