Preservation of mitochondrial membrane potential is necessary for lifespan extension from dietary restriction

Dietary restriction (DR) increases lifespan in many organisms, but its underlying mechanisms are not fully understood. Mitochondria play a central role in metabolic regulation and are known to undergo changes in structure and function in response to DR. Mitochondrial membrane potential (Δψ_m) is the driving force for ATP production and mitochondrial outputs that integrate many cellular signals. One such signal regulated by Δψ_m is nutrient-status sensing. Here, we tested the hypothesis that DR promotes longevity through preserved Δψ_m during adulthood. Using the nematode Caenorhabditis elegans, we find that Δψ_m declines with age relatively early in the lifespan, and this decline is attenuated by DR. Pharmacologic depletion of Δψ_m blocked the longevity and health benefits of DR. Genetic perturbation of Δψ_m and mitochondrial ATP availability similarly prevented lifespan extension from DR. Taken together, this study provides further evidence that appropriate regulation of Δψ_m is a critical factor for health and longevity in response to DR.