Serotonin Signaling Modulates Health and Lifespan in Drosophila melanogaster
Creators: name: Munneke, Allyson
Publisher: name: My University
Year: 2022
Subjects: subject: Drosophila
subject: aging
subject: serotonin
subject: neuroscience
subject: genetics
subject: Science (General)
subject: Science

description: Sensory perception of environmental cues such as nutrients, mates, and threats, modulates aging across taxa. These effects on lifespan require the action of conserved neuromodulators, such as serotonin. Despite clear links between serotonin and lifespan in specific environmental contexts, little was known about the influence of serotoninergic signaling pathways on lifespan in normal environments. I therefore, aimed to understand how manipulation of serotonin signaling through each of its receptors influenced lifespan in Drosophila. I first discovered that loss of specific serotonin receptors induces profound differences in lifespan. Of the five receptors for serotonin, loss of three led to a shortened lifespan in both males and females; however, loss of two receptors (5-HT2A and 5-HT7) caused a lifespan extension in female flies, with no effect on male lifespan. Behavioral characterization of these receptor mutants revealed most mutants do not display broad changes in sleep, activity, and feeding behavior. This 1) implies loss of individual receptors does lead to drastic negative health consequences, and 2) decouples the lifespan extension from any behavioral changes. This supports the notion that loss of receptor signaling pathways influence lifespan, independent of behavioral changes. Of the changes in lifespan across the 5-HT receptor mutants, I was most interested in the manipulations that extended lifespan, loss of 5-HT2A or 5-HT7. I focused on the mechanisms underlying the lifespan extension in the 5-HT2A-/- mutant in greater detail, as additional data in the lab revealed 5-HT2A was an important modulator of lifespan in two separate contexts. I was involved with one of these projects studying the mechanisms by which flies’ perception of presumed threat cues in the environment influenced lifespan. Specifically, visual detection of dead conspecifics shortens lifespan, and this effect requires 5-HT2A signaling. Further, a previous project identified that lifespan is shorted when flies must choose between sugar and protein consumption and this lifespan phenotype requires 5-HT2A. Based on these data, I suspected 5-HT2A plays an important role in evaluation of the nutritional environment, and disruption of this by loss of 5-HT2A may influence lifespan. and I found that 5-HT2A plays an important role in determining a protein consumption target in the fruit fly. My findings indicate that 5-HT2A signaling is recruited to promote protein consumption, perhaps by establishing a heightened protein consumption target, and to enact a physiological state of higher protein utilization that subsequently accelerates aging. In the absence of this receptor, protein demand remains chronically unsatisfied, which leads to an adaptive lowering of protein utilization and metabolism, extending lifespan. Together, the results from these projects support the notion that manipulating distinct aspects of serotonin signaling induces variable effects on lifespan. Closer examination of one receptor, 5-HT2A, revealed new insights into the ways in which organisms cope with nutrient stress and highlight how perception of nutrient demand influence lifespan. This work also opens the door for further investigations into the direct effects on lifespan that result from manipulations of serotonin signaling pathways.