Serotonin, together with neurons that express a specific serotonin receptor (5-HT2A), modulate this hunger state, and loss of 5-HT2A increases lifespan up to 50% in nutrient-rich conditions( 17). The existence of this drive and its ability to influence physiology is demonstrated by the observation that perception of protein-containing food without its consumption reverses the beneficial effects of protein-restricted diets in Drosophila and C. Many animals, including humans, develop a motivational drive for protein, which has also been described in Drosophila in response to starvation and mating( 12– 14). It seems likely that the effects of diet on aging and behavior share mechanistic foundations in the motivational states they promote, yet little is known about the molecular nature of these states. Similarly, the taste and smell of specific nutrients modulate lifespan in, among other species, the fruit fly, Drosophila melanogaster, and the nematode, Caenorhabditis elegans( 8– 11). In mice, appetite is promoted by environmental cues that predict future food consumption, presumably by influencing broader neural states that specify nutrient-specific drive, or hunger( 6, 7). Remarkably, an animal need not consume its diet to be affected by it. Many animals eat until they have consumed a specific amount of protein, for example, and the protein:carbohydrate ratio that results in part from seeking this target is a major factor in modulating lifespan( 5). Both effects derive not only from the energetic content of the diet but also its composition( 2– 4). The physiological need for nutrients motivates animals to forage and feed, and forced limitation in food availability slows aging across taxa( 1). The relationship between an animal and its diet influences behavior and aging in remarkable ways. #Cst studio suite download umich drivers#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. 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. Preventing the histone acetylome from being molded by dietary BCAAs abrogates both increased feeding and extended lifespan. 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. 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. Here we show that the molecular encoding of hunger slows aging in Drosophila. 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.
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