Linking the Mitochondrial and Epigenetic Pathways of Life Span Extension

描述(申请人提供)：衰老是发生在所有真核生物中的一个基本的生物学过程。尽管进行了大量的研究，但这一复杂过程背后的分子和细胞机制仍然知之甚少。改变饲料中的线粒体功能和营养成分是两种延长寿命的条件，由于它们出现在迄今测试的所有模式生物中，因此在衰老领域引起了极大的兴趣。线粒体形态和功能的改变与各种生物体的衰老密切相关。此外，延长不同物种寿命的遗传和饮食操作依赖于正常的线粒体功能。矛盾的是，线粒体功能的某些干扰也可以延长酵母、蠕虫、苍蝇和哺乳动物的寿命。因此，线粒体在寿命调节中的确切作用仍然是个谜。最近的研究还表明，表观遗传调节因子控制着多种生物的寿命。尽管有强有力的证据支持线粒体和表观遗传调控在决定寿命中的重要性，但在后生动物中，这两个长寿调节轴之间的关系(如果有的话)尚未在后生动物中建立。我们对模式生物果蝇的初步研究揭示了线粒体功能和表观遗传修饰之间的一种新的联系。我们发现，线粒体的功能状态可以直接影响组蛋白H3乙酰化，这是一种表观遗传调节，可以强烈影响细胞核中的基因转录。我们的遗传学研究强烈暗示组蛋白乙酰转移酶GCN5是介导线粒体诱导的H3乙酰化的关键酶。此外，我们的结果暗示雷帕霉素复合体靶标-2(TORC2)参与了这一过程。这些发现从逻辑上引出了我们的中心假设，即线粒体和饮食变化(例如，饮食限制-DR)通过影响GCN5介导的组蛋白H3的乙酰化来激活长寿促进基因的转录来延长寿命，并且这一过程是由TORC2介导的。这项拟议的工作将利用果蝇独有的强大工具来测试这一关于线粒体和表观遗传变化之间关系的新假设，以促进寿命。这项提议有两个具体目标。在目标1中，我们将研究GCN5在线粒体和饮食改变诱导的寿命延长中的作用和组织特异性需求。在目标2中，我们将确定GCN5和TORC2在介导线粒体和饮食变化对寿命延长影响方面的关系。这些研究将通过阐明TORC2和GCN5在这一过程中的作用，为线粒体代谢和饮食对寿命影响的延寿信号网络的机制提供新的见解。这最终将为干预衰老过程提供新的方法，并为治疗一系列与年龄相关的疾病提供新的治疗策略。

DESCRIPTION (provided by applicant): Aging is a fundamental biological process that occurs in all eukaryotic organisms. Despite intensive research, the molecular and cellular mechanisms underlying this complex process remain poorly understood. Altering mitochondrial function and nutrient composition in diets are two life span- extension conditions that are drawing considerable interests in the aging field due to their occurrence in all model organisms tested so far. Changes in mitochondrial morphology and function have been intimately associated with aging in diverse organisms. Moreover, genetic and dietary manipulations that extend life span in various species are dependent on normal mitochondrial function. Paradoxically, certain perturbations of mitochondrial function can also extend life span in yeast, worms, flies, and mammals. Thus, the exact role of mitochondria in life span regulation remains enigmatic. Recent studies have also implicated epigenetic regulators in controlling life span in multiple organisms. Despite the strong evidence supporting the importance of mitochondrial and epigenetic regulations in life span determination, the relationship, if any, between these two longevity-regulating axes in the aging process has not been established in metazoans. Our preliminary studies in the model organism Drosophila have uncovered a novel connection between mitochondrial function and epigenetic modifications. We found that the functional status of mitochondria can directly affect histone H3 acetylation, an epigenetic regulation that can strongly influence gene transcription in the nucleus. Our genetic studies strongly implicated the histone acetyltransferase GCN5 as a key enzyme mediating mitochondria-induced H3 acetylation. Moreover, our results implicated the involvement of target of rapamycin complex-2 (TORC2) in this process. These findings led logically to our central hypothesis that mitochondrial and dietary alterations (e.g., dietary restriction-DR) extend life span by impinging on GCN5-mediated acetylation of histone H3 to activate the transcription of longevity promoting genes, and that this process is mediated by TORC2. The proposed work will employ the powerful tools uniquely available in Drosophila to test this novel hypothesis concerning the relationship between mitochondrial and epigenetic changes in promoting longevity. There are two specific Aims in this proposal. In Aim 1, we will examine the role and tissue- specific requirement of GCN5 in mitochondrial and dietary alteration-induced life span extension. In Aim 2, we will determine the relationship between GCN5 and TORC2 in mediating the effects of mitochondrial and dietary alterations on life span extension. These studies will offer novel insights into the mechanisms of a prolongevity signaling network underlying the effects of mitochondrial metabolism and diet on life span by elucidating the roles of TORC2 and GCN5 in the process. This will ultimately offer new ways to interfere with the aging process and provide novel therapeutic strategies to treat a battery of age-related diseases.