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 早期生命的长期影响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导致死亡率上升和肥胖风险增加， 糖尿病和慢性心脏病。这些影响可能是介导的，部分，由压力反应， 涉及下丘脑的神经内分泌、代谢和心脏对激发的级联反应- 垂体-肾上腺（HPA）轴和自主神经系统。为了支持这一观点， 提出，反复的社会和环境压力-无论是在早期生活和成年-造成过度- 应激反应的激活、慢性应激和加速衰老。长期研究自然动物 人口提供了令人信服的模型来测试这些想法，因为他们往往有细粒度的，前瞻性的， 关于个人整个生命过程中社会和环境压力的纵向数据。但是，在这方面， 自然动物模型在测量压力反应的多个方面方面也面临相当大的挑战： 大多数人局限于测量糖皮质激素（GC）作为压力反应的唯一衡量标准， 只是HPA轴的一个方面，没有关于自主反应的信息。这种限制导致许多人 呼吁扩大工具，以衡量自然动物模型的老化压力反应。 我们在这项提案中的目标是：（1）扩大测量心脏代谢的工具， 通过验证可插入心脏监测器（ICM）， 加速度计，以测量心率、心率变异性和身体活动;以及（2）测试社交和 自主应激反应的环境驱动因素及其代谢后果。创新和 在肯尼亚灵长类动物研究所使用圈养狒狒验证ICMs，以及一个经过充分研究的自然 肯尼亚安博塞利的狒狒种群。先前在安博塞利的工作已经表明， 早年生活中的艰苦条件和成年后的社会孤立对成年人产生了深远的影响。 死亡率，为探索这些联系背后的压力反应奠定了基础。虽然早年生活中的逆境和 社会隔离导致成年期GC升高，终身GC高动物的存活率较低，GC 并不能调节早期逆境和寿命之间的联系。从更广阔的视角看待个人 压力反应及其后果是下一个重要步骤。结果将有助于第一个 任何物种的前瞻性纵向数据，以了解早期生活逆境和成年社会条件 相互作用形成急性自主应激反应、慢性应激和能量消耗。本研究将 在社会环境、压力反应和成人健康之间建立直接联系， 确定主要目标，以减轻压力对衰老的影响。

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.