P21 plus Senescent Macrophages Fuel Inflammation and Disease in Aging and Metabolic Dysfunction-Associated Steatotic Liver Disease

ABSTRACT: DNA damage or other cellular stress can lead to an irreversible cell cycle arrest, known as cellular senescence. While cellular senescence can be beneficial in some contexts such as wound healing and development, it is now recognized as a major source of sterile inflammation in aging tissues via the secretion of inflammatory factors known as the senescence-associated secretory phenotype (SASP). Targeting senescent cells is therefore an emerging strategy for treating age-related diseases, however, the identity and function of specific senescent cell types remain unclear. Here, we identify p21 plus senescent macrophages as a key source of chronic inflammation in aging and MASLD. To further investigate macrophage senescence, we developed an in vitro model of DNA damage-induced macrophage senescence, using primary mouse and human macrophages, which we leveraged to identify unique biomarkers that distinguish senescent macrophages from other established polarized states. We show that DNA damage or excess cholesterol induces stable macrophage senescence marked by an elevated SASP, mitochondrial dysfunction, and interferon signaling. These senescent macrophages accumulate in aged mouse livers, particularly in Kupffer cells, and are enriched in human cirrhotic liver tissue. Using transcriptomic profiling we identified a unique MSen signature to identify macrophage senescence both in vitro and in vivo in both mice and humans. We also showed that senescent macrophages can be selectively targeted for depletion using the senolytic ABT-263 (Navitoclax), which reduces liver steatosis and inflammation in MASLD models, highlighting macrophage senescence as a major source of inflammaging and promising therapeutic target in age-related diseases

INSTRUMENT(S): TripleTOF 6600

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Birgit Schilling  

PROVIDER: MSV000098058 | MassIVE | Fri May 30 20:54:00 BST 2025

SECONDARY ACCESSION(S): PXD064467

REPOSITORIES: MassIVE