Identification of the mechanisms responsible for the ovary-dependent extension of longevity and health span

项目摘要/摘要 衰老过程的两个特征是血脂异常和慢性炎症。更替衰老 老年小鼠的卵巢和年轻的卵巢可以改善年龄相关的血脂异常和慢性炎症 延长寿命。移植前生殖细胞的耗尽出人意料地提高了寿命- 年轻的、移植的卵巢和含有生殖细胞的卵巢一样，延长了效果，降低了 慢性炎症和血脂异常的严重程度。在原始物种中，性腺生殖细胞的枯竭可以 显著延长寿命和健康。然而，这些影响依赖于体细胞的保留 性腺和FOXO信号的上调。在哺乳动物中，FOXO抑制从头开始的甲基酶Dnmt3b， 这减少了与年龄相关的甲基化模式的侵蚀并减弱了与年龄相关的表观遗传学 重新编程。卵巢FOXO信号在绝经后由于FOXO-1的丢失而显著减少 产生卵巢组织。我们的长期目标是确定促进健康和降低年龄的卵巢因素- 相关疾病风险。我们在这项申请中的目标是1)确定如何移植新的卵巢， 延年益寿，影响与年龄相关的甲基化、转录、代谢和免疫变化 功能和2)确定在卵巢组织依赖延伸中起作用的生殖细胞非依赖性因子 关于健康的。我们的中心假设是1)正常情况下变得差异甲基化的基因组区域 在老化过程中，受移植的年轻卵巢的影响，甲基化变化较少， 导致血脂异常和慢性炎症的减少，2)许多这些提高生存能力的卵巢 影响是不依赖生殖细胞的，3)从年轻卵巢分离的体细胞将提供一种 将完整或生殖细胞耗尽的年轻卵巢移植到生殖后女性体内的益处相似 老鼠。为了验证我们的假设，我们提出了三个具体目标来确定年轻生殖细胞如何包含 年轻卵巢(目标1)、生殖细胞枯竭的年轻卵巢(目标2)和从年轻卵巢分离的体细胞 (目标3)影响健康、DNA甲基化、转录、血脂异常和慢性疾病的年龄相关变化 生殖后小鼠的炎症。我们假设年轻的卵巢移植将会改善 健康和缓慢/避免DNA甲基化变化，阻止新陈代谢的表观遗传重新编程-以及 生殖后雌性小鼠的免疫调节基因与幼鼠卵巢生殖细胞的耗竭 从年轻的卵巢中分离出的体细胞将产生类似于 接受完整的年轻卵巢。我们希望确定进化上保守的性腺的机制- 依赖的生存增强策略，旨在保护生物体的生殖系传播潜力。 我们还希望揭示一种生殖细胞非依赖的生存机制，并可能为临床 治疗模式，年轻卵巢模仿患者来源的iPS细胞将被移植给老年女性 避免与年龄相关的疾病风险，显著提高生活质量。

PROJECT SUMMARY/ABSTRACT Two hallmarks of the aging process are dyslipidemia and chronic inflammation. Replacement of senescent ovaries in old mice with young ovaries ameliorates age-associated dyslipidemia and chronic inflammation and extends longevity. Depletion of the germ cells prior to transplantation unexpectedly enhanced the longevity- extending effects of the young, transplanted ovaries and, as with germ cell-containing ovaries, decreased the severity of chronic inflammation and dyslipidemia. In primitive species, depletion of gonadal germ cells can significantly extend longevity and health. However, these effects are dependent on the retention of the somatic gonad and the up-regulation of Foxo signaling. In mammals, Foxo suppresses the de novo methylase Dnmt3b, which reduces the age-associated erosion of methylation patterns and abates age-related epigenetic reprogramming. Ovarian Foxo signaling is significantly reduced at menopause due to the loss of Foxo- producing ovarian tissue. Our long-term goal is to identify ovarian factors that promote health and reduce age- related disease risks. Our objective in this application is to 1) determine how transplanted new ovaries, which extend life and health span, affect age-related changes in methylation, transcription, metabolism and immune function and 2) to identify germ cell-independent factors that play a role in ovarian tissue-dependent extension of health. Our central hypothesis is that 1) genomic regions that normally become differentially methylated during aging will undergo fewer methylation changes under the influence of transplanted young ovaries, resulting in decreased dyslipidemia and chronic inflammation, 2) that many of these survival-enhancing ovarian influences are germ cell-independent and 3) that somatic cells isolated from young ovaries will provide a similar benefit as intact or germ-cell depleted young ovaries when transplanted in post-reproductive female mice. To test our hypotheses, we propose three specific aims to determine how young germ cell-containing young ovaries (Aim 1), germ cell-depleted young ovaries (Aim 2) and somatic cells isolated from young ovaries (Aim 3) affect age-related changes in health, DNA methylation, transcription, dyslipidemia and chronic inflammation in post-reproductive mice. We hypothesize that transplantation of young ovaries will improve health and slow/avert DNA methylation changes and block the epigenetic reprogramming of metabolism- and immune-regulating genes in post-reproductive female mice and that depletion of germ cells from young ovaries and somatic cells isolated from a young ovary will provide similar health and molecular changes as in recipients of intact young ovaries. We expect to identify mechanisms of an evolutionarily conserved, gonad- dependent survival-enhancing strategy designed to preserve the organism's germline transmission potential. We also expect to reveal a germ cell-independent survival mechanism and may provide the basis for a clinical therapeutic model, where young-ovary mimicking, patient-derived iPS cells will be transplanted to aged women to elude age-associated disease risks and significantly improve quality of life.