Aging is a complex process characterized by the accumulation of molecular damage that leads to cellular dysfunction and tissue deterioration. Among the various types of contributing molecular damage, aberrant protein crosslinks are recognized as a key contributor to age-related pathologies. Crosslinks occurring at lysine and arginine residues, such as advanced glycation end-products (AGEs) and carbamylation, have attracted considerable attention of the aging research community. In contrast, the roles of cysteine-derived crosslinks in aging pathobiology remain underappreciated. While native disulfide formation is essential for protein structure and function, the same redox features that make cysteine indispensable to protein biochemistry also render it particularly susceptible to nonspecific disulfide crosslinking. The body exploits specialized protective thiols such as glutathione to maintain redox homeostasis and counteract the deleterious effects of aberrant disulfide formation. However, these endogenous protective measures decline with aging, resulting in the accumulation of oxidative cysteine modifications. In this review, we highlight the emergent roles of cysteine-related molecular damage in age-related disease. Drawing inspiration from endogenous protective thiols, we survey progress in the development of small-molecule therapeutic thiols that show promise in mitigating damage caused by the accumulation of cysteine-derived crosslinks. Understanding the relationship between these aberrant crosslinks and protective thiol interventions in aging diseases, as well as how therapeutic thiols can be improved, is critical for the development of comprehensive treatments.
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