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

• 成果类型: Article
• 署名作者: Puszynska, Anna M.; Nguyen, Thao P.; Cangelosi, Andrew L.; Armani, Andrea; Roberts, Justin M.; Singh, Kristin A.; Cameron, James C.; Tseyang, Tenzin; Liu, Grace Y.; Lai, Steven; Sprenger, Hans-Georg; Yang, Jason; Colgan, William N.; Kedir, Jibril F.; Kajderowicz, Kathrin M.; Esantsi, Theodore K.; Lu, Yuancheng Ryan; Waite, Millenia; Kunchok, Tenzin; Lewis, Caroline A.; Schulte, Fabian; Bell, George W.; Sabatini, David M.; Weissman, Jonathan S.
• 署名单位: Massachusetts Institute of Technology (MIT); Whitehead Institute; Massachusetts Institute of Technology (MIT); University of Padua; Waters Corporation; Massachusetts Institute of Technology (MIT); Czech Academy of Sciences; Institute of Organic Chemistry & Biochemistry of the Czech Academy of Sciences; Massachusetts Institute of Technology (MIT); Howard Hughes Medical Institute; Massachusetts Institute of Technology (MIT); Stanford University; Stanford Medicine; Duke University; Duke University; University of Zurich; Memorial Sloan Kettering Cancer Center; Massachusetts Institute of Technology (MIT); University of Massachusetts System; UMass Chan Medical School; University of Massachusetts Worcester; University of California System; University of California Berkeley; Max Planck Society; Icahn School of Medicine at Mount Sinai
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.ady0832
• 发表日期: 2026-07-30
• 页码: eady0832
• 关键词: chaperone-mediated autophagy; AGE-RELATED-CHANGES; life-span; alzheimers-disease; ACID-PHOSPHATASE; apolipoprotein-e; nervous-system; type-4 allele; cathepsin-b; neurons

摘要

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.