Role of exceptional longevity genotypes in protection against frailty in aging

描述（由申请人提供）：尽管有大量遗传成分的证据，但人类寿命（长寿）的遗传生物学因素仍然未知。我们的主要假设是，独特的基因型和表型可以预防与年龄相关的疾病，以确保异常健康的长寿。在过去的14年里，我们招募了长寿基因项目（LGP）的发现队列，并获得了重要的遗传数据，支持百岁老人与无关对照组相比具有保护性基因型的假设。然后，我们在第二项独立的NIH资助的LonGenity研究（P01 AG 027734）中测试了这一假设，该研究招募了：（i）长寿父母的后代（OPEL-LonGenity）和（ii）正常存活父母的后代（OPUS-LonGenity）。LGP和LonGenity队列中的受试者是德系犹太成年人（AJs），他们在遗传和社会经济地位方面相对同质，为遗传发现提供了力量。LonGenity的研究表明，OPEL表型和相关的长寿基因型成功地与老年人的心血管、代谢和认知健康改善相关。我们现在建议将我们的研究扩展到脆弱表型，建立在令人兴奋的新的初步数据上，这些数据是由美国老龄化研究联合会提供的试点资金获得的，该研究将特殊的长寿表型和基因型与身体功能和脆弱联系起来。术语“虚弱”在临床上用作一个全球概念，用于描述老年人常见的力量、耐力和平衡受损的状况，易受创伤和其他压力因素的影响，以及发病、残疾和死亡的高风险。我们的目标是评估在LonGenity研究中的1400名老年人中，特殊长寿性状和基因型在降低其重要身体功能成分（如步态、平衡和力量）发生虚弱和年龄相关下降的风险中的作用。这项提案将由脆弱、步态障碍和痴呆症专家Verghese博士和LonGenity研究的PI、世界著名遗传学家Barzilai博士共同指导。提出了以下三个目标。 1.研究长寿家族史在降低衰老过程中身体衰退和虚弱风险方面的作用。 2.确定长寿相关的遗传因素在降低衰老中身体衰退和虚弱风险中的作用，并检查长寿和虚弱相关基因型之间的相互作用，并在3个外部队列中验证研究结果。 3.检查生物暴露（已建立的长寿基因的蛋白质产物，其相关中间体和血管生物标志物）对异常长寿与衰老中身体功能纵向变化之间的关联的影响。我们的新项目基于LonGenity研究奠定的研究基础设施，强大的跨学科合作，独特的人口，遗传发现和科学基础。如果可以证明独特的遗传和生物学变化有助于预防虚弱，那么就有可能开发和测试干预措施来预防虚弱和身体功能下降，这可能会提供超出目前公认疾病治疗所获得的额外益处。

DESCRIPTION (provided by applicant): Despite evidence of a substantial genetic component, the inherited biological factors that underlie human life span (longevity) remain unknown. Our main hypothesis is that unique genotypes and phenotypes protect against age-related diseases to assure exceptional healthy longevity. In the past 14 years we recruited our discovery cohort of the Longevity Genes Project (LGP), and obtained significant genetic data supporting the hypothesis for protective genotypes in centenarians compared with unrelated controls. We then tested this hypothesis in a second independent NIH funded LonGenity study (P01 AG027734), which recruited: (i) offspring of parents of exceptional longevity (OPEL-LonGenity) and (ii) offspring of parents who had usual survival (OPUS-LonGenity). The subjects in LGP and LonGenity cohorts are Ashkenazi Jewish adults (AJs) who are relatively homogenous genetically and in their social-economic status, lending strength to genetic discovery. The LonGenity study demonstrated that the OPEL phenotype and associated longevity genotypes were successfully linked to improved cardiovascular, metabolic, and cognitive health in aging. We now propose to extend our study to the frailty phenotype, building on exciting new preliminary data obtained with pilot funding from the American Federation of Aging Research that links exceptional longevity phenotypes and genotypes to physical function and frailty. The term "frailty" is used clinically as a global concept to describe a condition, common in older adults, of impaired strength, endurance, and balance, vulnerability to trauma and other stressors, and high risk for morbidity, disability, and mortality. Our goal is to evaluate the roleof exceptional longevity trait and genotypes in decreasing risk of developing frailty and age-related declines in its important physical function constituents such as gait, balance, and strength in 1400 older adults in the LonGenity study. This proposal will be jointly directed by Dr. Verghese, an expert in frailty, gait disorders and dementia, and Dr. Barzilai, PI of the LonGenity study and a world renowned geneticist. The following three aims are proposed. 1. Study the role of family history of longevity on reducing risk of physical decline and frailty in aging. 2. Determine the role of longevity related genetic factors in reducing risk of physical decline and frailty in agingas well as examine the interplay between longevity and frailty- associated genotypes and validate the findings in 3 external cohorts. 3. Examine the effect of biological exposures (protein products of established longevity genes, their relevant intermediates and vascular biomarkers) on the association between exceptional longevity and longitudinal change in physical function in aging. We base our new project on the research infrastructure, strong interdisciplinary collaborations, unique population, genetic discoveries, and scientific foundation laid by the LonGenity study. If distinct genetic and biological changes can be shown to contribute to the prevention of frailty, it may be possible to develop and test interventions to prevent frailty and physical function decline that may provide additional benefits beyond those obtained from treatments from currently recognized diseases.