Mechanisms of the Mlx and Max Transcriptional Network in Aging

描述(申请人提供)：我们已经确定了线虫Myc相关转录因子在衰老过程中的功能作用。这个家族由两个不同的异源二聚体组成，分别是MDL和MML复合体，它们在转录和寿命控制中扮演着相反的角色。MML复合体可以延长寿命并激活靶基因转录，而MDL复合体则缩短寿命并抑制基因活性。这些复合体与胰岛素/胰岛素样生长因子信号和饮食限制在基因和分子上相互作用。因此，Myc转录因子家族代表了新发现的这些中枢衰老相关途径的汇聚点。我们将研究MML和MDL复合体影响寿命的分子机制。哺乳动物的同源转录因子与营养感知、新陈代谢控制和疾病有关。我们将使用代谢组学来发现MDL/MML复合体改变的特定代谢途径，并使用遗传和功能基因组方法将这些代谢变化与长寿联系起来。MML和MDL转录复合体代表了一个进化上保守的实体，将营养感知、代谢和衰老结合在一起。在这里提出的实验中，表征新发现的Myc转录因子在不同长寿信号之间动态相互作用中的作用，可能有助于开发治疗与年龄相关的疾病和代谢紊乱(如糖尿病、葡萄糖耐量异常和胰岛素抵抗)的基本策略，以促进人类健康。

DESCRIPTION (provided by applicant): We have identified a functional role for Myc-related transcription factors of C. elegans in the process of aging. This family consists of two different heterodimers, the MDL and MML complexes, respectively, which have opposing roles in transcription and longevity control. The MML complex can extend lifespan and activate target gene transcription, whereas the MDL complex shortens lifespan and represses gene activity. These complexes interact genetically and molecularly with both insulin/IGF signaling and with dietary restriction. Thus, the Myc family of transcription factors represents a newly discovered convergence point for these central aging related pathways. We will investigate the molecular mechanisms by which the MML and MDL complexes influence longevity. Orthologous mammalian transcription factors have been linked to nutrient sensing, metabolic control, and disease. We will use metabolomics to discover the specific metabolic pathways that are altered by the MDL/MML complexes and link those metabolic changes to longevity using genetic and functional genomic approaches. The MML and MDL transcriptional complexes represent an evolutionarily conserved entity for coupling nutrient sensing, metabolism, and aging. Characterizing the newly discovered role of Myc transcription factors in the dynamic interplay between distinct longevity signals, in the experiments proposed here, may facilitate the development of rationale strategies for the treatment of age-associated disease and metabolic disorders (e.g. diabetes, glucose intolerance, and insulin resistance) to promote human health.