Neuroprotective roles of klotho: Molecular pathways and therapeutic implications for cognitive health in neurological and psychiatric diseases.

Klotho, a pleiotropic protein initially identified for its role in kidney function, has garnered significant attention for its neuroprotective properties in various neurodegenerative diseases. It regulates key processes, such as oxidative stress, neuroinflammation, synaptic plasticity and myelination, all crucial for maintaining neuronal integrity and cognitive function. Preclinical studies demonstrate that klotho enhances amyloid-β and tau clearance, stabilizes synaptic function, supports oligodendrocyte maturation and mitigates excitotoxicity. Clinical findings show that higher α-klotho levels are associated with slower cognitive decline in Alzheimer's and Parkinson's diseases, improved outcomes in multiple sclerosis and better recovery after stroke. Notably, the protective effects of klotho appear most pronounced in individuals with high genetic or pathological risks, such as apolipoprotein E ε4 carriers in Alzheimer's disease. Despite these promising insights, the clinical application of klotho-based therapies is hindered by variability in biomarker assays, challenges in crossing the blood-brain barrier, and the need for precision-based interventions tailored to individual genetic profiles. Current strategies to enhance klotho activity include lifestyle changes, pharmacological agents, recombinant protein delivery and gene therapy. Although challenges remain, klotho stands as a potential therapeutic target for mitigating cognitive decline and promoting brain health across a range of neurodegenerative and cerebrovascular conditions.