Midlife Aging in the Dunedin Study Phase 52

我们研究计划的首要目标是发现为什么一些人比其他人衰老得更早、更快，以及可以做些什么来防止这种情况。越来越多地，具有预防意识的老年学家和老年学家将中年视为生命阶段，为预防或推迟缩短老年人健康寿命的多种疾病提供了有利的机会。但是，由于大多数关于衰老的研究都招募了早已过了中年的参与者，而且大多数针对年轻人的研究都没有将衰老衡量为随着时间的推移而发生变化的过程，因此令人惊讶的是，关于中年期间衰老的基本知识很少。我们的研究项目独一无二地填补了这一空白。这是一项建议，在52岁时跟踪调查一年内在一个城市出生的1037名婴儿的队列，并从那以后对其进行详尽的研究：新西兰的达尼丁纵向研究。在步入中年的过程中，队列中的一些成员在生理上变得比同龄人更老，而另一些人在生理上仍然年轻。拟议的后续行动将使我们能够量化每个队列成员在8个不同领域的衰老速度或速度：生物老化、功能老化、面部老化、社会老化、性老化、炎症性老化、微血管老化和认知老化(目标1)。这8个领域通常是由不同的科学学科在竖井中研究的，但我们将在一个队列中一起研究它们，以吸引科学认识到整个人的衰老经历中的巨大异质性。我们将开发8种老化中的每一种的测量方法，通过对每种类型的3波或更多波数据进行建模。要将每个人的下降(与年龄相关的下降，人们的变化；他们的斜率)与他们的水平(最初的健康状况，人们从哪里开始；他们的截获)区分开来，至少需要三个数据波。少于3波的研究将多年来(老龄化)的下降与早年(而不是衰老)以来的低得分混为一谈。建议在52岁时进行的随访是必要的，以增加这群参与者的基本第三次中年浪潮。这一后续行动将创建史无前例的独特数据集。我们将进一步产生关于每种衰老的早期生活先兆的新知识(目标2)。我们还将产生关于8种老龄化对老年痴呆疾病的风险的新知识(目标3)。这涉及到检验一个假设，即快速老龄化的个体表现出加速的大脑衰老。这一点将在52岁时通过第二波神经成像得到证实。我们之前对45岁的达尼丁参与者的大脑进行了成像。我们将测试7年来功能神经连通性的变化和脑结构的临床测量，同时校正测量误差。它还涉及检验一种假设，即快速老龄化的人在52岁时血浆阿尔茨海默氏病生物标记物的得分较高。为了扩大科学进步，我们将向研究界提供一个可靠、有效、开放访问的DNA甲基化版本，其中每一个都是衡量一个人衰老速度的8个新指标(目标4)。为了评估未被充分代表的种族血统群体的研究结果的概括性，我们将把8项新的DNA甲基化措施输出到有甲基化的黑人、西班牙裔和亚洲队列，在这些人群中，我们已经建立了研究老龄化速度的合作。

The overarching goal of our research program is to discover why some people age earlier and faster than others, and what might be done to prevent this. Increasingly, prevention-minded gerontologists and geroscientists look to midlife as the life stage offering a propitious opportunity to prevent or delay the multiple diseases that shrink older adults' health span. But because most studies of aging have enrolled participants well past midlife, and most studies of younger adults have not measured aging as a process of change over time, there is surprisingly little basic knowledge about aging during midlife. Our research program uniquely fills this gap. This is a proposal to follow up at age 52 a cohort of all 1037 infants born in one city in one year and exhaustively studied ever since: the Dunedin Longitudinal Study, in New Zealand. Some cohort members are becoming biologically older than their peers as they pass through midlife, others remain biologically younger. The proposed follow-up will allow us to quantify how fast or slowly each cohort member is aging in each of 8 different domains: the pace of biological aging, functional aging, facial aging, social aging, sexual aging, inflammatory aging, microvascular aging, and cognitive aging (Objective 1). These 8 domains are typically studied by different scientific disciplines in silos, but we will study them together in one cohort to attract scientific recognition to the great heterogeneity within the whole-person experience of aging. We will develop a measure of each of the 8 kinds of aging, by modelling 3 or more waves of data on each. Three data waves are the minimum requirement to disentangle each person's decline (aging-related decline, how people have changed; their slope) from their level (initial health, where people started; their intercept). Studies with fewer than 3 waves conflate decline over the years (aging) with low scores present since earlier life (not aging). The proposed follow-up at age 52 is necessary to add the essential 3rd midlife wave for this cohort of participants. This follow-up will create an unprecedented unique dataset. We will further generate new knowledge about the early-life antecedents of each kind of aging (Objective 2). We will also generate new knowledge about the risk each of the 8 kinds of aging poses for late-life dementing disease (Objective 3). This involves testing the hypothesis that fast-aging individuals exhibit accelerated brain aging. This will be established through a second wave of neuroimaging at age 52. We previously imaged the brains of Dunedin participants at age 45. We will test 7-year changes in functional neural connectivity and clinical measures of brain structure, while correcting for measurement error. It also involves testing the hypothesis that fast-aging individuals have elevated scores at age 52 on plasma Alzheimers disease biomarkers. To amplify scientific progress, we will deliver to the research community a reliable, valid, open-access DNA-methylation version of each of the 8 new measures of how rapidly a person has been aging (Objective 4). To evaluate generalizability of findings for under-represented ethnic-ancestry groups, we will export the 8 new DNA-methylation measures to Black, Hispanic, and Asian cohorts with methylation, where we have established collaborations to study the pace of aging.