Brain aging and neurodegenerative diseases: physiological insights from anti-aging protein Klotho
5 affiliations
- 1Department of Physiology, Yonsei University Wonju College of Medicine Wonju 26426 Korea
- 2Department of Global Medical Science, Yonsei University Wonju College of Medicine Wonju 26426 Korea
- 3Organelle Medicine Research Center, Yonsei University Wonju College of Medicine Wonju 26426 Korea
- 4Institute of Mitochondrial Medicine, Yonsei University Wonju College of Medicine Wonju 26426 Korea
- 5Vinmec Research Institute of Stem Cell and Gene Technology, College of Health Sciences, VinUniversity Hanoi 100000 Vietnam
Abstract
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 anti-aging 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.
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BibTeX
@article{do2026brain,
title = {{Brain aging and neurodegenerative diseases: physiological insights from anti-aging protein Klotho}},
author = {Phuong Anh Do and Huu Son Nguyen and Seung-Kuy Cha},
journal = {The Korean Journal of Physiology \& Pharmacology : Official Journal of the Korean Physiological Society and the Korean Society of Pharmacology},
year = {2026},
month = nov,
doi = {10.4196/kjpp.26.015},
url = {https://doi.org/10.4196/kjpp.26.015},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Brain aging and neurodegenerative diseases: physiological insights from anti-aging protein Klotho
AU - Phuong Anh Do
AU - Huu Son Nguyen
AU - Seung-Kuy Cha
PY - 2026
DA - 2026/11/01
JO - The Korean Journal of Physiology & Pharmacology : Official Journal of the Korean Physiological Society and the Korean Society of Pharmacology
DO - 10.4196/kjpp.26.015
UR - https://doi.org/10.4196/kjpp.26.015
AB - 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 anti-aging 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.
SN - 1226-4512
SN - 2093-3827
ER -