Kocsisova Zuzana, Bagatelas Elena D, Santiago-Borges Jesus, Lei Hanyue Cecilia, Egan Brian M, Mosley Matthew C, Anderson Aaron M, Schneider Daniel L, Schedl Tim, Kornfeld Kerry
Department of Developmental Biology, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63108, USA.
Department of Genetics, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63108, USA.
PNAS Nexus. 2025 Aug 26;4(8):pgaf220. doi: 10.1093/pnasnexus/pgaf220. eCollection 2025 Aug.
Adult stem cells maintain and rejuvenate a wide range of tissues, and the progressive, age-related decline of adult stem cells is a hallmark of aging. We propose that the germline is an experimentally tractable model of adult stem cell aging and that stem cell exhaustion is a cause of reproductive senescence. Because these are the only stem cells in adult worms, this system provides a unique opportunity to exploit the power of to address stem cell exhaustion during aging. Here, we show that reproductive aging occurs early in adult life in multiple species in the genus , indicating that this is a feature of both female/male and hermaphrodite/male species. Our results indicate that cellular and molecular changes in germline stem cells are a cause of reproductive aging, since we demonstrated that defects in stem cell number and activity were well correlated with extended progeny production in , , and mutants. Ectopic expression of the Notch effector SYGL-1 in germ line stem cells was sufficient to delay stem cell aging, indicating that the conserved Notch pathway can act cell autonomously to control age-related decline of adult stem cells. These animals displayed increased progeny production in midlife without a depression of early progeny production, a pattern of reproductive aging distinct from previous mutants. These results suggest that age-related declines of stem cell number and activity are a cause of reproductive aging in and the Notch signaling pathway may be a control point that mediates this decline.
成体干细胞维持并使多种组织恢复活力，而成体干细胞随年龄增长的渐进性衰退是衰老的一个标志。我们提出，生殖系是成体干细胞衰老的一个易于实验操作的模型，并且干细胞耗竭是生殖衰老的一个原因。由于这些是成年线虫中仅有的干细胞，该系统提供了一个独特的机会来利用[具体方法]的力量来解决衰老过程中的干细胞耗竭问题。在这里，我们表明生殖衰老在多个[属名]物种的成年期早期就会发生，这表明这是雌性/雄性和雌雄同体/雄性物种的共同特征。我们的结果表明，生殖系干细胞中的细胞和分子变化是生殖衰老的一个原因，因为我们证明了在[线虫名1]、[线虫名2]和[线虫名3]突变体中，干细胞数量和活性的缺陷与后代产生的延长密切相关。Notch效应器SYGL-1在生殖系干细胞中的异位表达足以延缓干细胞衰老，这表明保守的Notch信号通路可以在细胞自主发挥作用，以控制成体干细胞与年龄相关的衰退。这些动物在中年时后代产量增加，而早期后代产量没有下降，这种生殖衰老模式与之前的突变体不同。这些结果表明，干细胞数量和活性与年龄相关的衰退是[线虫名]生殖衰老的一个原因，并且Notch信号通路可能是介导这种衰退的一个控制点。
