p21+TREM2+ senescent macrophages fuel inflammaging and metabolic dysfunction-associated steatotic liver disease
Cellular senescence drives chronic sterile inflammation during aging via the senescence-associated secretory phenotype, yet the senescent cell types responsible are poorly defined. Macrophages share multiple features of senescence, including inflammatory secretion, yet whether macrophages can adopt a senescent state remains unclear. Here we identify p21⁺Trem2⁺ senescent macrophages as a major source of inflammaging, using primary mouse and human macrophage models of DNA damage and cholesterol-induced senescence characterized by multi-omic profiling. We found that senescent macrophages exhibit a distinctive p21-TREM2 expression profile and senescence-associated secretory phenotype, driven in part by type I interferon signaling via cytosolic mitochondrial DNA. We also found that senescent macrophage accumulation occurs in aging, metabolic dysfunction-associated steatotic liver disease mouse livers, and is enriched in human cirrhotic liver tissue. Finally, senolytic treatment targeting senescent macrophages reduced liver inflammation and steatosis in both aged mice and mice with metabolic dysfunction-associated steatotic liver disease. These findings establish macrophage senescence as a central driver of chronic inflammation in aging and metabolic liver disease, and a tractable therapeutic target.
Authors
- Jacob Rose
- Abhijit Kale (ORCID: https://orcid.org/0000-0002-1105-6953)
- Birgit Schilling (ORCID: https://orcid.org/0000-0001-9907-2749)
- Indra Heckenbach (ORCID: https://orcid.org/0000-0001-7038-4677)
- Yuming Jiang (ORCID: https://orcid.org/0000-0001-7444-3849)
- Grasiela Torres
- Mark Larsen (ORCID: https://orcid.org/0000-0002-2800-3487)
- Lia Farahi (ORCID: https://orcid.org/0000-0002-4599-1050)
- Aldons Jake Lusis (ORCID: https://orcid.org/0000-0001-9013-0228)
- Eric Verdin (ORCID: https://orcid.org/0000-0003-3703-3183)
- Alexander J. Napior
- Itzetl Avila (ORCID: https://orcid.org/0000-0002-4596-647X)
- Cyril Lagger (ORCID: https://orcid.org/0000-0003-1701-6896)
- Anthony J. Covarrubias (ORCID: https://orcid.org/0000-0002-7884-652X)
- João Pedro de Magalhães (ORCID: https://orcid.org/0000-0002-6363-2465)
- Julia J. Mack (ORCID: https://orcid.org/0000-0002-9239-8436)
- Isaiah Little (ORCID: https://orcid.org/0000-0002-3073-553X)
- Steven J. Bensinger (ORCID: https://orcid.org/0000-0002-9657-4206)
- Jesse G. Meyer (ORCID: https://orcid.org/0000-0003-2753-3926)
- Chantle Edillor
- Morten Scheibye‐Knudsen (ORCID: https://orcid.org/0000-0002-6637-1280)
- M Krieger (ORCID: https://orcid.org/0009-0003-9957-0969)
- Julia Gensheimer (ORCID: https://orcid.org/0000-0001-6579-9579)
- Charles Brenner (ORCID: https://orcid.org/0000-0002-4955-3226)
- Kushan Chowdhury (ORCID: https://orcid.org/0000-0002-5310-3623)
- Mridul Sharma (ORCID: https://orcid.org/0000-0002-1963-3591)
- K. Williams (ORCID: https://orcid.org/0000-0002-9641-3760)
- Ram Singh
- Edwin D.J. Lopez Gonzalez
- Anika Dhingra
- Lizeth Estrada
- Carla M. Koehler
- Ronak Hegde
- Andreea C. Alexandru
- Simon Hui
- Cristian Ponce (ORCID: https://orcid.org/0009-0009-9399-8925)
- Christina Y. Deng (ORCID: https://orcid.org/0009-0000-9141-8899)
- Jose A. Soto (ORCID: https://orcid.org/0000-0002-2246-8961)
- Ivan A. Salladay-Perez
Institutions
- Kyiv School of Economics (UA)
- University of Copenhagen (DK)
- Cedars-Sinai Medical Center (US)
- Buck Institute for Research on Aging (US)
- University of California, Los Angeles (US)
- UCLA Health (US)
- Department of Health and Aged Care (AU)
- City of Hope (US)
- Comprehensive Cardiovascular (US)
- Broad Center (US)
- UCLA Jonsson Comprehensive Cancer Center
Publication Details
- Journal
- Nature Aging
- Published
- 2026-04-16
- DOI
- https://doi.org/10.1038/s43587-026-01101-6
- Citations
- 1
- Primary Topic
- Telomeres, Telomerase, and Senescence
- Type
- article
- Field-Weighted Citation Impact
- 19.92
Funders
- American Federation for Aging Research
- American Heart Association
- National Cancer Institute
- National Institute of General Medical Sciences
- National Institute of Allergy and Infectious Diseases
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Center for Research Resources