The role of autophagy in aging and metabolism

有许多途径和过程似乎控制着衰老的速度和我们对与年龄相关的疾病的易感性，如神经退行性变、动脉粥样硬化和癌症。一个日益受到牵连的新兴过程是自噬。自噬最初是在酵母中描述的，它是一种受应激条件刺激的调节过程，最明显的是饥饿。一旦激活，自噬涉及旧的和受损的蛋白质和细胞器的循环，以便为新的细胞成分提供构建块。 我们最初对自噬的兴趣来自于我们证明依赖NAD的脱乙酰酶Sirt1是自噬的重要调节因子(Lee等人，PNAS，2008年)。我们进一步证明了蛋白质去乙酰化和自噬之间的联系，还牵涉到p300组蛋白乙酰转移酶在这一过程中(Lee at al.，JBC，2009)。我们还利用不同的小鼠模型分析了自噬的生理作用。特别是，我们已经证明了基本自噬基因ATG7的条件性敲除会导致糖尿病状态(Wu等人，Aging，2009)。 目前，我们正在使用细胞和动物模型来研究自噬的生物学和生理学作用。特别是，我们已经证明了ATG7、P53和细胞周期进展之间的重要联系(Lee等人，科学，2012年)。我们还描述了自噬在体外和体内内皮细胞分泌生物活性分子中的作用(Torisu等人，《自然医学》，2013)以及自噬在动脉粥样硬化中的作用(Torisu等人，Aging Cell，2016)。我们正在积极研究自噬在血管生物学的各个方面的作用(Nussenzweig等人，Circ Res.，2015)。我们还刻画了mTOR表达式的一个亚纯模型。MTOR是自噬的重要负调控因子。我们的结果(Wu等人，Cell Reports，2013)表明，降低mTOR可以延长寿命并以节段性方式延缓衰老。我们认为，这些影响可能部分归因于MTPR在调节自噬通量方面的作用。 我们最近还产生了我们认为是第一只体内能够检测到有丝分裂的Reporer小鼠(Sun等人，Mol Cell，2016)。我们相信这将是该领域的重要试剂。这个系统是基于日本一个组织之前描述的荧光报告程序Keima。正在进行的研究正在努力进一步了解吞丝运动的分子调控，以及衍生调节吞丝通量的小分子。许多研究正在进行中，以评估在各种生理和病理生理环境中使用该模型的有丝分裂吞噬水平。

There are many pathways and processes that appear to regulate the rate of aging and our susceptibility to age-related diseases such as neurodegeneration, atherosclerosis and cancer. One emerging process that has been increasingly implicated is autophagy. First described in yeast, autophagy is a regulated process stimulated by stressful condition most notably starvation. Once activated, autophagy involves the recycling of old and damaged proteins and organelles in order to provide building blocks for new cellular components. Our initial interest in autophagy came when we demonstrated that the NAD-dependent deacetylase Sirt1 was an important regulator of autophagy (Lee et al., PNAS, 2008). We further demonstrated a connection between protein deacetylation and autophagy by also implicating the p300 histone acetyltransferase in the process (Lee at al., JBC, 2009). We have also analyzed the physiological role of autophagy using various mouse models. In particular, we have demonstrated that conditional knockouts of the essential autophagy gene Atg7 results in a diabetic state (Wu et al., Aging, 2009). Currently, we are pursuing the biological and physiological role of autophagy using both cellular and animal models. In particular, we have demonstrated an important connection between Atg7, p53 and cell cycle progression (Lee et al., Science, 2012). We have also described a role for autophagy in the secretion of bioactive molecules from the endothelium both in vitro and in vivo (Torisu et al., Nature Medicine, 2013) and a role for autophagy in atherosclerosis (Torisu et al, Aging Cell, 2016). We are actively pursuing the role of autophagy in various aspects of vascular biology (Nussenzweig et al., Circ Res., 2015). We have also characterized a hypomorphic model of mTOR expression. mTOR is an important negative regulator of autophagy. Our results (Wu et al., Cell Reports, 2013) suggest that reducing mTOR can extend lifespan and slow aging in a segmental fashion. We believe these effects may in part be due to the role of mTPR in modulating autphagic flux. We have also recently generated what we feel is the first in vivo reporer mouse that allows for the detection of mitophagy (Sun et al., Mol Cell, 2016). We believe this will be an important reagent for the field. This system is based on the fluorescent reporer Keima, previously described by a group in Japan. Ongoing studies are attepting to further understand the molecular regulation of mitophagy, as well as deriving small molecules that regulate mitophagic flux. Numerous studies are underway to assess the level of mitophagy using this model in various physiological and patho-physiological settings.