Aging and diet alter the protein ubiquitylation landscape in the mouse brain

Antonio Marino, Domenico Fraia, Diana Panfilova, Amit Kumar Sahu, Alberto Minetti, Omid Omrani, Emilio Cirri and Alessandro Ori ()
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Antonio Marino: Leibniz Institute on Aging—Fritz Lipmann Institute (FLI)
Domenico Fraia: Leibniz Institute on Aging—Fritz Lipmann Institute (FLI)
Diana Panfilova: Leibniz Institute on Aging—Fritz Lipmann Institute (FLI)
Amit Kumar Sahu: Leibniz Institute on Aging—Fritz Lipmann Institute (FLI)
Alberto Minetti: Leibniz Institute on Aging—Fritz Lipmann Institute (FLI)
Omid Omrani: Leibniz Institute on Aging—Fritz Lipmann Institute (FLI)
Emilio Cirri: Leibniz Institute on Aging—Fritz Lipmann Institute (FLI)
Alessandro Ori: Leibniz Institute on Aging—Fritz Lipmann Institute (FLI)

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-60542-6

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