Loss of metabolic homeostasis is a hallmark of aging and many age-related chronic diseases. This is accompanied by dysregulation of mitochondrial dynamics (fusion and fission) and morphology. Conversely, dietary restriction (DR), reduced food intake without malnutrition, slows aging in every organism tested thus far and protects against multiple chronic diseases, in part by maintaining metabolic health. However, cellular processes causally linking aging, DR and mitochondrial network state with aging remain unclear. Moreover, whether manipulating mitochondrial dynamics might promote healthy aging is unknown. Our long- term objective is to elucidate how DR promotes healthy aging to allow the development of novel therapeutics to treat age-related disease. Key barriers currently restricting progress on our understanding of how mitochondrial dynamics affect healthy aging are 1) a lack of non-interventional tools to study cell biology/organelle structure and function in live, multicellular animals as they age and 2) the current paradigm that specific mitochondrial states are universally ?youthful/pro-longevity? or ?aged/pro-aging?. Unpublished data from our lab challenge this paradigm: We show three conserved longevity pathways that all require mitochondrial dynamics to increase lifespan in C. elegans. Crucially however, each pathway has opposing requirements for mitochondrial network state. Here, we will develop new in vivo tools in the model organisms C. elegans to be able to fully define mitochondrial dynamic state in different tissues during normal aging and in the three pathways with differential mitochondrial requirements. Mitochondrial network state can impact multiple physiological and cellular processes including mitophagy, metabolic plasticity and inter-organelle interactions. Using C. elegans we will develop non interventional in vivo read outs of each of these outputs in a transparent multicellular organism, allowing us to define how interventions that remodel mitochondrial networks affect healthy aging.
This proposed research is relevant to the mission of the NIH because uncovering the underlying mechanisms linking mitochondrial network state and healthy aging/age-related pathology will provide novel therapeutics to both prevent and cure multiple age-onset diseases, which represent an ever growing burdens to public health.
