Protein damage and repair in aging: mechanisms, homeostasis and disease

Proteome integrity is continuously challenged by diverse forms of molecular damage, yet, in contrast to DNA, proteins have long been considered largely disposable rather than repairable. This view has shaped the prevailing paradigm of proteostasis, in which damaged proteins are primarily eliminated and replaced. However, emerging evidence from both prokaryotic and eukaryotic systems indicates that enzymatic protein repair is more widespread and functionally significant than previously appreciated. In this review, we re-examine protein repair as a distinct and under-recognized component of proteostasis, complementing degradation and resynthesis pathways. We provide a mechanistic framework that integrates major forms of protein damage, including oxidation, nitration, chlorination, glycation, and spontaneous isomerization, with their corresponding repair systems. We argue that the apparent scarcity of protein repair pathways reflects not their absence, but the biochemical complexity, energetic cost, and substrate heterogeneity inherent to protein damage. Importantly, we connect these mechanisms to the pathogenesis of major age-related diseases, including neurodegenerative, cardiovascular, metabolic disorders, and cancer, highlighting how the progressive failure of protein repair contributes to proteome instability and cellular dysfunction. We further discuss the energetic trade-offs between repair and turnover, proposing that repair is selectively deployed under conditions where replacement is inefficient or deleterious. By integrating biochemical, evolutionary, and translational perspectives, this review positions protein repair as an axis of proteostasis and outlines emerging opportunities for therapeutic intervention targeting protein damage in agingaging and disease.