Brain aging and neurodegenerative diseases: physiological insights from anti-aging protein Klotho

Brain aging is accompanied by progressive disturbances in calcium signaling, mitochondrial function, redox balance, neuroimmune regulation, and barrier-fluid homeostasis, collectively increasing susceptibility to neurodegenerative diseases. Therefore, identifying physiological regulators that stabilize these interconnected processes is central to understanding brain aging. Klotho, an antiaging protein initially characterized by its systemic roles in mineral metabolism and lifespan regulation, has emerged as a key modulator of cellular and tissue homeostasis across multiple organs, including the central nervous system. In the brain, Klotho is predominantly expressed in the choroid plexus and selectively in neuronal and oligodendroglial populations, positioning it at the interface of barrier physiology and neural function. Experimental studies have indicated that Klotho contributes to cerebrospinal fluid homeostasis, synaptic plasticity, neurogenesis, myelination, and resistance to metabolic and oxidative stress. Rather than acting through disease-specific pathways, Klotho stabilizes the core physiological axes that govern neuronal resilience, including Ca²⁺ signaling, mitochondrial-redox homeostasis, neuroimmune balance, growth factor signaling, and barrier integrity. Consistent with these physiological roles, reduced Klotho availability is associated with cognitive decline and multiple neurodegenerative disorders. This review positions Klotho as a central determinant of cognitive reserve and neuro-resilience, providing a unifying physiological framework that links systemic homeostasis to brain aging and explains how disruption of Klotho signaling amplifies vulnerability to neurodegenerative disease, whereas its preservation supports lifelong brain integrity.