Role of dS6 phosphorylation in dTORC1/dS6K mediated longevity in Drosophila

描述（由申请人提供）：肥胖是一种世界性的流行病，仅在美国每年就有30多万人死亡。此外，这也是医疗保健费用激增和令人不安的观察结果背后的主要原因：几十年来，北美人的寿命首次出现下降。肥胖的一个直接后果是增加了许多与年龄有关的病理的可能性，包括糖尿病、心血管疾病、神经退行性疾病和癌症。粮食的可得性、丰富性和相对低廉的价格助长了这种流行病。控制这种疾病的关键障碍是无法克服促进食物获取和以脂肪库形式储存能量储备的主要人类遗传特征。据推测，这些特征是在进化过程中被选择出来的，这是长期食物短缺的结果，随着时间的推移，它们已经战胜了那些抑制食物摄入的特征。鉴于这些限制和肥胖流行的规模，开发新的干预策略至关重要，例如靶向药物治疗。这些策略的成功将取决于对驱动这些反应的分子机制的基本理解。相反，与营养过剩相比，饮食限制是一种强有力的环境操纵，可以增加“健康寿命”，因为它不仅可以延长寿命，还可以延缓与年龄有关的疾病的发作。尽管在深入的研究中，导致肥胖引起的与年龄相关疾病相关的病理与饮食限制引起的健康寿命增加相关的潜在分子机制仍然难以解决。尽管如此，mTORC1介导的信号通路在这两种反应中都发挥了重要作用。在营养超载的情况下，这一途径被完全激活，并导致肥胖和胰岛素抵抗。相反，在饮食限制的条件下，这种信号通路被抑制，这已被证明有助于增加健康寿命。重要的是，在更简单的真核生物中信号通路的保守性和健康跨度研究的快速性使得对模式生物（如果蝇）的研究在阐明人类健康跨度相关疾病方面具有宝贵的价值。此外，在不同生物中的研究表明，从酵母到人类，mTORC1信号通路的营养臂是高度保守的，是饮食限制效果的中心介质。S6K1是mTORC1的下游靶点，其在小鼠中的缺乏已被证明可以增加胰岛素敏感性，增加对饮食引起的肥胖的抵抗力，并延长寿命，同时使动物免于许多与年龄相关的病理。S6K1的几个下游底物已经被确定；然而，影响健康寿命的因素尚不清楚。我们认为，作为S6K1的第一个下游底物，dS6的磷酸化在饮食限制介导的健康寿命延长中起着重要作用。我们提供了初步的数据来支持这一新的假设。

DESCRIPTION (provided by applicant): Obesity is a worldwide epidemic that accounts for more than 300,000 deaths per year in the United States alone. Moreover, it is the major reason behind the explosion in health care costs and the disquieting observation that, for the first time in decades, human life span is decreasing for North Americans. A direct consequence of obesity is the enhanced probability of a number of age-related pathologies including diabetes, cardiovascular disease, neurodegenerative disorders, and cancer. The epidemic has been fueled by the availability, abundance, and relatively low cost of food. The critical barrier in controlling the disease has been the inability to overcome dominant human genetic traits that promote the acquisition of food and the storage of energy reserves in the form of adipose depots. It is hypothesized that these traits were selected for during evolution as a consequence of the chronic scarcity of food and that, over time, they have prevailed over those traits that suppress food intake. Given these limitations and the magnitude of the obesity epidemic, it is critical to develop novel intervention strategies, such as targeted drug therapies. The success of such strategies will depend on a basic understanding of the molecular mechanisms that drive these responses. In contrast, to nutritional overload, dietary restriction is a robust environmental manipulation that increases "healthspan", as it not only prolongs life span but also delays the onset of age-related diseases. Although under intense investigation, the underlying molecular mechanisms that lead to obesity-induced pathologies associated with age-related diseases versus those of dietary restriction-induced increases in healthspan have remained difficult to resolve. Nonetheless, one signaling pathway that has emerged as a major player in both responses is that mediated by mTORC1. Under conditions of nutritional overload, this pathway is fully activated and known to contribute to obesity and insulin resistance. In contrast, under conditions of dietary restriction this signaling pathway is suppressed, which has been demonstrated to contribute to increased healthspan. Importantly, conservation of signaling pathways in simpler eukaryotes and the rapidity with which healthspan studies can be carried out make research in model organisms such as Drosophila invaluable in elucidating healthspan-related diseases in humans. Moreover, studies in different organisms have shown that the nutrient arm of the mTORC1 signaling pathway is highly conserved from yeast to man and is a central mediator of the effect of dietary restriction. S6K1 is a well established downstream target of mTORC1 whose deficiency in the mouse has been shown to increase insulin sensitivity, increase resistance to diet-induced obesity, and increase life span, while sparing animals from much age-related pathology. Several downstream substrates of S6K1 have been identified; however, those mediating healthspan are unknown. We propose that phosphorylation of dS6, the first-identified downstream substrate of S6K1, is an essential player in dietary restriction-mediated healthspan extension. We provide preliminary data to support this novel hypothesis. PUBLIC HEALTH RELEVANCE: Obesity, which has recently become a worldwide epidemic, is well recognized for its deleterious effects on health whereas dietary restriction increases healthspan, as it delays the onset of age- related diseases. The mTORC1/S6K1 signaling pathway has emerged as a major player in both states: under conditions of nutritional overload, this pathway contributes to obesity and insulin resistance while under conditions of dietary restriction it is suppressed and increases healthspan. The proposed project will use Drosophila model and analyze a downstream effector of this signaling pathway, the phosphorylation of S6, to reveal the mechanisms by which it affects dietary restriction mediated healthspan extension.