Senescent glia link mitochondrial dysfunction and lipid accumulation

China N. Byrns, Alexandra E. Perlegos, Karl N. Miller, Zhecheng Jin, Faith R. Carranza, Palak Manchandra, Connor H. Beveridge, Caitlin E. Randolph, V. Sai Chaluvadi, Shirley L. Zhang, Ananth R. Srinivasan, F. C. Bennett, Amita Sehgal, Peter D. Adams, Gaurav Chopra and Nancy M. Bonini ()
Additional contact information
China N. Byrns: University of Pennsylvania
Alexandra E. Perlegos: University of Pennsylvania
Karl N. Miller: Sanford Burnham Prebys Medical Discovery Institute
Zhecheng Jin: University of Pennsylvania
Faith R. Carranza: University of Pennsylvania
Palak Manchandra: Purdue University
Connor H. Beveridge: Purdue University
Caitlin E. Randolph: Purdue University
V. Sai Chaluvadi: University of Pennsylvania
Shirley L. Zhang: Perelman School of Medicine at the University of Pennsylvania
Ananth R. Srinivasan: University of Pennsylvania
F. C. Bennett: University of Pennsylvania
Amita Sehgal: Perelman School of Medicine at the University of Pennsylvania
Peter D. Adams: Sanford Burnham Prebys Medical Discovery Institute
Gaurav Chopra: Purdue University
Nancy M. Bonini: University of Pennsylvania

Nature, 2024, vol. 630, issue 8016, 475-483

Abstract: Abstract Senescence is a cellular state linked to ageing and age-onset disease across many mammalian species1,2. Acutely, senescent cells promote wound healing3,4 and prevent tumour formation5; but they are also pro-inflammatory, thus chronically exacerbate tissue decline. Whereas senescent cells are active targets for anti-ageing therapy6–11, why these cells form in vivo, how they affect tissue ageing and the effect of their elimination remain unclear12,13. 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 senescence14,15, 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.

Date: 2024
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DOI: 10.1038/s41586-024-07516-8

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