MECHANISMS OF AGING REGULATION BY DROSOPHILA GERMLINE

描述(申请人提供)：当繁殖受到抑制时，许多动物的寿命可以延长，但对这种作用的机制知之甚少。线虫的证据表明，体细胞性腺可以产生一种信号来确保长寿，而来自生殖系的信号会产生平衡的信号，从而加速衰老。这些信号的身份和运行情况尚不清楚。对于果蝇，我们建议了解这些衰老调节系统的功能。在我们的初步工作中，我们发现从成熟的成年性腺中失去生殖系干细胞，但不是原始性腺，足以延长男性和女性的寿命。我们将利用GSC丢失时间上的这些差异来识别诱导长寿保证所需的体细胞性腺的细胞和分子信号。我们的初步工作确定JAK/STAT和TGF2家族是当GSC丢失延长寿命时上调的细胞间信号的候选。对这项提议的研究将确定这些信号是否以及如何在控制衰老方面发挥作用。此外，虽然这些信号可能会影响衰老，但它们很可能通过影响系统循环激素的功能来间接实现这一点。由于胰岛素/IGF信号被认为是GSC丢失延长线虫寿命所必需的，我们评估了GSC丢失延长果蝇寿命时胰岛素信号的状态。考虑到胰岛素信号的减少会增加果蝇的存活率，我们预计在这些果蝇中胰岛素样肽的信息会更少。出乎意料的是，我们发现长寿成年人的胰岛素样信息增加了几倍。为了解释这一悖论，我们认为GSC的丧失延长了寿命，因为躯体性腺产生抑制躯体组织胰岛素敏感性的信号，而活跃的GSC抑制这一信号。进一步的初步数据与这个‘胰岛素阻抗’模型相一致：在没有生殖系的果蝇中，dFOXO的转录靶标升高，并且这些果蝇强烈表达胰岛素抑制的IGF样结合蛋白Imp-L2。这项提议中的研究将有力地检验这一假说，并建立生殖调节动物衰老的特定分子机制。与公共健康相关：生殖投资加速了动物的衰老，从线虫到昆虫，再到哺乳动物，包括人类。了解这种近乎普遍的衰老控制模式背后的细胞和分子机制，将为人类衰老如何受到生殖控制的激素系统的影响提供基本的见解。这项建议与果蝇黑腹果蝇合作，探索繁殖对昆虫和哺乳动物常见的候选衰老调节激素系统的影响。

DESCRIPTION (provided by applicant): Life span can be extended in many animals when reproduction is repressed, but little is known about the mechanisms of this action. Evidence from the nematode C. elegans suggests that the somatic gonad can produce a signal to ensure longevity, and signals from the germ lineage produce counterbalancing signals that accelerate aging. The identity and operation of these signals are unknown. With Drosophila melanogaster we propose to understand the function of these aging regulatory systems. In our preliminary work we find that loss of germline stem cells from the mature adult gonad, but not the primordial gonad, is sufficient to extend both male and female lifespan. We shall use these differences in the timing of GSC loss to identify cells and molecular signals of the somatic gonad required to induce longevity assurance. Our preliminary work identifies the JAK/STAT and TGF2 families as candidates for the cell-to-cell signaling that is up-regulated when loss of GSC extends lifespan. Research in this proposal will establish whether and how these signals play a functional role in the control of aging. Furthermore, while these signals may affect aging, they are likely to do so indirectly by affecting the function of systemically circulating hormones. Since insulin/IGF signaling is thought to be required for GSC loss to extend lifespan in C. elegans, we assessed the state of insulin signaling when GSC loss extends Drosophila lifespan. Given that reduced insulin signaling is known to increase Drosophila survival, we anticipated there would be fewer messages for insulin- like peptides in these flies. Unexpectedly, we found insulin-like message was several fold increased in long-lived adults. To explain this paradox we propose that GSC loss extends lifespan because the somatic gonad produces signals that repress the insulin sensitivity of tissues in the somatic body, and active GSC suppress this signal. Further preliminary data are consistent with this model of `insulin impedance': transcriptional targets of dFOXO are elevated in flies without germline, and these flies strongly express an insulin inhibitory IGF-like binding protein, Imp-L2. Studies in this proposal will robustly test this hypothesis and establish specific molecular mechanisms by which reproduction modulates animal aging. PUBLIC HEALTH RELEVANCE: Reproductive investment accelerates aging in animals ranging from nematodes, to insects, to mammals and including humans. Understanding the cellular and molecular mechanisms underlying this nearly universal mode of aging control will provide fundamental insights on how human aging is affected by the hormone systems controlled by reproduction. This proposal works with the fly Drosophila melanogaster to explore the effects of reproduction upon candidate aging regulatory hormone systems that are common to insects and mammals.