Enhancing Mask Activity in Dopaminergic Neurons Extends Lifespan in Flies

Abstract

Dopaminergic neurons (DANs) modulate essential brain functions involving memory formation, reward processing, and decision making. Here, I demonstrate a novel and important function of the DANs in the fly brain in regulating aging and longevity. I show that two distinct groups of DANs, when overexpressing the putative scaffolding protein Mask, can each significantly extend lifespan. Dopamine transmission is required to elicit beneficial effects when Mask is overexpressed in these neurons, but elevating dopamine production or supplementation of L-dopa is not sufficient to yield similar effects on longevity. The lifespan extension induced by Mask-overexpressing in the long-lived flies is accompanied by sustained adult locomotor and fecundity. And other physiological functions in the adult such as food intake, energy storage, and insulin production in the brain are not consistently altered by overexpressing Mask in either group of DANs. Our recent work demonstrated a novel cellular function of Mask in promoting microtubule (MT) dynamics. Overexpressing Unc-104 or moderately reducing p150 Glued level, interventions that can induce MTs dynamics, in the same groups of DANs also extend lifespan in flies. All together, these data unraveled an undocumented DANs-dependent mechanism that regulate systemic aging and longevity in flies, alterations of the cellular properties in subsets of DANs can have a profound impact on aging.