Senescent glia link mitochondrial dysfunction and lipid accumulation

• 成果类型: Article
• 署名作者: Byrns, China N.; Perlegos, Alexandra E.; Miller, Karl N.; Jin, Zhecheng; Carranza, Faith R.; Manchandra, Palak; Beveridge, Connor H.; Randolph, Caitlin E.; Chaluvadi, V. Sai; Zhang, Shirley L.; Srinivasan, Ananth R.; Bennett, F. C.; Sehgal, Amita; Adams, Peter D.; Chopra, Gaurav; Bonini, Nancy M.
• 署名单位: University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; Sanford Burnham Prebys Medical Discovery Institute; Purdue University System; Purdue University; University of Pennsylvania; Howard Hughes Medical Institute; University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; Purdue University System; Purdue University; Purdue University System; Purdue University; Purdue University System; Purdue University; Purdue University System; Purdue University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-6384
• DOI: 10.1038/s41586-024-07516-8
• 发表日期: 2024-06-13
• 页码: 475-+
• 关键词: differential expression analysis; cellular senescence; secretory phenotype; cells; longevity; biomarker; droplets; culture; niche; beta

摘要

Senescence is a cellular state linked to ageing and age-onset disease across many mammalian species(1,2). Acutely, senescent cells promote wound healing(3,4) and prevent tumour formation5; but they are also pro-inflammatory, thus chronically exacerbate tissue decline. Whereas senescent cells are active targets for anti-ageing therapy(6-11), why these cells form in vivo, how they affect tissue ageing and the effect of their elimination remain unclear(12,13). Here we identify naturally occurring senescent glia in ageing Drosophila brains and decipher their origin and influence. Using Activator protein 1 (AP1) activity to screen for senescence(14,15), we determine that senescent glia can appear in response to neuronal mitochondrial dysfunction. In turn, senescent glia promote lipid accumulation in non-senescent glia; similar effects are seen in senescent human fibroblasts in culture. Targeting AP1 activity in senescent glia mitigates senescence biomarkers, extends fly lifespan and health span, and prevents lipid accumulation. However, these benefits come at the cost of increased oxidative damage in the brain, and neuronal mitochondrial function remains poor. Altogether, our results map the trajectory of naturally occurring senescent glia in vivo and indicate that these cells link key ageing phenomena: mitochondrial dysfunction and lipid accumulation.