Serotonin and dopamine modulate aging in response to food odor and availability

Abstract

An organism’s ability to perceive and respond to changes in its environment is crucial for its health and survival. Here we reveal how the most well-studied longevity intervention, dietary restriction, acts in-part through a cell non-autonomous signaling pathway that is inhibited by the presence of attractive smells. Using an intestinal reporter for a key gene induced by dietary restriction but suppressed by attractive smells, we identify three compounds that block food odor effects in C. elegans, thereby increasing longevity as dietary restriction mimetics. These compounds clearly implicate serotonin and dopamine in limiting lifespan in response to food odor. We further identify a chemosensory neuron that likely perceives food odor, an enteric neuron that signals through the serotonin receptor 5-HT1A/SER-4, and a dopaminergic neuron that signals through the dopamine receptor DRD2/DOP-3. Aspects of this pathway are conserved in D. melanogaster. Thus, blocking food odor signaling through antagonism of serotonin or dopamine receptors is a plausible approach to mimic the benefits of dietary restriction.

Lifespan extension in female mice by early, transient exposure to adult female olfactory cues

“…Studies of the effects of sensory perception on aging and lifespan in invertebrates dates back at least to the work of Apfeld and Kenyon in Caenorhabditis elegans ( Apfeld and Kenyon, 1999 ), and in the years since, a variety of sensory modalities, including smell, taste, sight, and pain, have become established as important modulators of aging across invertebrate taxa ( Libert et al, 2007 ; Waterson et al, 2015 ; Riera and Dillin, 2016 ). Exposure of flies and worms to food-based odorants, for example, limit the benefits of dietary restriction and influence measures of healthy aging, including sleep and daily activity patterns ( Miller et al, 2022 ; Linford et al, 2015 ). Some of these studies have focused on how perception of conspecific pheromones, detected through olfaction and gustation, can modulate Drosophila and C. elegans lifespan ( Shi and Murphy, 2014 ; Maures et al, 2014 ; Gendron et al, 2014 ).…”

The effect of a pharmaceutical ghrelin agonist on lifespan in C57BL/6J male mice: A controlled experiment

“…Recent evidence in Drosophila melanogaster shows interesting linkages between CR and tissue‐specific aging (CLOCK gene regulation in eyes) that extend lifespan (Hodge et al, 2022 ). Work in Caenorhabditis elegans demonstrates the roles of serotonin and dopamine receptor antagonism in mimicking CR that result in increased longevity by way of the Fmo genes (Miller et al, 2022 ). Mammals and C. elegans share a common ancestral Fmo gene (Petalcorin et al, 2005 ).…”

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

“…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 ). In C. elegans, the perception of food cues blunts lifespan extension by dietary restriction and blocking serotonin signaling abrogates this effect ( Zhang et al, 2021 ; Miller et al, 2022 ). As postulated by Ro et al ( Ro et al, 2016 ), serotonin-dependent perception of perceived protein limitation modulates lifespan, and the findings from this study suggest that the inability to satisfy protein demand upon loss of 5-HT2A leads to a long-term reduction in protein motivation and may be one mechanism through which these lifespan effects arise.…”

“…When flies are presented with the opportunity to construct their own diet as opposed to the standard homogenous nutrient mixture, lifespan is shortened in a manner dependent on neuronal signaling through the 5-HT2A serotonin receptor ( Ro et al, 2016 ; Lyu et al, 2021 ). In C. elegans , the lifespan extension via dietary restriction is reduced when worms can smell, but not access, food, and this effect requires both dopamine and serotonin signaling ( Zhang et al, 2021 ; Miller et al, 2022 ).…”