Effect of longevity genomes on the GH/IGF-1 phenotype and disease-free survival

描述（由申请人提供）：我是一名老年医学医师兼科学家，拥有临床研究方法硕士学位和内分泌学培训，专注于发现预防年龄相关疾病的基因组机制。我在阿尔伯特·爱因斯坦医学院（爱因斯坦）老龄化研究所完成了两年的转化老年学和遗传学博士后培训，在Nir Barzilai医学博士的指导下，在此期间我得到了T32和AFAR的资助。随后，我加入了爱因斯坦学院，并获得了格伦衰老生物学机制研究奖。我目前由爱因斯坦的职业发展KL2基金资助。我提议的项目将在爱因斯坦目前进行的两项既定研究的环境下进行：(1)长寿基因计划（Longevity Genes Project， LGP），一项针对百岁老人和非相关对照的横断面研究，作为基因组元素和表型的发现队列，随后在(2)LonGenity中进行评估，一项针对百岁老人后代的独立纵向验证研究，这些百岁老人基因组丰富，而年龄匹配的对照组没有父母的长寿史。这些研究的总体假设是，独特的基因组元素可以预防与年龄相关的疾病，并导致健康长寿，这得到了观察和遗传证据的支持。我的指导委员会由Barzilai博士领导，他领导着Nathan Shock衰老生物学卓越中心，Glenn人类衰老生物学中心，并领导着爱因斯坦大学的长寿研究。在获奖期间，我将通过指导研究和教学培训，提高我在纵向研究方法、遗传学和衰老方面的知识，并提高我的领导能力。越来越多的证据表明，基因组改变导致生长激素/胰岛素样生长因子-1 （GH/IGF-1）信号的衰减，从而延长了动物模型和人类的生存时间并改善了健康状况。我的研究建议假设与长寿相关的基因组因子调节GH/IGF-1表型，进而介导对年龄相关疾病的保护并促进长寿。这一假设将在LonGenity队列中进行前瞻性测试，并将确定长寿基因组元素对GH/IGF-1表型的影响，以及心血管疾病、癌症、2型糖尿病、痴呆、虚弱和超常寿命的患病率和发病率。要测试的基因组元素将包括长寿基因型和通过候选基因方法、无偏倚全基因组关联研究方法和microRNA筛选方法在LGP中发现的microRNA。我早期研究GH/IGF-1表型对90岁老人的影响的结果最近发表在《Aging Cell》杂志上，并得到了国际媒体的报道。这个提议的项目提供了一个机会，可以发现可能导致健康衰老的药物开发，同时提供了一个肥沃的环境，我将成长为一个独立的老年学研究者和一个专注于衰老中内分泌途径的基因组调节的转化研究的领导者。

DESCRIPTION (provided by applicant): I am a gerontologist physician-scientist, with a Master's degree in Clinical Research Methods and training in Endocrinology, focused on the discovery of genomic mechanisms that protect against age-associated diseases. I completed two years of post-doctoral training in translational gerontology and genetics at the Albert Einstein College of Medicine (Einstein) Institute for Aging Research, under the mentorship of Nir Barzilai, MD, during which time I was funded by the T32 and AFAR grants. Subsequently, I joined the Einstein faculty and was recognized with the Glenn Award for Research in Biological Mechanisms of Aging. I am presently funded by a career development KL2 grant from Einstein. My proposed project will be carried out within the environment of two established studies currently conducted at Einstein: (1) Longevity Genes Project (LGP), a cross sectional study of centenarians and unrelated controls, which serves as the discovery cohort for the genomic elements and phenotypes that are subsequently evaluated in (2) LonGenity, an independent, longitudinal validation study of offspring of centenarians, who are enriched with longevity genomes, and age-matched controls without parental history of longevity. The overarching hypothesis of these studies is that unique genomic elements protect against age-related diseases and result in healthy longevity, which is supported by observational and genetic evidence. My mentoring committee is headed by Dr. Barzilai, who directs the Nathan Shock Center of Excellence in the Biology of Aging, the Glenn Center for the Biology of Human Aging, and leads the longevity studies at Einstein. During the award period I will advance my knowledge in the longitudinal study methods, genetics and aging, as well as enhance my leadership skills, through mentored research and didactic training. Expanding evidence suggests that genomic alterations, which result in the attenuation of the growth hormone/ insulin-like growth factor-1 (GH/IGF-1) signaling, result in extended survival and improved health in animal models and humans. My study proposal hypothesizes that longevity- related genomic factors regulate the GH/IGF-1 phenotypes, which in turn, mediate protection against age-related diseases and promote longevity. This hypothesis will be tested prospectively in the LonGenity cohort and will determine the effects of the longevity genomic elements on the GH/IGF-1 phenotypes, in addition to, the prevalence and incidence of cardiovascular disease, cancer, type 2 diabetes mellitus, dementia, frailty, and exceptional longevity. Genomic elements to be tested will include longevity genotypes and microRNAs discovered in LGP by a candidate gene approach, unbiased genome-wide association study approach, and microRNA screening approach. The results of my early work investigating the effect of the GH/IGF-1 phenotype in nonagenarians have recently been published in Aging Cell and received international media coverage. This proposed project presents an opportunity to make discoveries that may lead to drug development for healthy aging, while providing a fertile environment within which I will grow into an independent gerontology investigator and a leader in translational research focusing on genomic regulation of endocrine pathways in aging.