Mechanisms of the Mlx and Max Transcriptional Network in Aging

描述（由申请人提供）：我们已经确定了秀丽隐杆线虫myc相关转录因子在衰老过程中的功能作用。该家族由两种不同的异源二聚体组成，分别是MDL和MML复合物，它们在转录和寿命控制中具有相反的作用。MML复合体可以延长寿命并激活靶基因转录，而MDL复合体可以缩短寿命并抑制基因活性。这些复合物在基因和分子上与胰岛素/IGF信号和饮食限制相互作用。因此，Myc家族转录因子代表了这些中心衰老相关途径的新发现的趋同点。我们将研究MML和MDL复合物影响寿命的分子机制。同源哺乳动物转录因子与营养感知、代谢控制和疾病有关。我们将使用代谢组学来发现MDL/MML复合物改变的特定代谢途径，并使用遗传和功能基因组学方法将这些代谢变化与寿命联系起来。MML和MDL转录复合物代表了一个进化上保守的实体，用于耦合营养感知、代谢和衰老。在这里提出的实验中，表征新发现的Myc转录因子在不同寿命信号之间动态相互作用中的作用，可能有助于开发治疗年龄相关疾病和代谢紊乱（如糖尿病、葡萄糖耐受不良和胰岛素抵抗）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.