Multimodal control of mitochondrial energetics to shape biological aging

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The mitochondrial protonmotive force (PMF) is an electrochemical gradient across the inner mitochondrial membrane that powers ATP synthesis and other mitochondrial signaling. PMF is naturally variable under different situations, and can depend on nutrient status, cell or tissue type, and many other factors. Importantly, evidence suggests that PMF declines with age. This observation holds from yeast to mammalian tissues. However, it is still unclear whether this decline is a cause or a consequence of aging phenotypes. We show that PMF declines with age in C. elegans and human cells and that Dietary Restriction (DR), a well-characterized longevity intervention, prevents this loss. Furthermore, loss of PMF negates the effects of DR on C. elegans longevity, further suggesting that PMF is a fundamental regulator of biological aging. This proposal aims to test and fully characterize how PMF is a determinant of three different, but related, longevity paradigms: normative aging, DR, and hypoxia signaling. DR is a reduction in caloric intake without causing malnutrition that results in longevity. Hypoxia and signaling through hypoxia-inducible factor (HIF) extend lifespan and promotes health in different models. Interestingly, while DR seems to preserve PMF, hypoxia treatment decreases PMF acutely. These opposite effects on PMF in two different paradigms that extend lifespan must be investigated mechanistically. Lack of tools to specifically modulate PMF in isolation in living tissue or intact organisms is a critical gap in understanding how mitochondria regulate aging. This proposal aims to leverage what is known through DR and hypoxia signaling to study new, conserved mechanisms of metabolic decline with age in models of C. elegans longevity and human cell senescence. Until recently, there were no means to experimentally increase PMF in isolation from other aspects of metabolism and physiology. PMF can now be isolated as a single variable through optogenetics, the use of light-sensitive proteins to increase or decrease transmembrane electrochemical gradients in vivo. Mitochondrial optogenetics allows us to control mitochondria directly leaving other metabolic pathways intact. We propose that preserved mitochondrial energetics is a common causal factor for both DR-mediated longevity and hypoxia signaling. We will test our models using cutting-edge optogenetic techniques in parallel C. elegans and cellular models, which will ensure rigorous results and efficient pathways for translation of our findings. We will test how PMF complements DR in animals and at the cellular level, as well as how PMF interacts with hypoxia and HIF-mediated lifespan extension. We will further test how well-characterized nutrient sensing signaling is regulated by PMF to cause longevity. New insight into how the PMF specifically controls aging and longevity signaling will be an important investigation into the efficacy of targeting metabolism for protection against disease in humans. Understanding the fundamental parameters of metabolism and PMF in both worms and human cells will offer novel insights into what we already know, and will pave the way for discovering new mechanisms of longevity downstream of mitochondrial PMF.