Regulation of aging by germline stem cells in C. elegans

描述（由申请人提供）：在C。elegans，生殖系干细胞; 即产生精子和卵母细胞的细胞， 过程杀死生殖细胞前体可以延长大约60%的寿命。 这种寿命的延长不仅仅是由于不育，因为杀死 整个生殖系统的前体（生殖系以及 体细胞性腺）对寿命没有影响。为了使生殖细胞切除 延长寿命，β-16蛋白，一种叉头家族转录因子， 是必需的.因此，寿命延长需要转录的变化。在 此外，动物还需要功能性的β-12类固醇激素， 受体同源物因此，生殖系干细胞可以发挥其作用， 通过调节小行星激素来延缓衰老。通过使用突变来消除 生殖细胞的特定子集（精子，卵母细胞，生殖干细胞），我们有 发现生殖干细胞调节成年动物的衰老。如果 生殖系干细胞被迫退出有丝分裂并进入成熟分裂 动物，寿命延长。在这项研究中，我们将调查 生殖系干细胞影响衰老过程的机制。我们将 我们将确定α-16和α-12活动的作用部位， 确定这些基因的下游目标，延长寿命， 微阵列分析。此外，我们将筛选新的基因， 我们将开始确定它们的分子活性， 他们行动的时间和地点这些研究可以确定 不仅在C.也存在于高等生物中，包括 人类使用这些信息，可以提高 老年，并推迟与年龄有关的疾病，如癌症和 糖尿病此外，我们的发现可能会让我们深入了解 干细胞可以影响脊椎动物的内分泌信号。

DESCRIPTION (provided by applicant): In C. elegans, the germline stem cells; that is, the cells that give rise to sperm and oocytes, influence the aging process. Killing the germline precursors extends lifespan approximately 60%. This lifespan extension is not simply due to sterility, because killing the precursors of the entire reproductive system (the germline as well as the somatic gonad) has no effect on lifespan. In order for germline-ablation to extend lifespan, the DAF-16 protein, a forkhead-family transcription factor, is required. Thus, lifespan extension requires changes in transcription. In addition, the animals also require a functional DAF-12 steroid hormone receptor homologue. Thus, germline stem cells may exert their effects on aging by regulating asteroid hormone. By using mutations to eliminate specific subsets of germ cells (sperm, oocytes, germline stem cells), we have found that the germline stem cells regulate aging in adult animals. If the germline stem cells are forced to exit mitosis and enter meiosis in adult animals, lifespan is extended. In this study, we will investigate the mechanism by which germline stem cells influence the aging process. We will determine the sites of action of DAF-16 and DAF-12 activity, and we will identify downstream targets of these genes that extend lifespan using microarray analysis. In addition, we will screen for new genes that function in this pathway, and we will begin to determine their molecular activities and their times and sites of action. These studies could define pathways that regulate aging not only in C. elegans, but also in higher organisms, including humans. Using this information, it may be possible to improve the quality of old age, and to delay the onset of age-related diseases, such as cancer and diabetes. In addition, our findings may yield insights into the ways that stem cells can influence endocrine signaling in vertebrates.