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

Aging arises from complex interactions among multiple biochemical and metabolic products. Systems-level analyses of biological networks may provide insights into the causes and consequences of aging that evade single-gene or single-pathway studies. We have shown that dietary choice per se is sufficient to modulate aging and metabolic health in the vinegar fly, Drosophila melanogaster . In other words, how each meal is presented, or the way in which it is eaten, is influential, independent of the amount or type of nutrients that are consumed. For example, when major macronutrients were presented separately, male flies exhibited a rapid and significant increase in mortality rate and a reduced overall lifespan relative to those fed a single medium containing both sugar and yeast. These effects are mediated by specific components of serotonin signaling, as a mutation in serotonin receptor 2A ( 5-HT2A ) eliminated the effects of dietary choice. Here we show that dietary choice influenced several measures of metabolic network integrity, including connectivity, average shortest distance, community structure, and robustness, with the effects of the latter two restricted to tissues in the head. These changes in network structure were associated with organism resilience and increased susceptibility to genetic perturbation, as measured by starvation survival. Our data suggest that the behavioral or perceptual consequences of exposure to individual macronutrients, involving serotonin signaling through 5-HT2A, qualitatively change the state of metabolic networks throughout the organism from one that is highly connected and robust to one that is fragmented, fragile, and vulnerable to perturbations. ### Competing Interest Statement The authors have declared no competing interest.