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研究之一。 问题虽然不被视为一个医疗条件来治疗，老化是最普遍的 疾病相关状态。许多复杂的人类疾病都与衰老有关， 最重要的风险因素和推动这些疾病发展的过程。 从临床上讲，延长寿命意味着推迟与年龄有关的疾病的发作，如 癌症、神经变性疾病、II型糖尿病和肌肉减少症。模型研究 生物和百岁老人以及使用延长模型寿命的化合物 生物体（例如，雷帕霉素）作为与衰老相关的多种人类疾病的药物 这表明这些方法是可行的。同样清楚的是，老化过程可以是 自然加速和延迟（例如，哺乳动物的特征是在 寿命，它可以在进化过程中增加和减少）。这些寿命上的差异 哺乳动物之间的其他特征要比自然分离的大得多。 相同物种的模式生物，百岁老人和对照之间，或野生型之间 以及各种实验室中鉴定出的寿命更长的突变生物。此外，观察到的 哺乳动物寿命的变化是自然发生的，与实验室突变体不同， 但无法在自然环境中竞争。我们建议利用这个 寿命和相关生活史特征的多样性，以揭示调节 哺乳动物的物种寿命。为此，我们将利用比较基因组学的方法， 检查密切相关的短寿命和长寿命生物体的基因组对，进行分析， 寿命，生活史和其他特征在一组哺乳动物组织和细胞中使用 RNA-seq和代谢组学，确定寿命的关键调节因子，开发干预措施， 同时靶向这些调节剂，并将这些发现直接应用于细胞和生物体 以使短寿命物种向相关的长寿物种转变。我们建议 更好地理解寿命的因果关系和分子机制 控制将导致更好地了解人类疾病的老化，并将允许 开发延缓衰老过程的治疗方法，从而延缓人类衰老的发生。 与衰老有关的疾病。

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 of mammalian tissues and cells using RNA-seq and metabolomics, identify key regulators of lifespan, develop interventions that simultaneously target these regulators, and directly apply these findings to cells and organisms in order to shift short-lived species toward the state of related longer-lived species. We suggest that a better understanding of causal relationships and molecular mechanisms of lifespan control will lead to a better understanding of human diseases of aging and will allow development of treatments that delay the aging process, thereby delaying the onset of human diseases associated with aging.