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

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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.
Funding Information
  • National Institutes of Health (R01 CA103866)
  • National Institutes of Health (R01 AI47389)
  • National Institutes of Health (5F31DK113665)
  • National Institutes of Health (NRSA F31 CA232355)
  • American Foundation for Aging Research
  • Life Sciences Research Foundation
  • H2020 Marie Skłodowska-Curie Actions (101033310)
  • Hope Funds for Cancer Research (HFCR-20-03-01-02)
  • NHS Innovation Accelerator (1 R21 AG072511)
  • William N. and Bernice E. Bumpus Foundations
  • Milky Way Research Foundation
  • Longevity Impetus Grant
  • Peter J. Eloranta Summer Research Fellowship

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