Genetic Analysis of Aging in C. elegans

描述（由申请人提供）：衰老的遗传分析揭示了可以延长整个动物王国寿命的途径。但是，这些长寿途径如何被自然因素激活，它们如何协调组织之间的衰老速度，以及它们最终如何影响细胞衰老，仍然没有得到很好的理解。这一信息至关重要，因为它可以为我们提供新的方法，让我们更长时间地保持健康，年轻和无病。二十年前，我们的实验室发现，现在已知编码胰岛素/IGF-1受体和FOXO转录因子的基因可以减缓衰老，使C.优雅从那时起，这笔赠款的资金使我们能够大大提高我们对这一途径的理解，并发现新的长寿途径。在下一个资助期内，我们将解决有关衰老的关键，未回答的问题，建立在这项赠款的发现基础上。1.自然界中的长寿途径是如何调节的？我们已经发现，特定的化学感受回路控制C。elegans的衰老，至少部分是通过调节FOXO活性。由于神经元已知会影响哺乳动物的胰岛素/IGF-1信号传导和寿命，使用强大的新成像和遗传方法，我们将询问这种C。elegans神经感觉回路的运作，以及它如何激活体内的FOXO。2.我们发现，一旦FOXO在单个组织中被激活，它可以通过激活FOXO独立的长寿途径来减缓其他组织的衰老。这些下游途径是什么？我们的研究结果表明，脂质起着关键作用。我们将测试这一假设，并确定额外的下游信号组件。3.一个关键的未回答的问题是，不同的长寿途径在多大程度上汇聚在相同的下游细胞过程中，以及它们是否以不同或共同的方式调节这些下游过程。我们将使用遗传和基因组技术，再加上我们开发的强大的新生物信息学方法，来解决这个问题。4.最后，使用我们已经确定的衰老生物标志物，我们将剖析一个自然的抗衰老过程;细胞再生，并询问已知的长寿因素在多大程度上介导了这一过程。

DESCRIPTION (provided by applicant): The genetic analysis of aging has revealed pathways that can extend lifespan throughout the animal kingdom. But how these longevity pathways can be activated by natural cues, how they coordinate the rate of aging among the tissues, and how they ultimately influence cellular aging, are still not well understood. This information is vital,as it could suggest new ways to keep us healthy, youthful and disease-free for a longer time. Twenty years ago, our lab discovered that genes now known to encode an insulin/IGF-1 receptor and a FOXO transcription factor can slow aging and double the lifespan of C. elegans. Since that time, this grant's funding has allowed us to advance our understanding of this pathway substantially, and to discover new longevity pathways as well. During the next funding period, we will address key, unanswered questions about aging, building on discoveries from this grant. 1. How are longevity pathways regulated in nature? We have found that specific chemosensory circuits control C. elegans' aging, at least in part, by regulating FOXO activity. Because neurons are known to influence insulin/IGF-1 signaling and lifespan in mammals, using powerful new imaging and genetic approaches, we will ask how this C. elegans neurosensory circuit operates, and how it activates FOXO within the body. 2. We have found that once FOXO has been activated in a single tissue, it can slow the aging of other tissues by activating FOXO-independent longevity pathways. What are these downstream pathways? Our findings suggest that lipids play a key role. We will test this hypothesis, and identify additional downstream signaling components. 3. A key unanswered question is to what extent different longevity pathways converge on the same downstream cellular processes, and whether they regulate these downstream processes in distinct or common ways. We will use genetic and genomic techniques; coupled with a powerful new bioinformatics method we have developed, to address this question. 4. Finally, using biomarkers of aging we have identified, we will dissect a natural anti-aging process; cellular rejuvenation, and ask to what extent known longevity factors mediate this processes.