In discussions of aging, references to klotho usually mean α-klotho, a transmembrane protein, and specifically the fragment of α-klotho that projects beyond the cell membrane and is shed to circulate in the body, also known as soluble α-klotho. Soluble α-klotho interacts with cell receptors to produce beneficial changes in cell function in a range of tissues. Klotho has long been of interest to researchers because increased expression of α-klotho slows aging, whereas reduced expression accelerates aging. Past research has focused on beneficial effects resulting from soluble α-klotho in the kidney and brain. Improved function in these organs might be enough to explain systemic benefits throughout the body, but as shown here soluble α-klotho likely has direct effects on cells in other tissues as well.
We investigate the effects of α-Klotho, an anti-aging hormone, on cell proliferation across three tissues with varying regenerative capacities in the context of aging. Using young and old wild-type mice, alongside old heterozygous Klotho-deficient mice, we administered soluble α-Klotho (sKL) daily for 10 weeks to elucidate the impact of α-Klotho deficiency and its supplementation. Our investigation spanned three organs: the small intestine, the kidney, and the heart.
We measured cell cycle markers (BrdU, Ki-67, and phospho-histone-3), Sirtuin-1, DNA-damage response pathways (gamma-H2Ax, ATM, CHK2), and the aging phenotypes. Supplementation of sKL significantly enhances proliferative markers and attenuates many aging changes. Mechanistic studies show that sKL acts through the Sirt1-CHK2 pathway to promote cell proliferation. In summary, Klotho deficiency exacerbated aging phenotypes, reduced regenerative capacity, and impaired cellular proliferation. Supplementation with sKL effectively counters these age-related declines across multiple tissues by enhancing cellular proliferation and attenuating aging phenotypes through the Sirt1-CHK2 signaling pathway.
Link: https://doi.org/10.1038/s41514-025-00286-1
View the full article at FightAging
