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Researchers at the Leibniz Institute on Aging – Fritz Lipmann Institute (FLI) in Jena found that oxidative stress in the aging brain inhibits the activity of deubiquitylases. These enzymes are essential for regulating protein degradation. As a result, ubiquitin tags on proteins are no longer efficiently removed. This can indirectly impair the function of the proteasome, the cell’s central proteolytic degradation machinery. Notably, this effect is reversible: enzyme activity can be restored in vivo by antioxidants. The study, published in “Nature Communications”, thus identifies oxidative stress -mediated protein oxidation as a reversible chemical process in brain aging.
Jena/Potsdam. As we age, the brain undergoes various changes. Neurons function less efficiently, and key regulatory systems within the cells become unbalanced. Protein quality control, which ensures that proteins are properly processed, recycled, or broken down, is particularly affected.
Considering this, researchers at the Leibniz Institute on Aging—Fritz Lipmann Institute (FLI), and the Health and Medical University Potsdam, together with other partners from Italy and Germany, investigated how oxidative stress caused by the accumulation of reactive oxygen species contributes to protein oxidation and thus affects these processes in the aging brain. The goal was to determine the degree to which this stress interferes with the cells’ molecular control systems and what consequences it has for protein balance, also known as protein homeostasis.
The focus was on how oxidative stress affects the function of deubiquitylases (DUBs). These are enzymes that remove ubiquitin tags from proteins, thereby regulating their degradation or further processing. With age, a kind of “molecular rusting” occurs in the cells, that is, the accumulation of oxidative damage, which particularly affects these sensitive enzymes.
The study, now published in “Nature Communications”, shows that oxidative stress and protein oxidation specifically reduce the activity of deubiquitylases without, however, altering their quantity. This is caused by chemical changes to the sensitive cysteine residues of the enzymes, which limit their function. “We see that oxidative stress has a regulatory effect, acting like a brake to specifically slow down the central enzyme functions,” explains Dr. Alessandro Ori, former group leader at the FLI and lead author of the study.
Protein homeostasis in the brain gets out of balance
The consequences extend beyond individual proteins and affect entire cellular networks, particularly the ubiquitin-proteasome system, which is responsible for protein degradation. This throws protein homeostasis in the brain out of balance.
“What is particularly striking is that these changes occur very early in the aging process, even before other parts of the protein degradation system are impaired,” adds Amit Kumar Sahu, PhD student at the FLI and first author of the study.
Inhibition of deubiquitylases is reversible
Despite the functional impairment observed, this effect is not permanent. In follow-up experiments, the researchers were able to show that the inhibition of deubiquitylases can be reversed by the antioxidant NACET (N-acetylcysteine ethyl ester). This is a small, antioxidant-active molecule that serves in the body as a precursor to the important amino acid cysteine, which is needed, among other things, for the formation of the body’s own antioxidant glutathione.
“Our results show that the inhibition is not irreversible damage, but rather a regulated restriction of enzyme function,” explains Thorsten Pfirrmann, professor of biochemistry at the Health and Medical University in Potsdam and co-author of the study.
This makes it clear that the enzymes do not lose their structural integrity, that is, their fundamental spatial structure and composition, because of the inhibition but retain it. Rather, their activity is controlled by redox-dependent processes, i.e., chemical conditions within the cell.
Key processes of brain aging may be reversible
The research findings suggest that oxidative stress is not just a side effect of aging but actively influences key regulatory processes in the brain. At the same time, however, the NACET treatment offers a potential approach to specifically modulate these processes.
“We have identified a potential early target in the molecular aging of the brain,” the researchers say, “that may be important for the stability of cellular quality control.” In the long term, these findings could help us better understand the development of neurodegenerative diseases such as Alzheimer’s or Parkinson’s, in which disturbances in protein degradation play a central role.
Future studies must now show whether restoring enzyme activity has an impact on brain function, such as memory or other cognitive abilities in old age. This raises the question of whether age-related changes in the brain can not only be slowed down but also partially reversed.
Further studies are needed to determine whether these experimental findings in aging mice and killifish can be applied to humans. However, the results provide important initial evidence that key processes of brain aging may be reversible.
Publication
Oxidative stress causes a reversible decrease of deubiquitylases activity in old vertebrate brains. Sahu AK, Minetti A, Di Fraia D, Marino A, Winterhalter PR, Giustarini D, Rossi R, Simm A, Neri F, Galvagni F, Gerhardt C, Pfirrmann T, Ori A. Nat Commun. 2026 Apr 21;17(1):3653. doi: 10.1038/s41467-026-71921-y.
https://www.nature.com/articles/s41467-026-71921-y
Contact
Dr. Kerstin Wagner
Press & Public Relations
Phone: 03641-656378, Email: presse@leibniz-fli.de
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Background
The Leibniz Institute on Aging - Fritz Lipmann Institute (FLI) in Jena is a federal and state government-funded research institute and member of the Leibniz Association (Leibniz-Gemeinschaft). FLI conducts internationally recognized, high-impact research on the biology of aging at the molecular, cellular, and systems levels. Scientists from around 40 countries investigate the mechanisms of aging to uncover its root causes and pave the way for strategies that promote healthy aging. Further information: http://www.leibniz-fli.de.
The Leibniz Association connects 96 independent research institutions that range in focus from natural, engineering, and environmental sciences to economics, spatial, and social sciences and the humanities.
Leibniz Institutes address issues of social, economic, and ecological relevance. They conduct knowledge-driven and applied basic research, maintain scientific infrastructure and provide research-based services.
The Leibniz Association identifies focus areas for knowledge transfer to policy-makers, academia, business and the public. Leibniz institutions collaborate intensively with universities – in the form of “Leibniz ScienceCampi” (thematic partnerships between university and non-university research institutes), for example – as well as with industry and other partners at home and abroad.
They are subject to an independent evaluation procedure that is unparalleled in its transparency. Due to the importance of the institutions for the country as a whole, they are funded jointly by the Federation and the Länder, employing some 21,400 individuals, including 12,170 researchers. The entire budget of all the institutes is approximately 2,3 billion Euros. For more information: http://www.leibniz-gemeinschaft.de/en/.
Oxidative stress causes a reversible decrease of deubiquitylases activity in old vertebrate brains. Sahu AK, Minetti A, Di Fraia D, Marino A, Winterhalter PR, Giustarini D, Rossi R, Simm A, Neri F, Galvagni F, Gerhardt C, Pfirrmann T, Ori A. Nat Commun. 2026 Apr 21;17(1):3653. doi: 10.1038/s41467-026-71921-y.
Oxidative stress in the aging brain inhibits the activity of deubiquitylases. These enzymes are esse ...
Copyright: (Picture: FLI / Kerstin Wagner; AI-generated with Google Gemini)
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