It has been recognized for nearly a century that diet modulates aging. Despite early experiments suggesting that reduced caloric intake augmented lifespan, accumulating evidence indicates that other characteristics of the diet may be equally or more influential in modulating aging. We demonstrate that behavior, metabolism, and lifespan in Drosophila are affected by whether flies are provided a choice of different nutrients or a single, complete medium, largely independent of the amount of nutrients that are consumed. Meal choice elicits a rapid metabolic reprogramming that indicates a potentiation of TCA cycle and amino acid metabolism, which requires serotonin 2A receptor. Knockdown of glutamate dehydrogenase, a key TCA pathway component, abrogates the effect of dietary choice on lifespan. Our results reveal a mechanism of aging that applies in natural conditions, including our own, in which organisms continuously perceive and evaluate nutrient availability to promote fitness and well-being.

Hunger is an ancient drive, yet the molecular nature of pressures of this sort and how they modulate physiology are unknown. We find that hunger modulates aging in Drosophila . Limitation of branched-chain amino acids (BCAAs) or activation of hunger-promoting neurons induced a hunger state that extended life span despite increased feeding. Alteration of the neuronal histone acetylome was associated with BCAA limitation, and preventing these alterations abrogated the effect of BCAA limitation to increase feeding and extend life span. Hunger acutely increased feeding through usage of the histone variant H3.3, whereas prolonged hunger seemed to decrease a hunger set point, resulting in beneficial consequences for aging. Demonstration of the sufficiency of hunger to extend life span reveals that motivational states alone can be deterministic drivers of aging.

Hunger is, by necessity, an ancient motivational drive, yet the molecular nature of homeostatic pressures of this sort and how they modulate health and physiology are largely unknown. Here we show that the molecular encoding of hunger slows aging in Drosophila. We identify the branched-chain amino acids (BCAAs) as dietary hunger signals that extend lifespan despite increasing food intake when reduced, and in parallel show that optogenetic activation of a subset of hunger-promoting neurons is sufficient to recapitulate these effects. We find that remodeling of the neuronal histone acetylome is associated with dietary BCAA reduction, and that this requires BCAA metabolism in specific subsets of neurons. Preventing the histone acetylome from being molded by dietary BCAAs abrogates both increased feeding and extended lifespan. However, the mechanisms that promote feeding and modulate aging downstream of alterations in histone acetylation occur through spatially and temporally distinct responses; differential usage of the histone variant H3.3A in the brain is an acute response to hunger that promotes increased feeding without modulating lifespan, while a prolonged experience of hunger may slow aging by promoting a beneficial decrease of a set-point around which hunger levels are regulated. Identification of a molecular basis for the encoding of hunger and demonstration of its sufficiency in extending lifespan reveals that motivational states alone are deterministic drivers of aging and behavior.

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