Antiaging Properties of the Klotho Protein

TL;DR

The Klotho protein helps slow aging by reducing inflammation, protecting cells, and preventing age-related diseases.

Contribution

This paper identifies Klotho as a key antiaging protein that mitigates multiple aging hallmarks and age-related diseases.

Findings

Klotho improves mitochondrial function and reduces ROS, telomere attrition, and cellular senescence.

Klotho inhibits inflammation via NF-κB and NLRP3, benefiting conditions like atherosclerosis and Alzheimer’s.

Low Klotho levels cause hyperphosphatemia and cell injury, while Klotho mitigates fibrosis and sarcopenia.

Abstract

Mice genetically deficient in α-Klotho (henceforth Klotho) display accelerated aging. The mechanisms are only partially understood. Here, we examine how these relate to the 12 hallmarks of aging consisting of chronic inflammation (inflammaging), as well as damaging changes to the genome (DNA damage), telomeres, epigenetic regulation, proteostasis, nutrient sensing, mitochondria, stem cells, intercellular communication, macroautophagy, microbiome and cell replication (senescence). Inflammation aggravates the other hallmarks. We report that Klotho counters the majority of these hallmarks. It ameliorates mitochondrial function and reduces reactive oxygen species (ROS), telomere attrition and cellular senescence. It protects against inflammation by inhibiting NF-κB and the NLRP3 inflammasome. This applies to inflammaging, several chronic inflammatory diseases, atherosclerosis, diabetes, and Alzheimer’s disease. Klotho also counters some aging factors outside of these hallmarks. Low Klotho (often due to kidney disease) produces hyperphosphatemia, which injures cells (especially endothelial cells) and promotes aging. Another key action of Klotho is the mitigation of fibrosis in major organs (kidneys, heart, lungs and other), mainly through the inhibition of TGF-β and Wnt. Klotho also protects against muscle atrophy (sarcopenia)—a common feature of aging—and exhibits anti-cancer activity. We describe several factors that increase Klotho, and are potentially amenable to clinical therapy.

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