Social modifiers of the pace of aging across multiple domains and tissues

项目摘要 随着人口老龄化的迅速增长，与老龄化有关的发病率也相应迅速增加。 疾病然而，并不是每个福尔斯人都同时成为与衰老有关的疾病的受害者-- 发病年龄的变化和衰老疾病的进展。有证据表明，这种变化的一部分， 与社会逆境有关，如社会经济地位低和社会孤立。但究竟是如何 社会逆境“深入皮肤”以改变衰老的速度仍然难以捉摸。这方面的进展滞后 因为在整个生命周期中，需要对个人实现的生物学年龄进行全面的描述， 多个领域和器官系统，这在人类中基本上是不可行的。合适的动物模型，例如非- 在社会行为和衰老的自然变异与人类灵长类动物的自然变异同源的地方， 人类，并且可以在不同组织和老化领域的整个生命周期中进行跟踪。 这项建议的目的是建立一个自然衰老的社会贡献的生物学模型， 非人类灵长类动物的种群。为此，它借鉴了对自由生活的恒河猴种群的长期研究 猕猴这些动物提供了一个无与伦比的机会，以探索衰老及其社会决定因素， 由于它们与人类的亲缘关系， 社会逆境的同源自然标志，包括社会孤立和社会地位低下， 统治地位低，寿命相当短（3- 4倍）。这个项目测试了社会 逆境加速了多种组织类型的生物老化，并在三个中心老化领域：（i） 分子（例如，DNA甲基化和端粒磨损），（ii）免疫学（例如，炎症和白细胞 组合物），和（iii）物理的（例如，虚弱，包括关节活动性和身体状况）。 该项目的目标1旨在通过采取一个 方法是：（a）跨组织类型的横截面和（B）个体寿命的纵向。通过 通过跟踪组织类型和寿命的衰老，我们还将查明衰老变异的可修改来源， 建立可改变的衰老领域的时间和性别特异性。目标2借鉴了详细的社会 表型来测试社会逆境如何以及在哪些领域加速衰老。 该项目将为衰老生物学中的两个主要问题提供变革性的见解。首先，它会产生 使用自然灵长类动物模型获得的关于衰老的分子、免疫学和物理特征的有价值的数据 for human人的aging老化.第二，它将揭示社会环境如何改变老龄化的速度，这将为老年人提供信息。 有针对性地制定社会和生理干预措施，以减轻与老龄化有关的负担 疾病在我们的老龄化人口。

PROJECT SUMMARY With a rapidly growing aging population comes a correspondingly rapid increase in the incidence of aging-related diseases. However, not everyone falls victim to aging-related diseases at the same time – there is substantial variability in the age at onset and progression of diseases of aging. Evidence suggests that part of this variation is associated with social adversity, such as low socioeconomic status and social isolation. But precisely how social adversity “gets under the skin” to alter the pace of aging remains elusive. Progress on this front lags because comprehensive portraits of individuals’ realized biological age are required across the lifespan in multiple domains and organ systems, a feat largely unfeasible in humans. A suitable animal model, such a non- human primate, is needed where natural variation in both social behavior and aging are homologous to that in humans, and can be tracked across the lifespan in different tissues and domains of aging. The objective of this proposal is to develop a biological model of the social contributions to aging in a natural population of nonhuman primates. To do so, it draws on a long-term study of a free-living population of rhesus macaques. These animals present an unparalleled opportunity to probe aging and its social determinants in a large population living in naturalistic circumstances because of their phylogenetic proximity to humans, homologous natural markers of social adversity, including social isolation and low social status represented by low dominance rank, and considerably shorter (3-4x) lifespans. This project tests the hypothesis that social adversity accelerates biological aging across multiple tissue types and in three central aging domains: (i) molecular (e.g., DNA methylation and telomere attrition), (ii) immunological (e.g., inflammation and leukocyte composition), and (iii) physical (e.g., frailty, including joint mobility and body condition). Aim 1 of this project aims to generate comprehensive aging profiles across domains and systems by taking an approach that is: (a) cross-sectional across tissue types and (b) longitudinal over individuals’ lifespans. By tracking aging across tissue types and the lifespan, we will pinpoint modifiable sources of aging variation, as well as establish the timing and sex-specificity of modifiable aging domains. Aim 2 draws on detailed social phenotypes to test how, and in what domains, social adversity accelerates aging. This project will lend transformative insights into two major issues in the biology of aging. First, it will generate valuable data on molecular, immunological and physical signatures of aging using a naturalistic primate model for human aging. Second, it will reveal how the social environment alters the pace of aging, which will inform the targeted development of social and physiological interventions that could reduce the burden of aging-related disease in our aging population.