Garigan Delia, Hsu Ao-Lin, Fraser Andrew G, Kamath Ravi S, Ahringer Julie, Kenyon Cynthia
Department of Biochemistry and Biophysics and Program in Neuroscience, University of California-San Francisco, San Francisco, CA 94143-0448, USA.
Genetics. 2002 Jul;161(3):1101-12. doi: 10.1093/genetics/161.3.1101.
The genetic analysis of life span has revealed many interesting genes and pathways; however, our understanding of aging has been limited by the lack of a way to assay the aging process itself. Here we show that the tissues of aging worms have a characteristic appearance that is easy to recognize and quantify using Nomarski optics. We have used this assay to determine whether life-span mutations affect the rate of aging, to identify animals that age more rapidly than normal, and to infer the cause of death in C. elegans. Mutations that reduce insulin/IGF-1 signaling double the life span of C. elegans, and we find that tissue decline is slowed in these mutants. Thus this endocrine system appears to influence the rate at which tissues age. This effect extends even to the germline, which is the only mitotically active tissue in the adult. We find that Nomarski microscopy also allows a ready distinction between short-lived mutants that age more rapidly than normal and those that are simply sick, and we have identified an RNAi clone that confers a dramatic rapid-aging phenotype. This clone encodes the C. elegans heat-shock factor (HSF), a transcription factor that regulates the response to heat and oxidative stress. This suggests that heat-shock proteins, many of which act as chaperones, may function in normal animals to slow the rate of aging. Finally, we have identified a cause of death of C. elegans: namely, proliferating bacteria. This suggests that increased susceptibility to bacterial infections contributes to mortality in these animals, just as it does in humans.
对寿命的遗传分析揭示了许多有趣的基因和信号通路；然而，由于缺乏一种检测衰老过程本身的方法，我们对衰老的理解一直受到限制。在此我们表明，衰老线虫的组织具有一种特征性外观，使用诺马斯基光学显微镜很容易识别和量化。我们利用这种检测方法来确定寿命突变是否影响衰老速率，识别比正常情况衰老更快的动物，并推断秀丽隐杆线虫的死亡原因。降低胰岛素/胰岛素样生长因子-1信号传导的突变使秀丽隐杆线虫的寿命延长了一倍，我们发现这些突变体中的组织衰退减缓。因此，这种内分泌系统似乎影响组织衰老的速率。这种影响甚至扩展到生殖系，生殖系是成虫中唯一具有有丝分裂活性的组织。我们发现，诺马斯基显微镜检查还能轻易区分比正常情况衰老更快的短命突变体和那些只是生病的突变体，并且我们已经鉴定出一个能赋予显著快速衰老表型的RNA干扰克隆。该克隆编码秀丽隐杆线虫热休克因子（HSF），一种调节对热和氧化应激反应的转录因子。这表明许多作为伴侣蛋白的热休克蛋白可能在正常动物中发挥作用，以减缓衰老速率。最后，我们已经确定了秀丽隐杆线虫的一个死亡原因：即增殖的细菌。这表明对细菌感染易感性的增加导致了这些动物的死亡，就像在人类中一样。
