Generating new knowledge to support reversibility interventions

 描述(由申请人提供)：本申请响应了一项关于“早期确立的生物行为风险因素的中年可逆性”(RFA-AG-14-006)的研究。人口老龄化增加了与年龄相关的疾病的公共卫生负担，如心血管疾病、2型糖尿病和痴呆症。现在已经知道，这种与年龄相关的疾病的发病机制涉及器官系统逐渐积累的损害，从生命的前半部分开始，特别是在接触早期不良反应的人中。人们还知道，年龄相关的疾病和早期死亡是早期生活中各种不利经历的先兆。尽管这些事实表明，及早预防是必要的 生活中的逆境，逆境是无法完全预防的(对于婴儿潮一代来说，要预防早年的逆境已经太晚了)。因此，人们对针对中年成年人的干预越来越感兴趣，以扭转早年逆境造成的损害。这一兴趣赋予了从童年到中年跟踪队列的现有研究新的科学意义，因为它们可以提供证据基础，以提供信息并加快新干预策略的发展。RFA呼吁进行这样的研究。我们建议在NIA资助的达尼丁多学科健康与发展研究中进行数据分析，这是一项关于问题和积极的终身发展过程的纵向出生队列研究。我们的数据资源包括出生时、3岁、5岁、7岁、9岁、11岁、13岁、15岁、18岁、21岁、26岁、32岁以及最近38岁的临床评估，在队列进入中年时保留了95%。这些数据结合了人口/经济调查、临床质量健康评估、生物库、全基因组SNP数据以及行政-记录联系。首先，我们将产生结果指标，以检测一般人群在中年早期器官系统生物标记物下降的个体差异，这一阶段将应用未来的可逆性干预。其次，我们将比较对早期逆境的回顾和前瞻性测量的表现。未来的可逆性干预将不得不依赖于中年参与者对逆境的回顾报告，因此有必要知道这一过程进行得有多顺利 去工作。第三，我们将测试早年逆境和中年老龄化之间的联系与多基因遗传风险和与年龄相关疾病的家族史之间的关系。基因或家族史是否会影响对可逆性干预的反应性？第四，我们将确定潜在的可逆的行为和社会因素，这些因素中介了早期生活中的逆境和中年生物衰老之间的联系。预计研究结果将支持未来中年干预措施的随机临床试验设计，旨在逆转早年逆境的影响，预防与年龄相关的疾病，并提高晚年的幸福感。

 DESCRIPTION (provided by applicant): This application responds to a call for research on the "mid-life reversibility of early-established bio-behavioral risk factors" (RFA-AG-14-006). Population aging increases the public-health burden of age-related conditions, such as cardiovascular disease, type 2 diabetes, and dementia. It is now known that the pathogenesis of such age- related diseases involves gradually accumulating damage to organ systems, beginning in the first half of the life course, particularly in people exposed to early-life adversty. It is also known that age-related diseases and early mortality are portended by a variety of adverse experiences in early life. Although these facts imply that it is desirable to prevent early life adversities, adversity cannot be fully prevented (and it is too late to prevent early- life adversity for the baby-boomer generation). Therefore there is growing interest in interventions for midlife adults, to reverse the damage done by early-life adversity. This interest lends new scientific significance to existing studies that have followed cohorts from childhood to midlife, because they can provide an evidence base to inform and speed the development of novel intervention strategies. The RFA extends a call for such studies. We propose to undertake data analyses in one such study, the NIA-funded Dunedin Multidisciplinary Health & Development Study, a longitudinal birth-cohort study of both problematic and positive processes of lifelong development. Our data resource comprises in-clinic assessments at birth and ages 3, 5, 7, 9, 11, 13, 15, 18, 21, 26, 32, and most recently 38 years, with 95% retention as the cohort enters midlife. The data combine demographic/economic surveys, clinical-quality health assessments, a bio-bank, genome-wide SNP data, and administrative-record linkage. First, we will generate outcome measures to detect individual differences in decline of biomarkers for organ systems in the general population at early midlife, the stage when future reversibility interventions will be applied. Second, we will compare the performance of retrospective versus prospective measures of early-life adversity. Future reversibility interventions will have to rely on midlife participants' retrospective reports of adversity, so there is a need to know how well this is going to work. Third, we will test how the connection between early-life adversity and midlife aging relates to polygenic genetic risk and family history of age-related diseases. Will genotype or family history influence responsiveness to reversibility interventions? Fourth, we will identify potentially reversible behavioral and social factors that mediate the connection from early-life adversity to midlife biological aging. Findings are expected to support the design of future randomized clinical trials of midlife interventions intended to reverse the effects of early-life adversity, prevent age-related diseases, and enhance wellbeing in late life.