The role of autophagy in aging and metabolism

有许多途径和过程似乎可以调节衰老的速度和我们对年龄相关疾病的易感性，如神经变性，动脉粥样硬化和癌症。一个越来越多地被牵连的新兴过程是自噬。自噬首先在酵母中被描述，是一种受应激条件刺激的调节过程，最明显的是饥饿。一旦被激活，自噬涉及旧的和受损的蛋白质和细胞器的回收，以便为新的细胞成分提供构建模块。 当我们证明NAD依赖性脱乙酰基酶Sirt1是自噬的重要调节剂时，我们对自噬的最初兴趣出现了（Lee et al.，PNAS，2008）。我们还通过在该过程中涉及p300组蛋白乙酰转移酶进一步证明了蛋白质脱乙酰化和自噬之间的联系（Lee等人，JBC，2009年）。我们还使用各种小鼠模型分析了自噬的生理作用。特别地，我们已经证明了必需的自噬基因Atg 7的条件性敲除导致糖尿病状态（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。特别地，我们已经证明了Atg7、p53和细胞周期进程之间的重要联系（Lee等人，Science，2012）。我们还描述了自噬在体外和体内从内皮分泌生物活性分子中的作用（Torisu等人，Nature Medicine，2013）和自噬在动脉粥样硬化中的作用（Torisu et al，Aging Cell，2016）。我们正在积极研究自噬在血管生物学各个方面的作用（Nussenzweig et al.，瑟克水库，2015）。我们还表征了mTOR表达的亚纯模型。mTOR是自噬的重要负调节因子。我们的结果（Wu等人，Cell Reports，2013）表明，减少mTOR可以延长寿命并以分段方式减缓衰老。我们认为这些作用可能部分是由于mTOR在调节自噬通量中的作用。目前的分析包括各种条件性小鼠模型，其中自噬以组织特异性方式被删除。 我们最近还产生了我们认为是第一个允许检测线粒体自噬的体内reporer小鼠（Sun等人，Mol Cell，2016）。我们相信这将是该领域的一个重要试剂。该系统基于日本一个小组先前描述的荧光报告器Keima。 正在进行的研究试图进一步了解线粒体自噬的分子调控，以及衍生调节线粒体自噬通量的小分子。许多研究正在进行中，以评估使用该模型在各种生理和病理生理环境中的线粒体自噬水平。

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 mTOR in modulating autphagic flux. Current analysis include various conditional mouse models in which autophagy is deleted in a tissue-specific fashion. 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.