Drosophila serotonin 2A receptor signaling coordinates central metabolic processes to modulate aging in response to nutrient choice

Abstract

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.

Serotonin signaling modulates aging-associated metabolic network integrity in response to nutrient choice

“…We predicted that the effect of knockdown on this phenotype would be magnified in flies fed a choice diet because of the putative fragility of the observed networks ( Figure 6A). Consistent with our previous findings 31 , control males that were fed a choice diet for 10 days exhibited a smaller decline in starvation resistance relative to their siblings fed a fixed diet ( Figure 6C). Importantly, knocking down any one of the three enzymes exacerbated the differences between a choice and a fixed diet, as predicted by our model (Figures 6D-6F).…”

“…Knocking down critical metabolic enzymes was more deleterious in animals with vulnerable network structures (i.e., flies fed a choice diet, see Figure 6E-6F). On the other hand, loss of serotonin receptor 5-HT2A increased network robustness in a choice environment and also rescued choice-induced declines in starvation resistance 31 . Nevertheless, the preservation of network structure alone may not provide a complete picture of the mechanisms that influence physiological robustness, as the manifestation of biological robustness occurs on many different levels 3 .…”

“…presenting 10% w/v sugar and 10% w/v yeast in separate wells) increased mortality ( Figure 1A) and reduced mean lifespan of wildtype males when compared with siblings that were presented with a single, complete food of the same macronutrient composition (i.e. 10% w/v sugar and 10% w/v yeast mixture) 31 . A dietary switch at 20 days of adult life rapidly increased/decreased mortality when flies were transferred to a choice or fixed diet, respectively ( Figure 1B and 1C).…”

“…Metabolomics data were collected in a separate study 31 . We briefly summarized our methods here, while the full details can be found from our publication 31 .…”

“…For instance, research from C. elegans revealed that, despite their well-known role in modulating appetite and feeding behavior 22,30 , specific serotonin receptors regulate fat metabolism independent of feeding 25 . Most recently, we discovered that serotonin 2A (5-HT2A) receptor in D. melanogaster modulates lipid storage, stress resistance, and longevity in response to nutrient availability and independent of feeding 31 .…”