Age-related decline in protein turnover highlights cystatin C dysfunction and links proteostasis collapse to...

One of the key hallmarks of aging is the breakdown of proteostasis-the finely tuned balance of protein synthesis, folding, trafficking, and degradation that maintains proteome integrity and cellular function. In this study, we employed ¹⁵N metabolic labeling to assess protein turnover in young and aged mice. Among the proteins examined, cystatin C exhibited the largest age-related reduction in turnover, alongside decreases in other proteins involved in neuroprotection, structural stability, and neurotransmission, including transthyretin, proteolipid protein 1, and the astrocytic glutamate transporter SLC1A3. Reduced proteostatic capacity is likely to increase neuronal susceptibility to proteotoxic stress, protein aggregation, and excitotoxic injury. Immunohistochemical analysis revealed a punctate accumulation of cystatin C in cortical layer IV, a region particularly vulnerable to age-related pathology. Moreover, gene expression profiling showed region-specific upregulation of inflammatory markers (Cd11b, Fcgr1, and Cr3), suggesting enhanced degradation of brain structures through phagocytic activity. Together, these findings demonstrate that aging disrupts proteostasis in a protein- and region-specific manner, with cystatin C emerging as a central mediator linking impaired clearance to neuroinflammation and cortical vulnerability. Interventions aimed at enhancing autophagy, proteasome function, or chaperone activity may represent promising strategies to counteract proteostasis collapse and mitigate neurodegeneration in the aging brain.