Lifespan extension by reverse fasting

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Project Summary In our application entitled" Lifespan extension by reverse fasting," we propose a new model connecting energy metabolism and aging. In this model, longevity mechanisms are triggered by an energy deficit in which the food intake does not provide enough energy to match the animal's energy expenditure (classical fasting). This model further suggests that increasing energy expenditure while keeping food intake constant (reverse fasting) should also generate an energy deficit that triggers longevity. In this application, we use C. elegans to test these ideas. We find that the G protein-coupled receptor SER-7 controls energy expenditure. Activation of SER-7 by serotonin dose-dependently increases energy demand, mitochondrial respiration, and subsequently food intake. In wild-type N2 animals increasing energy demand by exogenous serotonin is consistently matched by an equivalent increase in food intake, preventing the generation of an energy deficit. Testing eight different longevity mutants, we find that the ability to upregulate energy expenditure and food intake is severely restricted in all but one of them, revealing the existence of a general energy-saving mechanism in longevity mutants. For example, daf-2(e1370) mutants have roughly half the respiration and food intake rate of wild-type animals, and their food intake in response to serotonin is severely bunted. However, we identified a daf-2 mutant with an almost wild-type respiration and food intake profile. Only the response to exogenous serotonin at high concentrations is slightly blunted, suggesting the proposed energy-saving mechanism observed in daf-2(e1370) is not active. We find that the lack of an energy- saving mechanism in that daf-2 mutant elevates the metabolic set point at which the dauer pathway is triggered. The result is an animal that activates the dauer pathway at a point when it already eats twice as much as wild type. This daf-2 mutant is the first confirmation of the reverse fasting hypothesis. It shows that it is possible to generate animals that live long and overeat, as long as the energy expenditure is higher than the energy intake. This application aims to identify the fasting/starvation-induced energy-saving mechanism and to show that its inactivation will enable many longevity mutants to overeat and live long.