Generating new knowledge to support reversability interventions

该提案响应了关于“早期生物行为风险因素的中年可逆性”研究的呼吁（RFA-AG-14-006）。人口老龄化增加了与年龄有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。现在已知，这种与年龄有关的疾病的发病机制涉及器官系统的逐渐累积损伤，从生命历程的前半期开始，特别是在暴露于早期生活逆境的人中。人们还知道，与年龄有关的疾病和过早死亡是由早年生活中的各种不利经历预示的。尽管这些事实表明，预防早期生活中的逆境是可取的，但逆境不能完全预防（而要预防婴儿潮一代的早期生活中的逆境也为时已晚）。因此，人们对中年人的干预越来越感兴趣，以扭转早年逆境造成的损害。这种兴趣为现有的研究提供了新的科学意义，这些研究从童年到中年一直跟踪队列，因为它们可以提供证据基础，为新的干预策略的开发提供信息和加速。RFA呼吁进行此类研究。我们建议在一项这样的研究中进行数据分析，即由美国国立卫生研究院资助的达尼丁多学科健康与发展研究，这是一项关于终身发展的问题和积极过程的纵向出生队列研究。我们的数据资源包括出生时和年龄为3、5、7、9、11、13、15、18、21、26、32以及最近38岁时的临床评估，随着队列进入中年，保留率为95%。这些数据结合了联合收割机人口/经济调查、临床质量健康评估、生物库、全基因组SNP数据和管理记录联系。首先，我们将产生结果的措施，以检测个体差异在一般人群中器官系统的生物标志物下降在中年早期，当未来的可逆性干预措施将被应用的阶段。其次，我们将比较早期生活逆境的回顾性和前瞻性措施的表现。未来的可逆性干预措施将不得不依赖于中年参与者对逆境的回顾性报告，因此有必要知道这将如何发挥作用。第三，我们将测试早期生活逆境和中年衰老之间的联系如何与多基因遗传风险和年龄相关疾病的家族史相关。基因型或家族史会影响可逆性干预的反应吗？第四，我们将确定潜在的可逆的行为和社会因素，介导从早期生活逆境到中年生物衰老的联系。研究结果预计将支持未来中年干预措施的随机临床试验设计，旨在扭转早期生活逆境的影响，预防年龄相关疾病，并提高晚年的幸福感。

This proposal 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 adversity. 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 indecline 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.