Aging and diet alter the protein ubiquitylation landscape in the mouse brain
Abstract Post-translational modifications (PTMs) regulate protein homeostasis, but how aging impacts PTMs remains unclear. Here, we used mass spectrometry to reveal changes in hundreds of protein ubiquitylation, acetylation, and phosphorylation sites in the mouse aging brain. We show that aging has...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-06-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-60542-6 |
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| author | Antonio Marino Domenico Di Fraia Diana Panfilova Amit Kumar Sahu Alberto Minetti Omid Omrani Emilio Cirri Alessandro Ori |
| author_facet | Antonio Marino Domenico Di Fraia Diana Panfilova Amit Kumar Sahu Alberto Minetti Omid Omrani Emilio Cirri Alessandro Ori |
| author_sort | Antonio Marino |
| collection | DOAJ |
| description | Abstract Post-translational modifications (PTMs) regulate protein homeostasis, but how aging impacts PTMs remains unclear. Here, we used mass spectrometry to reveal changes in hundreds of protein ubiquitylation, acetylation, and phosphorylation sites in the mouse aging brain. We show that aging has a major impact on protein ubiquitylation. 29% of the quantified ubiquitylation sites were affected independently of protein abundance, indicating altered PTM stoichiometry. Using iPSC-derived neurons, we estimated that 35% of ubiquitylation changes observed in the aged brain can be attributed to reduced proteasome activity. Finally, we tested whether protein ubiquitylation in the brain can be influenced by dietary intervention. We found that one cycle of dietary restriction and re-feeding modifies the brain ubiquitylome, rescuing some but exacerbating other ubiquitylation changes observed in old brains. Our findings reveal an age-dependent ubiquitylation signature modifiable by dietary intervention, providing insights into mechanisms of protein homeostasis impairment and highlighting potential biomarkers of brain aging. |
| format | Article |
| id | doaj-art-775f740ce2e44910a97b0986b5b45dfd |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-775f740ce2e44910a97b0986b5b45dfd2025-08-20T03:10:34ZengNature PortfolioNature Communications2041-17232025-06-0116111710.1038/s41467-025-60542-6Aging and diet alter the protein ubiquitylation landscape in the mouse brainAntonio Marino0Domenico Di Fraia1Diana Panfilova2Amit Kumar Sahu3Alberto Minetti4Omid Omrani5Emilio Cirri6Alessandro Ori7Leibniz Institute on Aging—Fritz Lipmann Institute (FLI)Leibniz Institute on Aging—Fritz Lipmann Institute (FLI)Leibniz Institute on Aging—Fritz Lipmann Institute (FLI)Leibniz Institute on Aging—Fritz Lipmann Institute (FLI)Leibniz Institute on Aging—Fritz Lipmann Institute (FLI)Leibniz Institute on Aging—Fritz Lipmann Institute (FLI)Leibniz Institute on Aging—Fritz Lipmann Institute (FLI)Leibniz Institute on Aging—Fritz Lipmann Institute (FLI)Abstract Post-translational modifications (PTMs) regulate protein homeostasis, but how aging impacts PTMs remains unclear. Here, we used mass spectrometry to reveal changes in hundreds of protein ubiquitylation, acetylation, and phosphorylation sites in the mouse aging brain. We show that aging has a major impact on protein ubiquitylation. 29% of the quantified ubiquitylation sites were affected independently of protein abundance, indicating altered PTM stoichiometry. Using iPSC-derived neurons, we estimated that 35% of ubiquitylation changes observed in the aged brain can be attributed to reduced proteasome activity. Finally, we tested whether protein ubiquitylation in the brain can be influenced by dietary intervention. We found that one cycle of dietary restriction and re-feeding modifies the brain ubiquitylome, rescuing some but exacerbating other ubiquitylation changes observed in old brains. Our findings reveal an age-dependent ubiquitylation signature modifiable by dietary intervention, providing insights into mechanisms of protein homeostasis impairment and highlighting potential biomarkers of brain aging.https://doi.org/10.1038/s41467-025-60542-6 |
| spellingShingle | Antonio Marino Domenico Di Fraia Diana Panfilova Amit Kumar Sahu Alberto Minetti Omid Omrani Emilio Cirri Alessandro Ori Aging and diet alter the protein ubiquitylation landscape in the mouse brain Nature Communications |
| title | Aging and diet alter the protein ubiquitylation landscape in the mouse brain |
| title_full | Aging and diet alter the protein ubiquitylation landscape in the mouse brain |
| title_fullStr | Aging and diet alter the protein ubiquitylation landscape in the mouse brain |
| title_full_unstemmed | Aging and diet alter the protein ubiquitylation landscape in the mouse brain |
| title_short | Aging and diet alter the protein ubiquitylation landscape in the mouse brain |
| title_sort | aging and diet alter the protein ubiquitylation landscape in the mouse brain |
| url | https://doi.org/10.1038/s41467-025-60542-6 |
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