Atlas of Lysosomal Aging Reveals a Molecular Clock of Storage Disorder-Associated Metabolites

Puszynska, A. M., Nguyen, T. P., Cangelosi, A. L., Armani, A., Roberts, J. M., Singh, K. A., Cameron, J. C., Tseyang, T., Liu, G. Y., Lai, S., Sprenger, H.-G., Yang, J., Colgan, W. N., Kedir, J. F., Kajderowicz, K. M., Esantsi, T. K., Lu, Y. R., Waite, M., Kunchok, T., Lewis, C. A., Schulte, F., Bell, G. W., Sabatini, D. M., Weissman, J. S.

Whitehead Institute for Biomedical Research · biorxiv

Paper

Abstract

Lysosomal dysfunction is a well-recognized feature of aging, yet its systematic molecular investigation remains limited. Here, we employ a suite of tools for rapid lysosomal isolation to construct a multi-tissue atlas of the metabolite changes that murine lysosomes undergo during aging. Aged lysosomes in brain, heart, muscle and adipose accumulate glycerophosphodiesters and cystine, metabolites that are causally linked to juvenile lysosomal storage disorders like Batten disease. Levels of these metabolites increase linearly with age, preceding organismal decline. Caloric restriction, a lifespan-extending intervention, mitigates these changes in the heart but not the brain. Our findings link lysosomal storage disorders to aging-related dysfunction, uncover a metabolic lysosomal \"aging clock\", and open avenues for the mechanistic investigation of how lysosomal functions deteriorate during aging and in age-associated diseases.

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Research summary

The paper claims that lysosomal metabolite accumulation serves as a molecular clock for aging and is linked to age-related dysfunction. This research addresses the underlying mechanisms of aging through the lens of lysosomal function, which is crucial for understanding and potentially mitigating age-related diseases.

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