Sexual Deprivation, Emotion, and Longevity: Neuropeptidergic Regulation of Aging in Drosophila

Abstract

While researchers often focus on the brain as a victim of aging via neurodegenerative diseases, recent work has demonstrated that the aging process is regulated by neural mechanisms. Thus, we asked which mechanisms and inputs might be important for the brain to regulate aging. We found that in male Drosophila melanogaster, the costs of reproduction on survival are mediated entirely through perception of the opposite sex, and that mating itself is actually beneficial. These effects are mediated through distinct neural circuits, with neuropeptide F (npf, an NPY homolog) required for the negative effects of pheromones and corazonin (crz, a GnRH homolog) driving the beneficial effects of mating. dFoxo, a common mediator of aging, regulates these effects on aging through an insulin-independent mechanism. Investigation of the dynamics of the effects of pheromones on mortality revealed two hypotheses: either population mortality rates reverse as a result of heterogeneity in individual probabilities of death, or the effects of pheromones on mortality rates are reversible in individuals. By combining in vivo and in silico approaches, we revealed that both explanations are correct, with individual reversibility dominating dynamics early in life, and heterogeneity becoming important in middle-age. Using a more global approach, we examined the effects of manipulating 78 distinct subsets of neurons on lifespan, and identified specific brain structures that are of prime importance for modulating aging. One of these structures is home to neurons expressing diuretic hormone 44 (Dh44, a CRH homolog). Dh44 and one of its receptors, Dh44R1, modulate lifespan, likely through insulin-like signaling pathways. Furthermore, this effect of Dh44 on lifespan is independent of diet, a fact obtained in part using the Fly Liquid-food Interaction Counter (FLIC), a novel assay developed to continuously measure feeding behavior in individual flies. The evolutionarily conserved neural circuits identified herein link aging to neural states consistent with primitive emotions in Drosophila, and these mechanisms deserve further exploration for their potential to explain connections between stress, emotions, and health in humans.