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.

1Sensory perception modulates health and aging across taxa. Understanding the nature of relevant cues 2 and the mechanisms underlying their action may lead to novel interventions that improve the length 3 and quality of life. In humans, psychological trauma is often associated with the recognition of dead 4 individuals, with chronic exposure leading to persistent mental health issues including depression and 5 post-traumatic stress disorder. The mechanisms that link mental and physical health, and the degree to 6 which these are shared across species, remain largely unknown. Here we show that the vinegar fly, 7Drosophila melanogaster, has the capability to perceive dead conspecifics in its environment and that this 8 perceptive experience induces both short-and long-term effects on health and longevity. Death 9 perception is mediated by visual and olfactory cues, and remarkably, its effects on aging are eliminated 10 by targeted attenuation of serotonin signaling. Our results suggest a complex perceptive ability in 11Drosophila that reveals deeply conserved mechanistic links between psychological state and aging, the 12 roots of which might be unearthed using invertebrate model systems. 13 14In humans, psychological stress is often induced by our perception of alarming or distasteful stimuli, 1 and the recognition of dead individuals is one of the most potent. This perceptive ability is not 2 uncommon in the animal kingdom, as individuals from a wide range of species respond to their dead. 3Social insects, including ants and honey bees, exhibit necrophoresis in which dead colony members are 4 systematically removed from the nest to promote hygienic conditions 1 . Dead zebrafish scents provoke 5 defensive behavior in live individuals 2 , and the sight of a dead conspecific induces alarm calling in 6 scrub-jays 3 , suggesting that dead individuals may indicate danger. Elephants and nonhuman primates 7 exhibit stereotypical behaviors toward dead individuals associated with permanent loss of a group 8 member 4,5 . Such natural behaviors resemble human emotions that are associated with our own 9 experiences of death, which include anger, fear, anxiety, and depression. Short-term effects of these 10 psychologically stressful conditions include emotional dysregulation, hyperactivity, eating disorders, 11 and alcohol abuse 6 . Long-term consequences of exposure to death are evident in first responders as 12 well as active military troops; they include both psychological effects, such as post-traumatic stress 13 disorder and depression, and physical effects, such as headaches, fatigue, and cardiovascular disease 7,8 . 14 Even the quality of human aging has been related to mental health 9,10 , but this association belies a 15 mechanistic understanding of the relationship. 16Despite its prevalence in our society, the mechanisms underlying death perception, the life-long 17 consequences of such experiences, and the degree to which they are shared across species remain 18 largely unknown. Reasons for this include an inherent ...