Encoding of hunger by the neuronal epigenome slows aging in Drosophila

Abstract

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.

The serotonin receptor 5-HT2A modulates lifespan and protein feeding in Drosophila melanogaster

“…Long-term discrepancies between nutrient expectation and consumption have been shown to modulate global physiology and lifespan, also in a serotonin-dependent manner. Chronic Frontiers in Aging frontiersin.org activation of serotoninergic hunger circuits extends lifespan in flies and leads to a short-term increase in food consumption, which eventually dissipates, putatively as an adaptation to sustained hunger (Weaver et al, 2022). Similarly, relative to diets high in branched-chain amino acids (BCAA)s, flies consuming diets low in BCAAs show higher expression of serotonin synthesis enzymes and serotonin levels in PLP brain neurons, show extended lifespan, and show a short-term increase in feeding that restores to baseline after two weeks (Weaver et al, 2022).…”

“…Chronic Frontiers in Aging frontiersin.org activation of serotoninergic hunger circuits extends lifespan in flies and leads to a short-term increase in food consumption, which eventually dissipates, putatively as an adaptation to sustained hunger (Weaver et al, 2022). Similarly, relative to diets high in branched-chain amino acids (BCAA)s, flies consuming diets low in BCAAs show higher expression of serotonin synthesis enzymes and serotonin levels in PLP brain neurons, show extended lifespan, and show a short-term increase in feeding that restores to baseline after two weeks (Weaver et al, 2022). The alterations in serotonin levels caused by low BCAA diets was also seen in a recently published mouse study, suggesting that low BCAAs causes these changes using similar mechanisms of action (Solon-Biet et al, 2019).…”

Behavioral dissection of hunger states inDrosophila

“…Such measures may be of total caloric intake or consumption of specific nutrients, but it is unclear whether these measures are representative of hunger that is driven by energetic need, nutrient deficiency, or some other motivation, which has led to variation in the way measures of homeostatic hunger are reported and interpreted (for review of mammalian brain circuits that modulate feeding, see (Alcantara et al, 2022; Andermann & Lowell, 2017; Saper et al, 2002)). However, the observation that most animals, including humans, regulate food intake around a protein target and the identification of discrete neuronal populations that regulate protein-specific feeding in model systems suggest that levels of homeostatic hunger may be primarily determined by the amount of protein an animal requires and thus, in recent years, protein intake has become a common method for measuring need-based hunger (Gosby et al, 2011; Liu et al, 2017; Ro et al, 2016; Simpson et al, 2003; Weaver et al, 2022).…”