Reversal of Age-Associated Damage in the Planarian Germline

项目摘要 与年龄有关的疾病是发病率、死亡率和医疗保健支出的主要原因之一 无论是在美国还是在世界范围内。与年龄相关的生育率下降是最早的和 男性和女性最常见的衰老症状，几乎四分之一的夫妇 18岁和45岁的人患有生育力受损或不孕不育。尽管辅助生殖技术可以帮助 生育能力受损的夫妇会产生可存活的后代，这可能非常昂贵，而且不能从根本上治疗 问题是：生殖系老化。现有的关于衰老的文献相对较少，主要集中在常规模型上 寿命相对较短的生物以及各种治疗方法如何减缓而不是预防它们的衰退 它完全，甚至可以逆转衰老。可以忽略不计的衰老、高度再生、两性的浮游动物S。 地中海菌为研究生殖系老化提供了一种独特的模式系统，因为它是为数不多的研究 积极逆转衰老表型。我观察到，稻瘟病菌经历了与年龄相关的衰退。 在其繁殖力方面，可以通过将行星动物一分为二并允许它们再生来逆转。总目标 我的项目的一部分是确定衰老如何损害稻草的生育能力，以及再生如何克服 这种损害。根据初步数据，我假设与年龄相关的分子损伤 在睾丸和(特别是)卵巢的性腺晚期前体细胞中积聚，损害 成熟生殖细胞的产生，在再生过程中，这些受损的细胞被 恢复生育能力的功能等价物。为了评估这一假设，我将寻求解决以下问题 明确的目标。目的1：我将检测配子发生的标志物的变化，以确定生殖细胞和生态位细胞 人口受到老龄化和年轻化的影响。目标2：我将使用一组分子生物标记物 分离性腺以确定年龄相关的生物标记物是否随着时间的推移在性腺中积累，以及 再生使性腺恢复到更年轻的状态。目标3：我将使用选择性交配实验来 确定生育能力受损是由于睾丸、卵巢或两者都有缺陷。从这些实验中，我 将了解更多关于稻瘟病菌生殖系老化的细胞、分子和生理原因， 以及再生是如何逆转它们的。这些结果也将有助于我们理解为什么其他 生物体无法防止与年龄相关的性腺退化，并有可能为 更强大的生育治疗，延长甚至恢复人类的生育能力。

Project Summary Age-related diseases are among the leading causes of morbidity, mortality, and healthcare expenditure both in the United States and the world at large. Age-associated declines in fertility are one of the earliest and most common symptoms of aging in both men and women, and almost one-fourth of couples between the ages of 18 and 45 suffer from impaired fertility or infertility. Although assisted reproductive technology can help couples with impaired fertility produce viable offspring, it can be very expensive and does not treat the root of the problem: germline aging. Existing literature on aging is relatively sparse, focusing on conventional model organisms with relatively short lifespans and how various treatments can slow their decline rather than prevent it entirely, or even reverse aging. The negligibly-senescent, highly-regenerative, hermaphroditic planarian S. mediterranea presents a unique model system to study germline aging because it is one of the few species to actively reverse an aging phenotype. I have observed that S. mediterranea experiences an age-related decline in its fertility that can be reversed by bisecting the planarians and allowing them to regenerate. The overall goal of my project is to determine how aging impairs fertility in S. mediterranea, and how regeneration overcomes this impairment. Based on preliminary data, I hypothesize that age-associated molecular damage accumulates in late gonadal precursor cells of the testes and (especially) ovaries, compromising the production of mature germ cells, and that during regeneration these impaired cells are replaced by functional equivalents to restore fertility. To evaluate this hypothesis, I will seek to address the following specific aims. Aim 1: I will assay changes in markers of gametogenesis to determine how germ and niche cell population are affected by aging and rejuvenation. Aim 2: I will use a panel of molecular biomarkers on isolated gonads to determine if age-associated biomarkers accumulate in the gonads over time, and if regeneration restores the gonads to a more youthful state. Aim 3: I will use selective mating experiments to determine if impairments in fertility are due to defects in the testes, ovaries, or both. From these experiments, I will learn more about the cellular, molecular, and physiological causes of germline aging in S. mediterranea, and how regeneration manages to reverse them. These results will also help us understand why other organisms are unable to prevent age-related gonadal degeneration, and potentially lay the groundwork for more robust fertility treatments that extend or even restore fertility in humans.