{
  "id": 5542185,
  "title": "Genotoxic and metabolic stress drive divergent senescence programs in human microglia",
  "url": "https://urgent.news/2026/09/04/genotoxic-and-metabolic-stress-drive-divergent-senescence-programs-in",
  "topic": "science",
  "section": "Science",
  "published": "2026-09-04T00:00:00.000Z",
  "source": {
    "name": "bioRxiv",
    "slug": "biorxiv",
    "url": "https://www.biorxiv.org/content/10.64898/2026.08.31.748228v1?rss=1"
  },
  "original_language": "en",
  "account": "Microglial dysfunction is a key aspect of brain aging, often associated with the presence of senescent microglial cells that contribute to persistent neuroinflammation. Both genotoxic stress and metabolic stress have been previously linked to microglial senescence; however, it remains unclear whether these stressors elicit distinct senescence programs.\n\nIn this study, researchers examined the effects of chronic genotoxic and metabolic stress on senescence-associated phenotypes in human microglial cells (HMC3). These cells were subjected to doxorubicin treatment to induce sustained DNA damage or chronic high-glucose conditions to model metabolic stress. Both stress conditions resulted in characteristic senescence features, such as cellular and nuclear enlargement, heightened senescence-associated beta-galactosidase activity, and decreased metabolic viability, without extensive cell death.\n\nBoth genotoxic and metabolic stress conditions activated the p53-p21 pathway and sustained DNA damage signaling. However, metabolic stress additionally triggered p16 expression and the peripheral nuclear localization of p21, indicating divergence in senescence regulatory pathways. Additionally, mitochondrial alterations were observed under both conditions; doxorubicin-induced stress was linked to the downregulation of NRF2-TFAM signaling, while high-glucose-induced stress led to NRF2-TFAM activation accompanied by increased KEAP1 expression, suggesting a constrained antioxidant response. Despite these alterations, mitochondrial content did not recover following stress.\n\nMoreover, both stressors triggered robust inflammatory activation. Genotoxic stress led to a chemokine-rich senescence-associated secretory phenotype, while metabolic stress induced an interferon-associated inflammatory signature. In summary, chronic genotoxic and metabolic stress induce distinct yet overlapping senescence programs marked by morphological changes, mitochondrial remodeling, and persistent inflammatory activation. These stress-specific responses could potentially influence neurodegenerative processes and disease susceptibility in different ways.",
  "summary": "Microglial dysfunction is a hallmark of brain ageing linked to the accumulation of senescent microglial phenotypes that promote chronic neuroinflammation. Both genotoxic and metabolic stress have been implicated in microglial senescence; yet, whether distinct stressors shape senescence programs remain unclear. Here, we investigated the impact of chronic genotoxic and metabolic stress on…",
  "key_points": [],
  "editors_take": null,
  "illustration": null,
  "coverage": {
    "outlets": 1,
    "also_reported_by": []
  },
  "ai_generated": true,
  "disclaimer": "Summaries, key points and the editor’s take are written by software from other outlets’ reporting and may contain errors — always check the linked original."
}