Gene regulatory analysis of social integration and resilience during aging

衰老过程中社会融合和复原力的基因调控分析

• 批准号: 9552972
• 负责人: Noah Snyder-Mackler
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-15 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9552972
• 关键词: Acute; Adult; Affect; Age; Aging; Alcoholism; American; Animal Model; Animals; Behavioral; Buffers; Chromatin; Companions; Complex; DNA Methylation; Dexamethasone; Disease; Elderly; Environment; Event; Exhibits; Female; Gap Junctions; Gene Components; Gene Expression; Gene Expression Regulation; Genetic; Genomics; Glucocorticoids; Goals; Grooming; Health; Homeostasis; Hormones; Human; In Vitro; Individual; Inflammation; Interpersonal Relations; Intervention; Knowledge; Leukocytes; Life; Link; Loneliness; Macaca; Macaca mulatta; Measurement; Measures; Mediating; Mentors; Molecular; Obesity; Pathway interactions; Pharmacology; Physiological; Play; Psychosocial Stress; Regulator Genes; Reporting; Research; Risk; Role; Scientist; Signal Transduction; Smoking; Social Behavior; Social Environment; Social support; Stress; Stress Tests; Testing; Training; Training Activity; Translational Research; Variant; acute stress; biological adaptation to stress; career; design; effective intervention; environmental intervention; experience; genome-wide; healthy aging; immune function; improved; improved outcome; in vivo; insight; mortality; practical application; predicting response; programs; psychologic; psychosocial; relating to nervous system; resilience; response; social; social integration; social stress; stress management; stress reactivity; stressor

Summary Almost half of American adults over 60 years old report being lonely, a condition that can have a major impact on health and mortality risk in later life. Adults with weak social relationships experience a 50% higher mortality rate than more socially integrated adults—an effect on par with that of smoking, obesity, or alcoholism. One explanation for this association is if better social integration increases resilience against stressful experiences, a hypothesis known as “stress buffering.” Yet despite the importance of social integration for human health, the behavioral and molecular mechanisms that mediate its potential role in stress buffering remain poorly understood, limiting its practical application to improving resilience during aging. The objective of the proposed study is to identify the genomic mechanisms that link social integration to stress sensitivity and inflammation during acute stress. If a main benefit of SI is to buffer against acute stress, I hypothesize that low levels of social integration will be associated with dysregulation of the gene regulatory response to acute stress. To test this hypothesis, I will leverage the advantages of studying rhesus macaques, a well-established animal model for human aging and social behavior. I propose a two-pronged approach that combines experimental manipulations of the social environment (Aims 1 and 3) with studies of free-ranging macaques (Aim 2), thus yielding insight into the relationship between acute stress and gene regulation in both a controlled setting and in a more natural environment. In both contexts, I will combine genome-wide gene expression, DNA methylation, and chromatin accessibility measurements to characterize the genomic pathways associated with social integration and its relationship with the acute stress response. I will also test whether these relationships are exaggerated for older animals, and whether the presence of a close social partner can enhance resilience to psychosocial stress. At its conclusion, this project will yield a detailed understanding of how social integration impacts gene regulation in pathways that become dysregulated with age and whether social support can buffer against acute stressors at the genomic level. Together, these results will advance our understanding of the mechanisms through which social integrations promotes resilience in the elderly. In addition, the proposed program of mentored training activities will allow me to develop a strong, independent research career in aging, focused on the nexus of aging, social behavior, and genomics.

总结 几乎一半的60岁以上的美国成年人报告说他们感到孤独，这种情况可能会导致严重的 影响晚年健康和死亡风险。社交关系薄弱的成年人比其他人高出50%。 死亡率高于社会融合程度更高的成年人--这一影响与吸烟、肥胖或 酒精中毒对这种联系的一种解释是，如果更好的社会融合能够提高对 压力体验，一个被称为“压力缓冲”的假设。尽管社会的重要性 整合对人类健康，行为和分子机制，介导其潜在的作用，在压力 缓冲仍然知之甚少，限制了其在老化过程中提高弹性的实际应用。 拟议研究的目的是确定将社会融合与 应激敏感性和急性应激期间的炎症。如果SI的主要好处是缓冲急性应激， 假设低水平的社会融合将与基因调控的失调有关， 急性应激反应。为了验证这个假设，我将利用研究恒河猴的优势， 这是一个成熟的人类衰老和社会行为的动物模型。我建议采取双管齐下的办法， 结合社会环境的实验操作（目标1和3）与自由放养的研究 猕猴（目的2），从而深入了解急性应激和基因调控之间的关系，在这两个 一个可控的环境和一个更自然的环境。在这两种情况下，我将联合收割机结合全基因组基因 表达，DNA甲基化和染色质可及性测量，以表征基因组 与社会融合相关的途径及其与急性应激反应的关系。我还将测试 这些关系是否被夸大了老年动物，以及是否存在密切的社会关系， 可以增强对心理压力的适应力。 在其结论，这个项目将产生一个详细的了解如何社会融合影响基因 随着年龄的增长，调节途径变得失调，以及社会支持是否可以缓冲急性 基因组水平的压力源。总之，这些结果将促进我们对这些机制的理解。 通过社会融合促进老年人的复原力。此外，拟议方案 有指导的培训活动将使我能够在老龄化方面发展一个强大的，独立的研究事业， 老龄化、社会行为和基因组学之间的联系。