The Lysosomal Clock: Are We Only as Old as Our Lysosomes?

Lysosomes are a major organelle involved in intracellular degradation, membrane traffic and metabolic signaling, but how their biochemical composition changes during normal aging remains poorly defined. Puszynska and colleagues now combine lysosome purification with metabolomics and lipidomics across tissues, species and ages to reveal a conserved signature of lysosomal aging characterized by accumulation of glycerophosphodiesters (GPDs) and cystine and remodeling of bis(monoacylglycero)phosphate (BMP). Strikingly, these changes are largely obscured in whole-tissue analyses and resemble metabolic abnormalities associated with lysosomal storage disorders, including CLN3 disease and cystinosis. The signature develops progressively with age, can predict chronological age, and is attenuated by caloric restriction in peripheral tissues but not in the brain. Within the brain, age-dependent metabolite accumulation is particularly prominent in microglia and is also detected in neurons, linking lysosomal aging to cell populations central to neurodegenerative disease. These findings define an organelle-level metabolic clock, suggesting that one might be only as young as one's lysosomes. Establishing whether GPDs, cystine and BMP remodeling merely mark lysosomal age or actively contribute to declining lysosomal degradation and membrane traffic may uncover a metabolic connection between physiological aging, lysosomal storage disorders and vulnerability to late-onset neurodegeneration.