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<p>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.</p>

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Regulation of stem cell aging and cellular proliferation by Klotho-Sirt1 pathways in heart, kidney and small intestine

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年11月25日

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  • Dao-Fu Dai,
  • Nastaran Daneshgar,
  • Kaihao Wang,
  • Pei-Ing Liang,
  • Dustin Bosch,
  • Chad Grueter

摘要

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.