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

项目总结 随着老龄化人口的快速增长，与老龄化相关的发病率也相应快速增加 疾病。然而，并不是每个人都同时成为与衰老相关的疾病的受害者--有大量的 老年性疾病发病年龄和进展的变异性。有证据表明，这种变异的一部分 与社会逆境有关，如社会经济地位低下和社会孤立。但确切地说是如何 改变老龄化速度的社会逆境仍然难以捉摸。这方面的进展滞后 因为需要在整个生命周期内对个人实现的生物年龄进行全面的描绘 多个领域和器官系统，这一壮举在人类很大程度上是不可行的。一个合适的动物模型，这样一个非 人类需要灵长类，因为在社会行为和衰老方面的自然变化与人类的 人类，并可以在不同的组织和领域的衰老的寿命跟踪。 这项建议的目标是建立一个生物学模型，说明社会对自然老龄化的贡献。 非人灵长类动物的数量。为了做到这一点，它利用了对自由生活的恒河猴种群的长期研究 猕猴。这些动物为探索衰老及其社会决定因素提供了一个无与伦比的机会 大量的种群生活在自然主义的环境中，因为他们与人类在进化上很接近， 社会逆境的同源自然标志，包括社会孤立和低社会地位，由 优势等级低，寿命相当短(3-4倍)。这个项目测试了这样一个假设，即社会 逆境加速了多种组织类型和三个中心衰老领域的生物衰老：(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 构成)，以及(Iii)身体(例如，脆弱，包括关节活动和身体状况)。 该项目的目标1旨在通过以下方式生成跨域和系统的全面老化配置文件 这一方法是：(A)横截面跨组织类型和(B)纵向跨个体寿命。通过 通过跟踪不同组织类型和寿命的老化情况，我们还将找出老化变化的可修改来源 因为确定了可改变的衰老区域的时间和性别特异性。目标2借鉴了详细的社交网络 测试社会逆境如何以及在哪些领域加速衰老的表型。 这个项目将对衰老生物学中的两个主要问题提供变革性的见解。首先，它将产生 使用自然灵长类动物模型研究衰老的分子、免疫学和物理特征的有价值的数据 对人类衰老有好处。第二，它将揭示社会环境如何改变老龄化的速度，这将告诉 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 我们老龄化人口中的疾病。

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.