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<p>Ovarian aging, marked by diminished follicle quantity and quality, is a key determinant of female fertility and overall health. While the antiaging protein KLOTHO is implicated in systemic aging processes, its role in ovarian aging remains unexplored. Hence, this study aimed to examine the role of KLOTHO in ovarian aging. We collected clinical samples, utilized an aging mouse model, and conducted functional studies in human granulosa-like KGN cells. Results showed that KLOTHO levels in follicular fluid declined with age and significantly decreased in patients with diminished ovarian reserve, correlating with reduced antral follicle count and anti-Müllerian hormone levels and increased follicle-stimulating hormone levels. Similarly, in mice, ovarian KLOTHO expression decreased with age. In KGN cells, KLOTHO knockdown induced cellular senescence, suppressed proliferation, promoted apoptosis, and disrupted steroidogenic function. Transcriptomic analysis demonstrated that the PI3K/AKT signaling pathway potentially mediates KLOTHO regulation. Therefore, KLOTHO may function as a key downregulated molecule during ovarian aging, whose function loss exacerbates the aging process by triggering granulosa cell senescence and dysfunction. Thus, KLOTHO could be a novel regulator and a potential intervention target for ovarian aging.</p>

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KLOTHO Deficiency Drives Ovarian Aging by Inducing Granulosa Cell Senescence and Dysfunction

  • 期刊论文

  • 发表日期：

    2026年4月17日

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  • Wenjing Du,
  • Ahui Liu,
  • Hongrui Li,
  • Xiaoling Ma,
  • Yongxiu Yang

摘要

Ovarian aging, marked by diminished follicle quantity and quality, is a key determinant of female fertility and overall health. While the antiaging protein KLOTHO is implicated in systemic aging processes, its role in ovarian aging remains unexplored. Hence, this study aimed to examine the role of KLOTHO in ovarian aging. We collected clinical samples, utilized an aging mouse model, and conducted functional studies in human granulosa-like KGN cells. Results showed that KLOTHO levels in follicular fluid declined with age and significantly decreased in patients with diminished ovarian reserve, correlating with reduced antral follicle count and anti-Müllerian hormone levels and increased follicle-stimulating hormone levels. Similarly, in mice, ovarian KLOTHO expression decreased with age. In KGN cells, KLOTHO knockdown induced cellular senescence, suppressed proliferation, promoted apoptosis, and disrupted steroidogenic function. Transcriptomic analysis demonstrated that the PI3K/AKT signaling pathway potentially mediates KLOTHO regulation. Therefore, KLOTHO may function as a key downregulated molecule during ovarian aging, whose function loss exacerbates the aging process by triggering granulosa cell senescence and dysfunction. Thus, KLOTHO could be a novel regulator and a potential intervention target for ovarian aging.