What is it about?
Klotho is a β-glucuronidase and unique hormone that protects against aging, as demonstrated in both rodents and humans. Klotho is expressed by the klotho gene and is recognized as an antiaging molecule with pleiotropic functions. New systems-based approaches are needed to elucidate the integrative role(s) of klotho (and klotho’s pleiotropic genes) and its potential to optimize clinical care of those with neurological and aging disorders.
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Why is it important?
Klotho is an important antiaging hormone, and its insufficiency appears to be important in many aging-associated diseases. Klotho and its associated molecules (e.g., FGF23) integrate a unique endocrine axis that governs multiple metabolic processes in mammals, including humans. The role of klotho in modulating canonical signaling pathways (e.g., TGF-β and IGF-1/PI3K/ Akt/FoxO) may be useful for developing new pharmacological interventions. Klotho-based interventions could offer mechanistic insights into novel therapeutics for human brain aging and associated diseases. It appears that klotho promotes brain resiliency, possibly by increasing network connectivity within critical brain regions, such as the prefrontal cortex, cingulate cortex, frontoparietal circuits, and others.
Perspectives
Individuals living with age-related cognitive issues (e.g., memory and cognitive deficits) and with neurodegenerative conditions, such as AD and PD, multiple sclerosis, and amyotrophic lateral sclerosis, may benefit from klotho-based therapeutics. In the near future, serum klotho concentrations could be potential biomarkers of brain senescence and cognitive health. In addition, klotho’s function as a gatekeeper in the choroid plexuses at the interface between the CNS and immune system could be leveraged in preventive therapies to address aging-related challenges.
Wilfredo Lopez-Ojeda
VA Medical Center and Wake Forest School of Medicine
Read the Original
This page is a summary of: Klotho and Senescence: From Molecules to Brain Function, Journal of Neuropsychiatry, January 2026, American Psychiatric Association,
DOI: 10.1176/appi.neuropsych.20250242.
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