Englander Institute for Precision Medicine

Senolytic treatment reduces oxidative protein stress in an aging male murine model of post-traumatic osteoarthritis.

TitleSenolytic treatment reduces oxidative protein stress in an aging male murine model of post-traumatic osteoarthritis.
Publication TypeJournal Article
Year of Publication2023
AuthorsChin AF, Han J, Clement CC, Choi Y, Zhang H, Browne M, Jeon OHee, Elisseeff JH
JournalAging Cell
Date Published2023 Nov
KeywordsAging, Animals, Cellular Senescence, Disease Models, Animal, Male, Mice, Osteoarthritis, Oxidative Stress, Senotherapeutics

Senolytic drugs are designed to selectively clear senescent cells (SnCs) that accumulate with injury or aging. In a mouse model of osteoarthritis (OA), senolysis yields a pro-regenerative response, but the therapeutic benefit is reduced in aged mice. Increased oxidative stress is a hallmark of advanced age. Therefore, here we investigate whether senolytic treatment differentially affects joint oxidative load in young and aged animals. We find that senolysis by a p53/MDM2 interaction inhibitor, UBX0101, reduces protein oxidative modification in the aged arthritic knee joint. Mass spectrometry coupled with protein interaction network analysis and biophysical stability prediction of extracted joint proteins revealed divergent responses to senolysis between young and aged animals, broadly suggesting that knee regeneration and cellular stress programs are contrarily poised to respond as a function of age. These opposing responses include differing signatures of protein-by-protein oxidative modification and abundance change, disparate quantitative trends in modified protein network centrality, and contrasting patterns of oxidation-induced folding free energy perturbation between young and old. We develop a composite sensitivity score to identify specific key proteins in the proteomes of aged osteoarthritic joints, thereby nominating prospective therapeutic targets to complement senolytics.

Alternate JournalAging Cell
PubMed ID37749958
PubMed Central IDPMC10652304
Grant ListT32 AG058527 / AG / NIA NIH HHS / United States

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