Atlas of lysosomal aging reveals a metabolite signature shared with lysosomal storage disorders
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.
Authors
- Tenzin Tseyang (ORCID: https://orcid.org/0009-0007-9410-3789)
- David M. Sabatini (ORCID: https://orcid.org/0000-0002-1446-7256)
- Theodore K. Esantsi
- Caroline A. Lewis (ORCID: https://orcid.org/0000-0003-1787-5084)
- Fabian Schulte (ORCID: https://orcid.org/0000-0001-9047-2674)
- Hans‐Georg Sprenger (ORCID: https://orcid.org/0000-0002-9864-5995)
- Jonathan S. Weissman (ORCID: https://orcid.org/0000-0003-2445-670X)
- Andrew L. Cangelosi (ORCID: https://orcid.org/0000-0002-6218-0399)
- Jibril F. Kedir
- Tenzin Kunchok (ORCID: https://orcid.org/0000-0001-6603-4607)
- Justin M. Roberts (ORCID: https://orcid.org/0000-0001-6112-7476)
- Grace Y. Liu (ORCID: https://orcid.org/0000-0001-5463-3055)
- Yuancheng Ryan Lu (ORCID: https://orcid.org/0000-0002-5982-3963)
- George W. Bell (ORCID: https://orcid.org/0000-0001-6826-2507)
- William Colgan (ORCID: https://orcid.org/0000-0002-8328-4672)
- Kathrin M. Kajderowicz (ORCID: https://orcid.org/0000-0002-5541-4150)
- Andrea Armani (ORCID: https://orcid.org/0000-0002-4765-9748)
- Anna M. Puszynska (ORCID: https://orcid.org/0000-0002-8751-5335)
- Jason Yang (ORCID: https://orcid.org/0009-0007-9977-0433)
- Millenia Waite
- Steven Lai (ORCID: https://orcid.org/0009-0004-6763-7839)
- Kristin A. Singh (ORCID: https://orcid.org/0009-0002-8279-5670)
- James C. Cameron (ORCID: https://orcid.org/0009-0005-7786-0345)
- Thao P. Nguyen (ORCID: https://orcid.org/0009-0000-3388-8884)
Institutions
- Howard Hughes Medical Institute (US)
- University of Padua (IT)
- Waters (United States) (US)
- Institute of Organic Chemistry (PL)
- Czech Academy of Sciences, Institute of Organic Chemistry and Biochemistry (CZ)
- Whitehead Institute for Biomedical Research (US)
- Massachusetts Institute of Technology (US)
Publication Details
- Journal
- Science
- Published
- 2026-07-30
- DOI
- https://doi.org/10.1126/science.ady0832
- Citations
- 1
- Primary Topic
- Biomedical Research and Pathophysiology
- Type
- article
- Field-Weighted Citation Impact
- 7.68
Funders
- NHS Innovation Accelerator
- American Foundation for Aging Research
- Life Sciences Research Foundation
- Hope Funds for Cancer Research
- Milky Way Research Foundation
- National Institutes of Health
- H2020 Marie Skłodowska-Curie Actions