Role of exceptional longevity genotypes in protection against frailty in aging

特殊长寿基因型在预防衰老过程中的衰弱中的作用

• 批准号: 8705135
• 负责人: NIR J BARZILAI
• 金额: $ 68.07万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8705135
• 关键词: Adult; Age; Aging; American; Ashkenazim; Biological; Biological Factors; Biological Markers; Blood Vessels; Buffers; CETP gene; Cardiovascular system; Centenarian; Cognitive; Data; Dementia; Development; Diagnostic; Disease; Economics; Elderly; Enrollment; Equilibrium; Family history of; Foundations; Funding; Gait; Gait abnormality; Genetic; Genotype; Goals; Health; High Density Lipoproteins; Homocysteine; Homocystine; Human; Incidence; Inherited; Insulin; Insulin-Like Growth Factor I; Interleukin-6; Intervention; Life; Link; Longevity; Low Prevalence; Low-Density Lipoproteins; Measures; Mediating; Metabolic; Morbidity - disease rate; Parents; Participant; Phenotype; Physical Function; Population Genetics; Positioning Attribute; Prevention; Preventive Intervention; Prospective Studies; Proteins; Recruitment Activity; Reporting; Research; Research Infrastructure; Risk; Role; SNP genotyping; Specific qualifier value; Study Section; Systems Biology; Testing; Thyrotropin Receptor; Trauma; United States National Institutes of Health; Validation; adiponectin; age related; base; cohort; disability; exome sequencing; follower of religion Jewish; frailty; genome wide association study; high risk; improved; insight; interdisciplinary collaboration; longevity gene; mortality; novel; offspring; prevent; prospective; public health relevance; response; social; stressor; trait

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.

描述（由申请人提供）：尽管存在大量遗传成分的证据，但构成人类寿命（长寿）的遗传生物因素仍然未知。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，以确保超常的健康长寿。在过去的 14 年里，我们招募了长寿基因计划 (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相比的保护性基因型的假设。然后，我们在 NIH 资助的第二项独立 LonGenity 研究 (P01 AG027734) 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) 存活率正常的父母的后代 (OPUS-LonGenity) ）。 LGP 和 LonGenity 队列的受试者是德系犹太人成年人 (AJ)，他们在基因和社会经济地位上都相对同质，这为基因发现提供了力量。 LonGenity 研究表明，OPEL 表型和相关的长寿基因型成功地与衰老过程中心血管、代谢和认知健康的改善相关。我们现在提议将我们的研究扩展到虚弱表型，以美国衰老研究联合会试点资助获得的令人兴奋的新初步数据为基础，该数据将特殊的长寿表型和基因型与身体功能和虚弱联系起来。 “虚弱”一词在临床上作为一个全球概念来描述老年人中常见的一种状况，即力量、耐力和平衡能力受损，容易受到创伤和其他压力源的影响，以及发病、残疾和死亡的高风险。我们的目标是在 LonGenity 研究中评估特殊的长寿特征和基因型在降低衰弱风险以及与年龄相关的重要身体功能成分（如步态、平衡和力量）下降的风险中的作用。该提案将由衰弱、步态障碍和痴呆症专家 Verghese 博士和 LonGenity 研究首席研究员、世界知名遗传学家 Barzilai 博士共同指导。提出以下三个目标。 1. 研究长寿家族史对于降低衰老过程中身体衰退和虚弱风险的作用。 2. 确定长寿相关遗传因素在降低衰老过程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（已确定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）对超长寿命和衰老过程中身体机能纵向变化之间关系的影响。我们的新项目以 LonGenity 研究奠定的研究基础设施、强大的跨学科合作、独特的种群、遗传发现和科学基础为基础。如果可以证明不同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预防虚弱和身体功能下降的干预措施，这些干预措施可能会提供超出目前公认​​的疾病治疗所带来的额外益处。