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; 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 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 在美国和整个世界。与年龄相关的生育能力下降是最早的， 男女衰老的最常见症状，以及几乎四分之一的夫妇 18岁和45岁的生育能力或不育。尽管辅助生殖技术可以帮助 生育不良的夫妻会产生可行的后代，它可能非常昂贵，并且不会对待 问题：种系衰老。现有关于衰老的文献相对稀疏，重点是传统模型 寿命相对较短的生物以及各种治疗方法如何减缓其下降而不是预防 它完全，甚至是反向老化。可忽略的，高度再生，雌雄同体的平角S. 地中海提出了研究种系衰老的独特模型系统，因为它是为数不多的物种之一 积极逆转衰老表型。我已经观察到地中海链球菌经历与年龄有关的下降 在其生育能力中，可以通过将平面人分为一分和允许他们再生来逆转。总体目标 我的项目是确定衰老如何损害地中海的生育能力，以及再生如何克服 这种障碍。根据初步数据，我假设该年龄相关的分子损伤 在睾丸的性腺前体细胞中积聚，尤其是（尤其是）卵巢，损害了 成熟生殖细胞的产生，在再生期间这些受损细胞被取代 恢复生育能力的功能等效物。为了评估这一假设，我将寻求解决以下内容 具体目标。目的1：我将测定配子发生标记的变化，以确定胚芽细胞的方式 人口受衰老和恢复活力的影响。目标2：我将在上面使用一组分子生物标志物 分离的性腺以确定随着时间的时间在性腺中与年龄相关的生物标志物以及是否存在 再生将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 确定生育障碍是由于睾丸，卵巢或两者兼而有之引起的。从这些实验中，我 将进一步了解地中海链球菌种系衰老的细胞，分子和生理原因， 以及再生如何扭转它们。这些结果也将帮助我们理解为什么其他 生物无法预防与年龄相关的性腺变性，并有可能为 更强大的生育能力延伸甚至恢复了人类的生育能力。