Upregulation of the Autophagy Adaptor p62/SQSTM1 Prolongs Health and Lifespan in Middle-Aged Drosophila

Autophagy, a lysosomal degradation pathway, plays crucial roles in health and disease. p62/SQSTM1 (hereafter p62) is an autophagy adaptor protein that can shuttle ubiquitinated cargo for autophagic degradation. Here, we show that upregulating the Drosophila p62 homolog ref(2)P/dp62, starting in midlife, delays the onset of pathology and prolongs healthy lifespan. Midlife induction of dp62 improves proteostasis, in aged flies, in an autophagy-dependent manner. Previous studies have reported that p62 plays a role in mediating the clearance of dysfunctional mitochondria via mitophagy. However, the causal relationships between p62 expression, mitochondrial homeostasis, and aging remain largely unexplored. We show that upregulating dp62, in midlife, promotes mitochondrial fission, facilitates mitophagy, and improves mitochondrial function in aged flies. Finally, we show that mitochondrial fission is required for the anti-aging effects of midlife dp62 induction. Our findings indicate that p62 represents a potential therapeutic target to counteract aging and prolong health in aged mammals. [Display omitted] •Upregulating p62 from midlife onward prolongs fly lifespan and health span•Midlife p62 induction improves proteostasis, in aged flies, via autophagy•Midlife p62 induction promotes mitochondrial fission and mitophagy in aged flies•Mitochondrial fission and autophagy are required for midlife p62-mediated longevity Autophagy has been proposed to promote longevity in diverse species, yet the underlying molecular mechanisms remain poorly understood. Using Drosophila, Aparicio et al. show that upregulating a prototypic autophagy receptor, p62/SQSTM1, from midlife onward slows aging and prolongs health span. Midlife p62 induction promotes mitochondrial fission and mitophagy to slow aging.