Mechanisms of lifespan control

描述（由申请人提供）：了解控制寿命的机制是最具挑战性的生物学问题之一。虽然不被视为一种需要治疗的医学状况，但衰老是最普遍的疾病相关状态。许多复杂的人类疾病都与衰老有关，这既是最重要的风险因素，也是推动这些疾病发展的过程。在临床上，延长寿命意味着延迟与年龄有关的疾病的发作，如癌症、神经退行性疾病、II型糖尿病和肌肉减少症。对模式生物和百岁老人的研究以及延长模式生物寿命的化合物的使用（例如，雷帕霉素）作为与衰老相关的多种人类疾病的药物表明这些方法是可行的。同样清楚的是，老化过程可以自然地加速和延迟（例如，哺乳动物的特点是寿命相差>100倍，在进化过程中寿命既可以增加也可以减少）。哺乳动物之间在寿命和其他性状上的差异远远大于同一种模式生物的自然分离物之间的差异，百岁老人和对照之间的差异，或者在各种实验室中鉴定的野生型和长寿突变生物之间的差异。此外，观察到的哺乳动物寿命的变化是自然发生的，与实验室突变体的特点是寿命延长，但无法在自然环境中竞争。我们建议利用这种多样性的寿命和相关的生活史特征，以揭示机制，调节物种的寿命在哺乳动物。为此，我们将利用比较基因组学的方法来检查密切相关的短寿命和长寿命生物体的基因组对，使用RNA-seq和代谢组学对哺乳动物组织和细胞的寿命，生活史和其他特征进行分析，确定寿命的关键调节器，开发同时针对这些调节器的干预措施，

DESCRIPTION (provided by applicant): Understanding of mechanisms that control lifespan is among the most challenging biological problems. Although not viewed as a medical condition to be treated, aging is the most prevalent disease-related state. Many complex human diseases are associated with aging, which is both the most significant risk factor and the process that drives the development of these diseases. Clinically, extending lifespan would mean delaying the onset of age-related diseases, such as cancer, neurodegenerative diseases, type II diabetes and sarcopenia. Studies of model organisms and centenarians as well as the use of compounds that extend lifespan in model organisms (e.g., rapamycin) as drugs for multiple human diseases associated with aging suggest that these approaches are feasible. It is also clear that the aging process can be naturally accelerated and delayed (e.g., mammals are characterized by >100-fold difference in lifespan, and it can both increase and decrease during evolution). These differences in lifespan and other traits among mammals are much larger than those among natural isolates of the same species of model organisms, between centenarians and controls, or between wild type and longer-lived mutant organisms identified in various laboratories. Moreover, the observed variation in mammalian lifespan occurs naturally, in contrast to laboratory mutants characterized by extended lifespan but unable to compete in the natural setting. We propose to employ this diversity in lifespan and associated life-history traits to uncover mechanisms that regulate species lifespan in mammals. For this, we will utilize methods of comparative genomics to examine pairs of genomes of closely related short- and long-lived organisms, carry out analysis of lifespan, life-history and other traits across a panel f mammalian tissues and cells using RNA-seq and metabolomics, identify key regulators of lifespan, develop interventions that simultaneously target these regulators,