Aging and neuropathic pain: Mitochondria-to-glia cascade, system mechanisms, and therapeutic strategies

Neuropathic pain (NP) creates a severe pathological condition that primarily affects elderly people because of their accumulated neurobiological changes that make them more susceptible to persistent pain. The aging process leads to multiple mechanisms that combine neurodegeneration with immunosenescence and mitochondrial dysfunction with impaired autophagy and glial priming, and ion channel dysregulation to create a nociceptive environment. This review examines how mitochondrial breakdown and dysfunctional autophagy, and ion channel disturbances with glial cell activation form a interconnected system which makes older people more prone to NP. The review also examines how the neuro-immune-metabolic and gut-brain axis maintain persistent pain across the lifespan while discussing its cellular pathology. Preclinical research shows that aged models develop more severe NP symptoms, yet clinical evidence reveals distinct diagnostic and therapeutic challenges that affect older adults. The review presents current treatment strategies which include mitochondrial protectants and autophagy enhancers together with immunomodulators and microbiome-based interventions, and gene therapies to develop appropriate multimodal therapies for different age group. Further, it combines mechanistic knowledge with translational viewpoints to demonstrate the immediate requirement for treating NP as a geroscience challenge to develop better pain management strategies for older adults.