Identification of rare variants and miRNAs associated with human longevity

摘要-项目1 人类遗传学和基因组学的最新进展为鉴定和鉴定 药物靶标的确认。衰老是许多慢性病的主要危险因素，包括心血管疾病。 疾病、神经退行性疾病和多种癌症。针对潜在风险的干预措施 预计老龄化过程将为人类健康带来重大好处，并大幅减少 与年龄相关的疾病和虚弱相关的社会和经济代价。在模型生物中的研究已经 证明衰老的速度以及与年龄相关的病理的频率和严重程度受到影响 通过保守的遗传途径和因子。此外，对这些基因或药物的操纵 保守的衰老途径可以显著延长实验动物的寿命和健康寿命。这 压倒性的证据为延缓衰老进程和减轻与年龄相关的疾病的新药带来了希望 通过调节保守的衰老途径而导致的人类疾病。这项提案中概述的实验 正是针对这一目标，通过将在模式生物中所取得的突破性发现转化为 人类的处境。与长寿相关的遗传和表观遗传变异是潜在的目标 治疗调节，并可为其作为药物靶点的治疗有效性提供强有力的支持 多个与年龄相关的疾病，而不是一次只患一种疾病。在这里，我们建议在功能上确定 描述遗传变异和表观遗传变异，后者以miRNA个体间变异的形式出现 与人类健康衰老和极端长寿相关的表达水平，用于治疗调节 提高人类健康水平和寿命。在项目1中生成的信息将提供一种机械的 了解基因分型、miRNA表达和相关基因之间的因果关系 表型，可能导致干预措施，促进没有基因的人的生存和健康 特别长寿的倾向。

ABSTRACT – PROJECT 1 Recent advances in human genetics and genomics provide novel opportunities for the identification and validation of drug targets. Aging is a major risk factor for many chronic diseases, including cardiovascular disease, neurodegenerative diseases and a wide range of cancers. Interventions targeting the underlying process of aging are expected to provide significant benefits to human health and substantially reduce the social and economic costs associated with age-related disease and frailty. Studies in model organisms have demonstrated that the rate of aging and the frequency and severity of age-related pathologies are influenced by conserved genetic pathways and factors. Furthermore, genetic or pharmacological manipulation of these conserved aging pathways can dramatically extend lifespan and healthspan in laboratory animals. This overwhelming evidence raises hopes for new drugs that slow the aging process and attenuate age-related disease in humans by modulating the conserved pathways of aging. The experiments outlined in this proposal are aimed at exactly this goal by translating the breakthrough discoveries made in the model organisms into the human situation. Genetic and epigenetic variants associated with longevity are potential targets for therapeutic modulation and can provide strong support for their therapeutic validity as a drug target against multiple age-related disease rather than a single disease at once. Here, we propose to identify and functionally characterize genetic and epigenetic variants, the latter in the form of inter-individual variation in miRNA expression levels, associated with human healthy aging and extreme longevity for therapeutic modulation to improve human health span and lifespan. The information generated in Project 1 will provide a mechanistic understanding of the causal relationships between genotypes, miRNA expression, and the associated phenotypes, potentially leading to interventions that promote survival and health in people without genetic predisposition to exceptional longevity.