Enhancing mask activity in dopaminergic neurons extends lifespan in flies

Dopaminergic neurons (DANs) are essential modulators for brain functions involving memory formation, reward processing, and decision-making. Here I demonstrate a novel and important function of the DANs in regulating aging and longevity. Overexpressing the putative scaffolding protein Mask in two small groups of DANs in flies can significantly extend the lifespan in flies and sustain adult locomotor and fecundity at old ages. This Mask-induced beneficial effect requires dopaminergic transmission but cannot be recapitulated by elevating dopamine production alone in the DANs. Independent activation of Gα_s in the same two groups of DANs via the drug-inducible DREADD system also extends fly lifespan, further indicating the connection of specific DANs to aging control. The Mask-induced lifespan extension appears to depend on the function of Mask to regulate microtubule (MT) stability. A structure-function analysis demonstrated that the ankyrin repeats domain in the Mask protein is both necessary for regulating MT stability (when expressed in muscles and motor neurons) and sufficient to prolong longevity (when expressed in the two groups of DANs). Furthermore, DAN-specific overexpression of Unc-104 or knockdown of p150^Glued , two independent interventions previously shown to impact MT dynamics, also extends lifespan in flies. Together, these data demonstrated a novel DANs-dependent mechanism that, upon the tuning of their MT dynamics, modulates systemic aging and longevity in flies.