Buck Institute for Age Research, Novato, CA 94945, USA.
Exp Gerontol. 2011 May;46(5):382-90. doi: 10.1016/j.exger.2010.11.036. Epub 2010 Dec 2.
Extensive studies in model organisms in the last few decades have revealed that aging is subject to profound genetic influence. The conserved nutrient sensing TOR (Target of Rapamycin) pathway is emerging as a key regulator of lifespan and healthspan in various species from yeast to mammals. The TOR signaling pathway plays a critical role in determining how a eukaryotic cell or a cellular system co-ordinates its growth, development and aging in response to constant changes in its surrounding environment? TOR integrates signals originating from changes in growth factors, nutrient availability, energy status and various physiological stresses. Each of these inputs is specialized to sense particular signal(s), and conveys it to the TOR complex which in turn relays the signal to downstream outputs to appropriately respond to the environmental changes. These outputs include mRNA translation, autophagy, transcription, metabolism, cell survival, proliferation and growth amongst a number of other cellular processes, some of which influence organismal lifespan. Here we review the contribution of the model organism Drosophila in the understanding of TOR signaling and the various biological processes it modulates that may impact on aging. Drosophila was the first organism where the nutrient dependent effects of the TOR pathway on lifespan were first uncovered. We also discuss how the nutrient-sensing TOR pathway appears to be critically important for mediating the longevity effects of dietary restriction (DR), a potent environmental method of lifespan extension by nutrient limitation. Identifying the molecular mechanisms that modulate lifespan downstream of TOR is being intensely investigated and there is hope that these are likely to serve as potential targets for amelioration of age-related diseases and enhance healthful lifespan extension in humans.
在过去几十年中，对模式生物的广泛研究揭示了衰老受到深刻的遗传影响。保守的营养感应 TOR（雷帕霉素靶蛋白）途径正成为各种生物（从酵母到哺乳动物）寿命和健康寿命的关键调节剂。TOR 信号通路在决定真核细胞或细胞系统如何协调其生长、发育和衰老方面起着关键作用，以适应其周围环境的不断变化。TOR 整合了来自生长因子、营养供应、能量状态和各种生理应激变化的信号。这些输入中的每一个都专门用于感知特定的信号，并将其传递给 TOR 复合物，TOR 复合物反过来将信号传递给下游输出，以适当地响应环境变化。这些输出包括 mRNA 翻译、自噬、转录、代谢、细胞存活、增殖和生长等许多其他细胞过程，其中一些过程会影响生物体的寿命。在这里，我们回顾了模式生物果蝇在理解 TOR 信号及其调节的各种生物学过程方面的贡献，这些过程可能会影响衰老。果蝇是第一个揭示 TOR 途径对寿命的营养依赖性影响的生物体。我们还讨论了营养感应 TOR 途径如何在介导饮食限制（DR）的长寿效应方面似乎至关重要，DR 是一种通过营养限制延长寿命的有效环境方法。鉴定调节 TOR 下游寿命的分子机制正在被深入研究，人们希望这些机制可能成为改善与年龄相关疾病和延长人类健康寿命的潜在靶点。
