Atlas of lysosomal aging reveals a metabolite signature shared with lysosomal storage disorders.

Anna M Puszynska, Thao P Nguyen, Andrew L Cangelosi, Andrea Armani, Justin M Roberts, Kristin A Singh, James C Cameron, Tenzin Tseyang, Grace Y Liu, Steven Lai, Hans-Georg Sprenger, Jason Yang, William N Colgan, Jibril F Kedir, Kathrin M Kajderowicz, Theodore K Esantsi, Yuancheng Ryan Lu, Millenia Waite, Tenzin Kunchok, Caroline A Lewis, Fabian Schulte, George W Bell, David M Sabatini, Jonathan S Weissman

Whitehead Institute for Biomedical Research, Cambridge, MA, USA.Whitehead Institute for Biomedical Research, Cambridge, MA, USA. · pubmed

Paper

Abstract

Lysosomal dysfunction is a well-recognized feature of aging. Here, we used a suite of tools for rapid lysosomal isolation to construct a multitissue atlas of the metabolite changes lysosomes undergo during aging. Aged lysosomes in brain, heart, muscle, and white adipose tissue accumulated glycerophosphodiesters and cystine, metabolites that are causally linked to juvenile lysosomal storage disorders, Batten disease, and cystinosis. Levels of these metabolites increased linearly with age, preceding organismal decline. Caloric restriction, a lifespan-extending intervention, mitigated these changes in the heart and muscle but not the brain. Our findings link lysosomal storage disorders to aging-related dysfunction 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 identifies a linear accumulation of specific metabolites (glycerophosphodiesters and cystine) in aged lysosomes that mirrors signatures of juvenile lysosomal storage disorders, suggesting a mechanistic link between lysosomal dysfunction and aging. This work is relevant because it characterizes a fundamental cellular decline mechanism (lysosomal waste accumulation) that contributes to organismal aging, although the findings are largely descriptive and incremental, establishing a correlation rather than a novel therapeutic intervention or causal proof that reversing this specific signature extends lifespan.

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