MECHANISMS OF AGING REGULATION BY DROSOPHILA GERMLINE

描述（由申请人提供）：当生殖受到抑制时，许多动物的寿命可以延长，但对这种作用的机制知之甚少。来自线虫C的证据。elegans认为，体细胞性腺可以产生一个信号，以确保长寿，和信号，从生殖谱系产生抵消信号，加速老化。这些信号的身份和操作是未知的。与果蝇，我们建议了解这些老化调节系统的功能。在我们的初步工作中，我们发现从成熟的成年性腺而不是原始性腺中损失生殖系干细胞足以延长男性和女性的寿命。我们将利用GSC丧失时间的这些差异来确定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了JAK/STAT和TGF 2家族作为细胞间信号传导的候选者，当GSC丧失延长寿命时，细胞间信号传导上调。这项提案中的研究将确定这些信号是否以及如何在控制衰老中发挥作用。此外，虽然这些信号可能会影响衰老，但它们可能会通过影响全身循环激素的功能间接地做到这一点。由于胰岛素/IGF信号被认为是GSC损失所必需的，以延长C. elegans，我们评估了当GSC损失延长果蝇寿命时胰岛素信号传导的状态。鉴于已知胰岛素信号的减少会增加果蝇的存活率，我们预计这些果蝇中胰岛素样肽的信息会更少。出乎意料的是，我们发现胰岛素样信息在长寿的成年人中增加了几倍。为了解释这一矛盾，我们提出，GSC损失延长寿命，因为体细胞性腺产生抑制体细胞中组织的胰岛素敏感性的信号，并且活性GSC抑制该信号。进一步的初步数据与这种“胰岛素阻抗”模型一致：dFOXO的转录靶点在没有种系的果蝇中升高，并且这些果蝇强烈表达胰岛素抑制性IGF样结合蛋白Imp-L2。这项研究将有力地验证这一假设，并建立生殖调节动物衰老的特定分子机制。公共卫生相关性：生殖投资加速动物衰老，从线虫到昆虫，到哺乳动物，包括人类。了解这种几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见解。这项建议与果蝇黑腹果蝇合作，探索生殖对昆虫和哺乳动物共同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.