Neuroretina of young and old mice treated with UA or vehicle

Macroautophagy decreases with age, and this change is considered a hallmark of the aging process. It remains unknown whether mitophagy, the essential selective autophagic degradation of mitochondria, also decreases with age. In our analysis of mitophagy in multiple organs in the mito-QC reporter mouse, mitophagy was either increased or unchanged in old versus young mice. Transcriptomic analysis showed marked upregulation of the type I interferon response in the retina of old mice, an effect that correlated with increased levels of cytosolic mtDNA and activation of the cGAS/STING pathway. Crucially, these same alterations were replicated in primary human fibroblasts from elderly donors. In old mice, pharmacological induction of mitophagy with urolithin A attenuated cGAS/STING activation and ameliorated deterioration of neurological function. These findings point to induction of mitophagy as a novel strategy to decrease age-associated inflammation and increase healthspan. Overall design: Young (6-8 months) or old (22-24 months) C57BL/6J mice were treated daily with 2.3 mg/kg/day of Urolithin A (UA) or Vehicle