Genotoxic and metabolic stress drive divergent senescence programs in human microglia
Platt, B.; Vincy Jose, N.; Kang, E.; Janssens, S. · neuroscience · 2026-09-04 · 原文
DOI：10.64898/2026.08.31.748228作者：4 位
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 senescence-associated phenotypes in the human microglia cell line HMC3. Cells were exposed to doxorubicin to induce sustained DNA damage or to chronic high-glucose conditions to model metabolic stress. Both stress paradigms induced characteristic senescence features including cellular and nuclear hypertrophy, increased senescence-associated {beta} galactosidase activity and reduced metabolic viability without significant cell loss. Both conditions activated the p53-p21 pathway and sustained DNA damage signalling, whereas metabolic stress additionally induced p16 expression and peripheral nuclear localisation of p21, suggesting divergence in senescence regulatory pathways. Mitochondrial alterations were evident under both conditions, Dox-induced stress was associated with downregulation of NRF2-TFAM
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1. 人话版
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.
2. 领域脉络
本文类目：neuroscience，属于其所在研究脉络的最新进展。
3. 机制拆解
Cells were exposed to doxorubicin to induce sustained DNA damage or to chronic high-glucose conditions to model metabolic stress.
Both stress paradigms induced characteristic senescence features including cellular and nuclear hypertrophy, increased senescence-associated {beta} galactosidase activity and reduced metabolic viability without significant cell loss.
4. 证据与数字
Here, we investigated the impact of chronic genotoxic and metabolic stress on senescence-associated phenotypes in the human microglia cell line HMC3.
Both conditions activated the p53-p21 pathway and sustained DNA damage signalling, whereas metabolic stress additionally induced p16 expression and peripheral nuclear localisation of p21, suggesting divergence in senescence regulatory pathways.
Mitochondrial alterations were evident under both conditions, Dox-induced stress was associated with downregulation of NRF2-TFAM
5. 反例与边界
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6. 跨领域连接与意外收获
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7. 可复用方法
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8. 术语表
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