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.

项目摘要 糖尿病相关疾病是发病率、死亡率和医疗保健支出的主要原因之一 在美国和全世界都是如此。与生育率下降相关的生育率下降是最早的， 男性和女性最常见的衰老症状，几乎四分之一的夫妇之间的 18至45岁的人生育能力受损或不育。虽然辅助生殖技术可以帮助 生育能力受损的夫妇产生可存活的后代，它可能非常昂贵，并且不能治疗根本性的疾病。 问题：生殖细胞老化。现有的老龄化文献相对稀少，主要集中在传统模型上 生命周期相对较短的生物，以及各种治疗方法如何减缓其衰退，而不是防止 甚至逆转衰老。可忽略衰老，高度再生，雌雄同体的真涡虫S。 地中海提出了一个独特的模型系统来研究生殖系衰老，因为它是少数几个物种之一， 积极地逆转衰老表型。我注意到S。地中海经历了与年龄相关的衰退 繁殖力的下降可以通过将涡虫一分为二并让它们再生来逆转。总目标 我的项目的一部分是确定衰老是如何损害S. mediorea，以及如何再生克服 这种损害。基于初步数据，我假设年龄相关的分子损伤 在睾丸和（特别是）卵巢的晚期性腺前体细胞中积累， 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 功能等同物以恢复生育能力。为了评估这一假设，我将试图解决以下问题 明确的目标。目的1：检测配子发生过程中标记物的变化，以确定生殖细胞和微生态细胞 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志物， 分离的性腺，以确定年龄相关的生物标志物是否随时间在性腺中积累，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， 确定生育能力受损是否是由于睾丸、卵巢或两者的缺陷。通过这些实验，我 将了解更多关于S.地中海， 以及再生是如何逆转它们的这些结果也将帮助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，并可能为 更强大的生育治疗，延长甚至恢复人类的生育能力。