MECHANISMS OF AGING REGULATION BY DROSOPHILA GERMLINE

描述（由申请人提供）：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。来自秀丽隐杆线虫的证据表明，体细胞性腺可以产生一种确保长寿的信号，而来自生殖谱系的信号可以产生加速衰老的平衡信号。这些信号的身份和作用是未知的。通过黑腹果蝇，我们想要了解这些衰老调节系统的功能。在我们的初步工作中，我们发现来自成熟成人性腺的生殖系干细胞的损失，而不是原始性腺，足以延长男性和女性的寿命。我们将利用这些GSC丢失时间的差异来识别诱导长寿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家族是细胞间信号传导的候选者，当GSC缺失延长寿命时，细胞间信号传导上调。本提案的研究将确定这些信号是否以及如何在控制衰老中发挥功能作用。此外，虽然这些信号可能影响衰老，但它们很可能是通过间接影响全身循环激素的功能来实现的。由于胰岛素/IGF信号被认为是线虫GSC损失延长寿命所必需的，因此我们评估了GSC损失延长果蝇寿命时胰岛素信号的状态。鉴于已知胰岛素信号的减少可以增加果蝇的存活率，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，在长寿的成年人中，胰岛素样信息增加了几倍。为了解释这一悖论，我们提出GSC损失延长寿命是因为体细胞性腺产生抑制体细胞组织胰岛素敏感性的信号，而活跃的GSC抑制了这一信号。进一步的初步数据与“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，这些果蝇强烈表达胰岛素抑制igf样结合蛋白Imp-L2。本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：生殖投资加速了从线虫、昆虫到哺乳动物，包括人类在内的动物的衰老。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，将为了解生殖控制的激素系统如何影响人类衰老提供基本的见解。本研究以果蝇黑腹果蝇为研究对象，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.