Sex-specific and cell-type-specific changes in chaperone-mediated autophagy across tissues during aging
Aging leads to progressive decline in organ and tissue integrity and function, partly due to loss of proteostasis and autophagy malfunctioning. A decrease with age in chaperone-mediated autophagy (CMA), a selective type of lysosomal degradation, has been reported in various organs and cells from rodents and humans. Disruption of CMA recapitulates features of aging, whereas activating CMA in mice protects against age-related diseases such as Alzheimer's, retinal degeneration and/or atherosclerosis. However, sex-specific and cell-type-specific differences in CMA with aging remain unexplored. Here, using CMA reporter mice and single-cell transcriptomic data, we report that most organs and cell types show CMA decline with age, with males exhibiting a greater decline with aging. Reduced CMA is often associated with fewer lysosomes competent for CMA. Transcriptional downregulation of CMA genes may further contribute to CMA decline, especially in males. These findings suggest that CMA differences may influence organ vulnerability to age-related degeneration.
Authors
- Mericka McCabe (ORCID: https://orcid.org/0000-0001-6758-2330)
- Adrián Martín‐Segura (ORCID: https://orcid.org/0000-0001-9369-0589)
- Ana Rosa Saez-Ibañez
- Aurora Scrivo (ORCID: https://orcid.org/0000-0001-7511-035X)
- Raquel Gómez‐Sintes (ORCID: https://orcid.org/0000-0003-2854-6964)
- Esperanza Arias (ORCID: https://orcid.org/0000-0002-7836-5072)
- Rebecca Sereda (ORCID: https://orcid.org/0000-0002-6168-3226)
- Ana María Cuervo (ORCID: https://orcid.org/0000-0002-0771-700X)
- Olaya Santiago‐Fernández (ORCID: https://orcid.org/0000-0002-5933-3104)
- Susmita Kaushik (ORCID: https://orcid.org/0000-0002-6096-5387)
- Inmaculada Tasset (ORCID: https://orcid.org/0000-0003-0730-6750)
- Kristen L. Lindenau (ORCID: https://orcid.org/0000-0001-6145-5322)
- Maryam Jafari (ORCID: https://orcid.org/0000-0001-5552-1127)
- Adrián Macho‐González (ORCID: https://orcid.org/0000-0001-7644-1759)
- Rabia R. Khawaja (ORCID: https://orcid.org/0000-0003-3907-988X)
- Mimi Kim (ORCID: https://orcid.org/0000-0002-8266-0226)
- Xianhong Xie (ORCID: https://orcid.org/0000-0002-2032-1587)
- Bhakti Chavda
Institutions
- Albert Einstein College of Medicine (US)
- Institut d'Investigació Biomédica de Bellvitge (ES)
- IMDEA Food (ES)
- Centro de Investigaciones Biológicas Margarita Salas (ES)
- University of Córdoba (ES)
Publication Details
- Journal
- Nature Aging
- Published
- 2025-02-05
- DOI
- https://doi.org/10.1038/s43587-024-00799-6
- Citations
- 24
- Primary Topic
- Autophagy in Disease and Therapy
- Type
- article
- Field-Weighted Citation Impact
- 32.50
Funders
- JPB Foundation
- Grace Science Foundation
- Ministerio de Ciencia Tecnología y Telecomunicaciones
- Instituto Carlos Slim de la Salud
- National Institute on Aging
- National Heart, Lung, and Blood Institute
- National Institute of General Medical Sciences
- National Institute of Diabetes and Digestive and Kidney Diseases