Copper Dyshomeostasis, Redox Buffering and Immune Aging Converge on Cuproptosis in Age-Related Diseases

Cuproptosis is a copper-dependent form of regulated cell death that is triggered when intracellular copper handling is perturbed and mitochondrial metabolism becomes the primary site of damage. Aging provides a biological context for this process because copper trafficking shifts, mitochondrial quality control and proteostasis decline, and immune function is remodeled toward immunosenescence with persistent low-grade inflammation. These age-associated changes can weaken antioxidant buffering, reshape labile copper pools, and lower the threshold at which copper stress is converted into mitochondrial proteotoxic injury. In parallel, inflammaging-related cytokines and NF-κB programs can alter copper import, export, and sequestration, while impaired efferocytosis prolongs danger signaling, creating feedforward loops that sustain tissue injury. In this review, we summarize the molecular features that distinguish cuproptosis from other death programs and discuss how redox buffering capacity, copper transport machinery, and mitochondrial metabolic state jointly determine cuproptosis sensitivity during aging. We then examine disease contexts in which these pathways are plausibly relevant, including hereditary copper-handling disorders and age-related neurodegenerative, cardiovascular, metabolic, and musculoskeletal disorders. Finally, we discuss key knowledge gaps and experimental priorities for interpreting cuproptosis-related signals in aged tissues, with emphasis on how copper handling, mitochondrial state, and immune remodeling jointly shape disease phenotypes.