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Type 2 diabetes accelerates senescence and drives skeletal dysfunction

ABSTRACT: Type 2 diabetes (T2D) causes multiple health complications, including skeletal fragility and elevated fracture risk, yet mechanisms underlying diabetic bone disease remain poorly understood. Senescent cells (SnCs) and their senescence-associated secretory phenotype (SASP) accumulate prematurely in T2D- affected tissues, but their causal role in skeletal pathology has not been fully defined. Building on our prior observation that T2D induced skeletal fragility and accelerated osteocyte senescence, we show that bone-resident mesenchymal cells including osteoprogenitors (Lin–/LepR+) and bone marrow adipocytes (BMAds), also exhibit elevated p16Ink4a expression and increased SASP production. Hematopoietic populations, including myeloid-, T- and B-cells, display increased p16Ink4a and robust SASP phenotypes. Integrated RNAseq, mass cytometry, and imaging analyses revealed T2D myeloid cells had DNA damage responses (pATM), telomere-associated foci [TAF]), and upregulation of the anti-apoptotic protein Bcl2, concistent with a senescence phenotype. Clearance of SnCs in T2D mice, using either genetic (p16-ATTAC) or pharmacological (D+Q) approaches, improved cortical thickness, reduced porosity, and enhanced bone strength. These skeletal improvements were associated with decreased bone resorption, increased bone formation, and reduced marrow adiposity. Together, our findings establish cellular senescence as a modifiable driver of diabetic skeletal fragility and support senolytic therapies as a translational strategy for improving bone health in T2D.

ORGANISM(S): Mus musculus

PROVIDER: GSE345407 | GEO | 2026/09/01

REPOSITORIES: GEO

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