Interrogation of the cellular and subcellular architecture of nutrient metabolism in conditions of dietary restriction

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Project Summary/Abstract The re-allocation of metabolic resources towards cell processes that promote somatic maintenance is a long- held hypothesis to explain how diverse longevity paradigms promote healthier aging. One of the best models of this hypothesis is dietary restriction (DR), which optimizes metabolic efficiency while maintaining animal fitness and longevity. However, we possess surprisingly little insight into how specific nutrient resources are differentially utilized at the cell level during DR. In addition to altering metabolic processes, DR promotes a dramatic remodeling of organelle structures and functions. Increasingly we understand that not only is the structure of a discrete organelle critical for its functional state, but also the spatial relationships and contact sites formed between different organelle networks. The restructuring of the overall subcellular architecture thus plays a critical role in determining metabolic performance. However, our preliminary data suggest that age-dependent accumulation of molecular damage causes remodeling of the endoplasmic reticulum (ER), a hub of inter- organellar communication. Our overarching hypothesis is thus that remodeling of inter-organelle interactions is is both a key route by which aging cells lose functional resilience and an essential mechanism of DR-mediated reprogramming of metabolism. To advance this hypothesis we propose to exploit new correlative electron microscopy (EM) and stable isotope imaging technology in a combination of mouse and C. elegans models to establish a framework for how DR restructures the organelle interactome and re-allocates nutrient flux between organelles. Altogether this proposal aims to establish a framework for how DR remodels the organelle interactome to promote healthy aging with a focus on the role of the ER.