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P21+TREM2+-Senescent Macrophages Fuel Inflammaging and Metabolic Dysfunction-Associated Steatotic Liver Disease.

ABSTRACT: Cellular senescence drives chronic sterile inflammation during aging via the senescence-associated secretory phenotype (SASP); however, the cell types responsible for this pathology remain poorly defined. Here, we identify p21⁺Trem2⁺ senescent macrophages as a major source of inflammaging. Using primary mouse and human macrophages, we developed a model of DNA damage and cholesterol-induced senescence and applied multi-omic profiling to fully characterize senescent macrophages. We found that senescent macrophages exhibit a distinctive p21-TREM2 expression profile and SASP, driven in part by type-I interferon signaling via secreted mitochondrial DNA. We also found that senescent macrophage accumulation occurs in aged and MASLD mouse livers and is enriched in human cirrhotic liver tissue. Finally, senolytic treatment targeting senescent macrophages reduced liver inflammation and steatosis in both aged and MASLD mice. Together, these findings establish macrophage senescence as a central driver of chronic inflammation in aging and metabolic liver disease, highlighting a promising, tractable therapeutic target.

ORGANISM(S): Mus musculus

PROVIDER: GSE318801 | GEO | 2026/02/11

REPOSITORIES: GEO

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	GSE318801_M1M2MSEN_counts_gene.csv.gz	Csv

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P21+TREM2+-Senescent Macrophages Fuel Inflammaging and Metabolic Dysfunction-Associated Steatotic Liver Disease. [Trem2ko]

Project description:Cellular senescence drives chronic sterile inflammation during aging via the senescence-associated secretory phenotype (SASP); however, the cell types responsible for this pathology remain poorly defined. Here, we identify p21⁺Trem2⁺ senescent macrophages as a major source of inflammaging. Using primary mouse and human macrophages, we developed a model of DNA damage and cholesterol-induced senescence and applied multi-omic profiling to fully characterize senescent macrophages. We found that senescent macrophages exhibit a distinctive p21-TREM2 expression profile and SASP, driven in part by type-I interferon signaling via secreted mitochondrial DNA. We also found that senescent macrophage accumulation occurs in aged and MASLD mouse livers and is enriched in human cirrhotic liver tissue. Finally, senolytic treatment targeting senescent macrophages reduced liver inflammation and steatosis in both aged and MASLD mice. Together, these findings establish macrophage senescence as a central driver of chronic inflammation in aging and metabolic liver disease, highlighting a promising, tractable therapeutic target.

2026-02-11 | GSE318802 | GEO

P21+TREM2+-Senescent Macrophages Fuel Inflammaging and Metabolic Dysfunction-Associated Steatotic Liver Disease [RNAseq_MASHABT263]

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P21+TREM2+-Senescent Macrophages Fuel Inflammaging and Metabolic Dysfunction-Associated Steatotic Liver Disease. [Blood]

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P21+TREM2+-Senescent Macrophages Fuel Inflammaging and Metabolic Dysfunction-Associated Steatotic Liver Disease. [macro_senescence]

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P21+TREM2+-Senescent Macrophages Fuel Inflammaging and Metabolic Dysfunction-Associated Steatotic Liver Disease [RNAseq_sgCMPK2]

2026-02-10 | GSE318651 | GEO

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

Project description: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

2025-05-30 | MSV000098058 | MassIVE

Targeting CyclinD1-CDK6 to Mitigate Senescence-Driven Inflammation and Age Associated Functional Decline

Project description:Cellular senescence contributes to aging and age-related diseases by driving chronic inflammation through the Senescence Associated Secretory Phenotype (SASP) and interferon-stimulated genes (ISGs). Cyclin D1 (CCND1), a key cell cycle regulator, is paradoxically upregulated in these non-proliferating cells. We show that CCND1 and its kinase partner CDK6 drive SASP and ISG expression in senescent cells by promoting DNA damage accumulation. This leads to the formation of cytoplasmic chromatin fragments (CCFs) that activate pro-inflammatory CGAS-STING signaling. The tumor suppressor p53 (TP53) and its target p21 (CDKN2A) antagonize this CCND1-CDK6–dependent DNA damage accumulation pathway to suppress the SASP. In aged mouse livers, senescent hepatocytes show increased Ccnd1 expression. Hepatocyte-specific Ccnd1 knockout or treatment with the Cdk4/6 inhibitor Palbociclib reduces DNA damage and ISGs in aged mouse liver. Notably, Palbociclib also suppresses frailty and improves physical performance of aged mice. These findings reveal a novel role for CCND1/CDK6 in regulating DNA damage and inflammation in senescence and aging, highlighting it as a promising therapeutic target.

2025-08-13 | GSE304160 | GEO

The lncRNA MIR31HG regulates the senescence associated secretory phenotype

Project description:Oncogene-induced senescence provides a barrier against malignant transformation. Senescent cells secrete pro-inflammatory cytokines, chemokines and growth factors collectively known as the senescence-associated secretory phenotype (SASP). Paradoxically, the SASP can also negatively impact the neighbouring tissues through inducing an inflammatory environment that promotes tumorigenesis and aged-related pathologies. We have previously shown that the lncRNA MIR31HG is overexpressed and located in the cytoplasm during BRAF-induced senescence. In young proliferating cells, nuclear MIR31HG inhibits p16/CDKN2A expression through interaction with polycomb repressor complexes (PRC1/2). Here, we show that MIR31HG regulates the expression and secretion of a subset of SASP components during BRAF-induced senescence. The SASP secreted from senescent cells depleted for MIR31HG fails to induce paracrine invasion without affecting the growth inhibitory effect. Mechanistically, MIR31HG interacts with the translation factor YBX1 facilitating its phosphorylation at serine 102 (p-YBX1S102) by the kinase RSK. p-YBX1S102 induces IL1A translation which acts as upstream regulator inducing the transcription of the other SASP mRNAs. Our results suggest a dual role for MIR31HG in senescence depending on its cellular localization and place the lncRNA as a potential therapeutic target in the treatment of senescence-related pathologies.

2021-03-02 | PXD017475 | Pride

The Senescence-associated Secretome of Hedgehog-deficient Hepatocytes Drives MASLD Progression

Project description:The burden of senescent hepatocytes correlates with MASLD severity but mechanisms driving senescence, and how it exacerbates MASLD are poorly understood. Hepatocytes become senescent when Smoothened (Smo) is deleted to disrupt Hedgehog signaling. We aimed to determine if the secretomes of Smo-deficient hepatocytes perpetuate senescence to drive MASLD progression. RNA seq analysis confirmed that hepatocyte populations of MASLD livers are depleted of Smo(+) cells and enriched with senescent cells. When fed CDA-HFD, Smo(-) mice had lower antioxidant markers and developed worse DNA damage, senescence, MASH and liver fibrosis than Smo(+) mice. Sera and hepatocyte-conditioned medium from Smo(-) mice were depleted of thymidine phosphorylase (TP), a protein that maintains mitochondrial fitness. Treating Smo(-) hepatocytes with TP reduced senescence and lipotoxicity; inhibiting TP in Smo(+) hepatocytes had the opposite effects and exacerbated hepatocyte senescence, MASH, and fibrosis in CDA-HFD-fed mice.Therefore, we found that inhibiting Hedgehog signaling in hepatocytes promotes MASLD by suppressing hepatocyte production of proteins that prevent lipotoxicity and senescence.

2024-10-01 | GSE273523 | GEO

Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer

Project description:Accumulation of senescent cells in the tumour microenvironment can drive tumourigenesis in a paracrine manner through the senescence-associated secretory phenotype (SASP). Using a new p16-FDR mouse line, we show that macrophages and endothelial cells are the predominant senescent cell types in murine KRAS-driven lung tumours. Single cell transcriptomics identify a population of tumour-associated macrophages, expressing a unique array of pro-tumourigenic SASP factors and surface proteins, that are also present in normal aged lungs. Genetic or senolytic ablation of senescent cells, and macrophage depletion, result in a significant reduction in tumour burden and increased mouse survival of KRAS-driven lung cancer models. Of translational relevance, we reveal the presence of macrophages with senescent features in human lung premalignant lesions, but not in adenocarcinomas. Together, our results have uncovered a population of senescent macrophages contributing to the initiation and progression of lung cancer, thus opening potential therapeutic avenues and cancer preventative strategies.

2023-06-02 | GSE230054 | GEO

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