LONGITUDINAL AUTOPHAGY PROFILING OF THE MAMMALIAN BRAIN REVEALS SUSTAINED MITOPHAGY THROUGHOUT HEALTHY AGING

Aging is the single greatest risk factor for neurodegenerative disease. Mitophagy safeguards cellular and tissue health by selectively eliminating damaged mitochondria. Mitophagy declines with age in short-lived model organisms, yet its physiological regulation in the aging mammalian brain and its relationship to other autophagy pathways remain poorly defined. I will present new insights into the spatiotemporal dynamics of mitophagy in the aging mammalian brain. Using high resolution spatiocellular mapping of genetically encoded optical reporter mice (mito-QC and auto-QC), our in vivo analyses reveal striking subset-specific dynamics in both mitophagy and macroautophagy across intact brain circuits. I will present these previously unrecognized age dependent trajectories, with a particular focus on inflection points in midlife, newly identified sites of mitophagy activity in clinically relevant and underexplored neural circuits and neuroimmune cellular subsets. I will also highlight emerging evidence of age-related endolysosomal dysfunction in the healthy mammalian brain, a mechanism further exacerbated in preclinical neurodegeneration. Together with emerging human data, our findings uncover spatiotemporally defined autophagy dynamics in the aging nervous system. I will also present our ongoing efforts to understand healthy brain aging in unconventional long-lived model systems. Our work provides a foundational resource to guide the development of precision therapeutic strategies targeting mitophagy and organelle homeostasis in neurological disease.