Reversal of Age-Associated Damage in the Planarian Germline

涡虫种系中年龄相关损伤的逆转

• 批准号: 10606234
• 负责人: Andrew Verdesca
• 金额: $ 4.77万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10606234
• 关键词: 3-Dimensional; Ablation; Address; Affect; Age; Aging; Assisted Reproductive Technology; Biological Assay; Biological Markers; Biological Models; Cell Differentiation process; Cells; Couples; Data; Defect; Disease; Educational process of instructing; Elderly; Epigenetic Process; Exhibits; Female; Fertility; Fluorescent in Situ Hybridization; Gametogenesis; Genes; Germ; Germ Cells; Goals; Gonadal structure; Health Expenditures; Healthcare Systems; Hermaphroditism; Human; Impairment; Infertility; Learning; Life; Literature; Longevity; Molecular; Morbidity - disease rate; Natural Fertility; Natural regeneration; Oligospermia; Organism; Output; Ovarian; Ovary; Partner in relationship; Patient-Focused Outcomes; Phenotype; Physiological; Pilot Projects; Planarians; Platyhelminths; Play; Population; Process; Production; Regenerative capacity; Rejuvenation; Reproductive Process; Research; Resistance; Role; Spermatids; Spermatogonia; Testis; Time; United States; Woman; age related; aged; asexual; capsule; cell regeneration; common symptom; cost; experience; experimental study; female reproductive system; fertility preservation; improved; in vivo; infertility treatment; insight; male; men; mitochondrial dysfunction; model organism; molecular marker; mortality; offspring; overpopulation; precursor cell; preservation; prevent; proteostasis; regenerative; reproductive; reproductive senescence; research study; senescence; single-cell RNA sequencing

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.

项目概要 与年龄相关的疾病是发病率、死亡率和医疗支出的主要原因之一 无论是在美国还是在全世界。与年龄相关的生育率下降是最早也是最严重的之一。 男性和女性最常见的衰老症状，以及近四分之一的夫妇 18 岁和 45 岁的人患有生育能力受损或不孕症。虽然辅助生殖技术可以帮助 生育力受损的夫妇可以生育可存活的后代，这可能非常昂贵，而且不能治疗生育力的根源 问题：种系衰老。现有关于衰老的文献相对较少，主要集中在传统模型上 寿命相对较短的生物体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，甚至逆转衰老。衰老可忽略不计、高度再生、雌雄同体的涡虫 S. 地中海提供了一个独特的模型系统来研究种系衰老，因为它是少数几个能够研究种系衰老的物种之一。 积极逆转衰老表型。我观察到地中海南海藻经历了与年龄相关的衰退 其生育能力可以通过将涡虫一分为二并让它们再生来逆转。总体目标 我的项目的目的是确定衰老如何损害地中海南部的生育能力，以及再生如何克服这一问题 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（尤其是）卵巢的晚期性腺前体细胞中积累，损害 产生成熟的生殖细胞，并且在再生过程中这些受损的细胞被替换 恢复生育能力的功能等同物。为了评估这个假设，我将寻求解决以下问题 具体目标。目标 1：我将检测配子发生标记物的变化，以确定生殖细胞和生态位细胞如何 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志物 分离性腺以确定与年龄相关的生物标志物是否随着时间的推移在性腺中积累，以及是否 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否是由于睾丸、卵巢或两者的缺陷所致。从这些实验中，我 将更多地了解地中海种系衰老的细胞、分子和生理原因， 以及再生如何设法扭转它们。这些结果也将帮助我们理解为什么其他 生物体无法预防与年龄相关的性腺退化，并可能为 更强大的生育治疗，可以延长甚至恢复人类的生育能力。