Fight Aging!

Klotho is one of the few robustly longevity-associated genes. The effects of increased klotho expression on life span in mice that are arguably large enough to be interesting even if one prefers more of a focus on damage repair in the treatment of aging. A number of companies are developing therapies based on either the delivery of klotho fragments shown to improve function in aged animals, or using gene therapies to promote klotho expression and secretion. While klotho is important in the aging kidney, it is the ability of circulating klotho to promote function in the aging brain that has attracted greater interest, perhaps in large part because the biochemistry of its influence on the brain is less well understood.

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.

Link: https://doi.org/10.4196/kjpp.26.015