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| Status |
Public on May 24, 2024 |
| Title |
Senescent glia link neuronal mitochondrial dysfunction and lipid droplet accumulation with age |
| Organism |
Drosophila melanogaster |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Senescence is a cellular state linked to aging and age-onset disease across many mammalian species. Acutely, senescent cells promote wound healing and prevent tumor formation; but they are also pro-inflammatory, thus chronically exacerbate tissue decline. While senescent cells are active targets for anti-aging therapy, why these cells form in vivo, how they affect tissue aging, and the impact of their elimination remain unclear. Here we identify naturally-occurring senescent glia in aged Drosophila brains and decipher their origin and influence. Using AP1 activity to screen for senescence, 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 life 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 aging phenomena: mitochondrial dysfunction and lipid accumulation.
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| Overall design |
In mice, eliminating senescent cells one day per week is sufficient to extend life and health span. Similarly in flies, we found that blocking AP1 activity in glia for 1 d/wk extends fly life and health span. To understand what changes in the brain when we target senescent glia and extend animal life and health, we performed bulk-RNA-seq on brains with (repoGS>UAS-puckered or repoGS>UAS-dsFosDN) or without (repoGS>UAS-GFP) glial AP1 activity blocked for 1 d/wk. Whole brains (n=20) were dissected from young (7d) or aged (42d) flies and used for bulk-RNA-sequencing and downstream gene expression analysis.
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| Contributor(s) |
Byrns CN, Perlegos AE, Bonini NM |
| Citation(s) |
38839958 |
| |
| Submission date |
Apr 14, 2024 |
| Last update date |
Jun 14, 2024 |
| Contact name |
Nancy M Bonini |
| E-mail(s) |
nbonini@sas.upenn.edu
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| Organization name |
University of Pennsylvania
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| Department |
Biology
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| Street address |
433 S University Ave
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| City |
Philadelphia |
| State/province |
PA |
| ZIP/Postal code |
19104 |
| Country |
USA |
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| Platforms (1) |
| GPL25244 |
Illumina NovaSeq 6000 (Drosophila melanogaster) |
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| Samples (18)
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| Relations |
| BioProject |
PRJNA1100203 |
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