Decline of chaperone-mediated autophagy in aging impairs macrophage clearance of senescent cells
Autophagy dysfunction and senescence are established drivers of aging, but their potential interaction remains poorly understood. Here we show that age-related decline of chaperone-mediated autophagy (CMA), a pathway for selective lysosomal protein degradation, changes senescent cell properties and impairs their immune clearance. CMA-deficient cells undergo senescence but acquire proteomic, metabolic and secretory features resembling those in aged senescent cells. Their senescence-associated secretory phenotype exhibits enhanced pro-senescence effects on neighboring cells and inhibits macrophage CMA, which impairs their ability to engulf senescent cells. Accordingly, blockage of CMA specifically in macrophages increases senescent cell accumulation in mice and delays senescence resolution during wound healing. Conversely, pharmacological CMA activation reduces senescent cell burden in aged mice and disease severity in a pulmonary fibrosis mouse model. Our findings identify CMA decline as a driver of senescent cell persistence and highlight CMA upregulation as a promising strategy to promote senescence resolution in aged organisms. This study looks at how the decline in chaperone-mediated autophagy in aging alters senescent cell properties leading to an impairment in their immune clearance. Utilizing proteomic and metabolomic analyses, the authors show that restoring autophagy enhances macrophage function and reduces senescent cell accumulation.
Authors
- Fanny Aprahamian (ORCID: https://orcid.org/0000-0002-2457-8435)
- Mericka McCabe (ORCID: https://orcid.org/0000-0001-6758-2330)
- Toren Finkel (ORCID: https://orcid.org/0000-0002-0726-3546)
- Evripidis Gavathiotis (ORCID: https://orcid.org/0000-0001-6319-8331)
- Yair M. Botbol (ORCID: https://orcid.org/0000-0003-2530-7482)
- Ronald R. Cutler (ORCID: https://orcid.org/0000-0001-7744-090X)
- Jazmín Calyeca
- Hu Chen (ORCID: https://orcid.org/0000-0001-8136-7442)
- Natalia-Del Pilar Vanegas (ORCID: https://orcid.org/0000-0001-5135-1714)
- Simone Sidoli (ORCID: https://orcid.org/0000-0001-9073-6641)
- 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)
- Kristen L. Lindenau (ORCID: https://orcid.org/0000-0001-6145-5322)
- Guido Kroemer (ORCID: https://orcid.org/0000-0002-9334-4405)
- Rabia R. Khawaja (ORCID: https://orcid.org/0000-0003-3907-988X)
- Ana Lucia Mora (ORCID: https://orcid.org/0000-0003-1653-8318)
- Sylvère Durand (ORCID: https://orcid.org/0000-0001-6356-1006)
- Zhaohui Liu (ORCID: https://orcid.org/0009-0000-3618-310X)
- Antonio Díaz (ORCID: https://orcid.org/0000-0001-7871-0828)
- Mauricio M. Rojas (ORCID: https://orcid.org/0000-0001-7340-4784)
- Felipe Vilicich (ORCID: https://orcid.org/0000-0002-7315-7346)
- Bhakti Chavda
Institutions
- Centre National de la Recherche Scientifique (FR)
- Albert Einstein College of Medicine (US)
- Inserm (FR)
- Université Paris Cité (FR)
- Université Paris-Saclay (FR)
- Institut Gustave Roussy (FR)
- Sorbonne Université (FR)
- Centre de Recherche des Cordeliers (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Hôpital Européen Georges-Pompidou (FR)
- University of Pittsburgh Medical Center (US)
Publication Details
- Journal
- Nature Aging
- Published
- 2026-10-05
- DOI
- https://doi.org/10.1038/s43587-026-01240-w
- Citations
- 1
- Primary Topic
- Autophagy in Disease and Therapy
- Type
- article
- Field-Weighted Citation Impact
- 4.87