Senescent glia link neuronal mitochondrial dysfunction and lipid droplet accumulation with age [19082R-38_MASTER]

Senescence is a cellular state linked to aging and age-onset disease across many mammalian species. Acutely, senescent cells promote wound healing and prevent tumor formation; but they are also pro-inflammatory, thus chronically exacerbate tissue decline. While senescent cells are active targets for anti-aging therapy, why these cells form in vivo, how they affect tissue aging, and the impact of their elimination remain unclear. Here we identify naturally-occurring senescent glia in aged Drosophila brains and decipher their origin and influence. Using AP1 activity to screen for senescence, we determine that senescent glia can appear in response to neuronal mitochondrial dysfunction. In turn, senescent glia promote lipid accumulation in non-senescent glia; similar effects are seen in senescent human fibroblasts in culture. Targeting AP1 activity in senescent glia mitigates senescence biomarkers, extends fly life and health span, and prevents lipid accumulation. However, these benefits come at the cost of increased oxidative damage in the brain, and neuronal mitochondrial function remains poor. Altogether, our results map the trajectory of naturally-occurring senescent glia in vivo and indicate that these cells link key aging phenomena: mitochondrial dysfunction and lipid accumulation. Through bulk-RNA-seq and a targeted RNAi screen, we determined that loss of select mitochondrial genes in neurons trigger AP1 activity in glia. To understand the neuronal changes associated with conditions of increased glial AP1 activity (neuronal loss of ND42 loss) vs conditions of reduced glial AP1 activity (neuronal loss of ND30 loss), we dissected whole brains dissected from 10d flies with neuronal knockdown of ND42 or ND30 then performed bulk RNA-sequencing for downstream gene expression analysis.