Developing insertable cardiac monitors to assess social and environmental effects on the autonomic stress response in a nonhuman primate model of aging

项目摘要 早期生命的漫长伸展仍然是人类健康中最持久的难题之一。从饥荒到 贫穷和忽视，不良的早期生活经历会导致更高的死亡率和肥胖风险， 糖尿病和慢性心脏病。这些效应可能在一定程度上是由应激反应、 神经内分泌、代谢和心脏反应的级联反应涉及下丘脑- 垂体-肾上腺(HPA)轴和自主神经系统。作为支持，几个主要的假说 提出，反复的社会和环境压力--无论是在早期生活还是成年--都会导致过度-- 激活应激反应，慢性应激，加速衰老。对天然动物的长期研究 人口为测试这些想法提供了令人信服的模型，因为它们通常具有细粒度、前瞻性、 来自个人整个生命过程的社会和环境应激源的纵向数据。然而， 自然动物模型在测量应激反应的多个方面也面临着相当大的挑战： 大多数人被限制在测量糖皮质激素(GC)作为应激反应的唯一衡量标准，反映 只是HPA轴的一个方面，没有关于自主反应的信息。这一限制导致许多人 呼吁扩展工具来测量自然衰老动物模型中的压力反应。 我们在这项建议中的目标是：(1)扩大心脏代谢的测量工具 通过验证可插入式心脏监测器(ICM)来验证应激在自然动物模型中的后果 用于测量心率、心率变异性和体力活动的加速计量法；以及(2)测试社交和 自主神经应激反应及其代谢后果的环境驱动因素。我们将发展和 使用肯尼亚灵长类研究所圈养的狒狒和经过充分研究的自然 在安博塞利，也是在肯尼亚，狒狒的数量。安博塞利之前的研究已经表明， 早年恶劣生活条件的积累和成年后的社会孤立对成年人产生了深刻的影响 死亡率，为探索这些联系背后的压力反应奠定了基础。而早年生活中的逆境和 社交隔离导致成年后GC升高，而GCs高的动物存活率较低 不要在早年的逆境和寿命之间牵线搭桥。获得更广阔的个人视角 压力反应及其后果是至关重要的下一步。结果将贡献第一 任何物种的前瞻性、纵向数据，以了解早期生活中的逆境和成人的社会状况 相互作用，形成急性自主应激反应、慢性应激反应和能量消耗。这项研究将 提供社会环境环境、压力反应和成人健康之间的直接联系，帮助 确定关键目标，以减轻生命过程中压力对衰老的影响。

Project Summary The long reach of early life remains one of the most enduring puzzles in human health. From famine to poverty and neglect, adverse early life experiences lead to higher mortality and elevated risk for obesity, diabetes, and chronic heart disease. These effects are likely mediated, in part, by the stress response, a cascade of neuroendocrine, metabolic, and cardiac responses to challenge involving the hypothalamic– pituitary–adrenal (HPA) axis and the autonomic nervous system. In support, several leading hypotheses propose that repeated social and environmental stressors—both in early life and adulthood—cause over- activation of the stress response, chronic stress, and accelerated aging. Long-term studies of natural animal populations offer compelling models for testing these ideas because they often have fine-grained, prospective, longitudinal data on social and environmental stressors from individuals across the life course. However, natural animal models also face considerable challenges in measuring multiple facets of the stress response: most are constrained to measuring glucocorticoids (GCs) as the sole measure of stress responses, reflecting just one aspect of the HPA axis with no information on autonomic responses. This limitation has led many to call for expanded tools to measure stress responses in natural animal models of aging. Our objectives in this proposal are to: (1) expand the tools for measuring the cardiometabolic consequences of stress in natural animal models by validating insertable cardiac monitors (ICMs) with accelerometry to measure heart rate, heart rate variability, and physical activity; and (2) test the social and environmental drivers of the autonomic stress response and its metabolic consequences. We will develop and validate ICMs using captive baboons at the Institute of Primate Research in Kenya, and a well-studied, natural population of baboons in Amboseli, also in Kenya. Prior work in Amboseli has already shown that an accumulation of harsh conditions in early life and social isolation in adulthood exert profound effects on adult mortality, setting the stage to probe the stress responses underlying these links. While early life adversity and social isolation lead to elevated GCs in adulthood, and animals with high lifelong GCs have lower survival, GCs do not mediate the link between early adversity and life span. Gaining a broader perspective on individual stress responses and their consequences is an essential next step. The results will contribute the first prospective, longitudinal data in any species to understand how early life adversity and adult social conditions interact to shape acute autonomic stress responses, chronic stress, and energy expenditure. This study will provide a direct link between socio-environmental circumstances, stress responses, and adult health, helping to identify key targets to mitigate the effects of stress over the life course on aging.