Mouse models for the influence of the social environment on health and aging

社会环境对健康和衰老影响的小鼠模型

• 批准号: 10512895
• 负责人: Alessandro Bartolomucci
• 金额: $ 31.13万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10512895
• 关键词: Address; Affect; Age; Aging; Algorithms; Animals; Assessment tool; Behavior; Behavioral; Biological; Biological Models; Cell Aging; Cessation of life; Cognitive; DNA Methylation; Data; Development; Disease; Early Intervention; Energy Metabolism; Epigenetic Process; Etiology; Experimental Designs; Female; Future; Genetic; Goals; Health; Human; Impairment; Individual; Intervention; Knowledge; Laboratories; Laboratory mice; Link; Longevity; Mammals; Measures; Modeling; Molecular; Mus; Natural History; Onset of illness; Pathogenicity; Phase; Physical Function; Physiological; Physiology; Prevalence; Process; Randomized; Research; Role; Shapes; Social Behavior; Social Environment; Social Functioning; Social Gradients; Social Interaction; Social Processes; Social isolation; Social support; Socioeconomic Status; Testing; Therapeutic; Time; Translating; base; burden of illness; comparative; design; doubly-labeled water; environmental enrichment for laboratory animals; flexibility; frailty; functional disability; genetic manipulation; healthspan; human old age (65+); improved; indexing; individual variation; innovation; insight; low socioeconomic status; male; mortality; mouse model; neglect; novel; predictive modeling; prevent; resilience; social; social adversity; social deprivation; social factors; social health determinants; social influence; social integration; social stress; therapy design; unethical

Summary A social gradient in health and aging is well established in humans; the greater the social connectedness and socioeconomic status (SES), the lower the burden of a plethora of diseases and mortality rate. Consistently, lack of social support and low SES are among the major negative determinants of health, increasing the prevalence and/or anticipating the onset of diseases. Unfortunately, diseases often only manifest at old age when therapeutic options and biological flexibility are limited. Additionally, the causal role of social context on aging is difficult to ascertain, requiring an experimental design in which social factors can be randomized to infer causation, which is unethical and often not feasible in humans. The evolutionary conserved role of social determinants of health and aging (SDoHA) and the ability to conduct randomized experimental designs in social mammals, offer the opportunity to reverse-translate observations made in humans to other animals. In particular, the use of laboratory mice has several advantages to study the effect of social factors on aging, including: their comparatively short lifespan when compared to other mammals enabling the completion of longevity studies in a reasonable timeframe; the ability to conduct intent-to-treat randomization designs of socio-behavioral variables; they are amenable to sophisticated genetic manipulations. However, the role of SDoHA is often neglected in biomedical aging research using mice, thus missing critical components of human aging. The objectives of this project are to: (i) develop rigorous socio-behavioral models suitable for aging studies in male and female mice; (ii) develop innovative assessment tools and a “comprehensive aging index” summarizing the global impairment in behavior, physical functions and physiology, and a that can predict functional impairment and longevity, (iii) identify social factors affecting individual variability in aging processes, and finally (iv) identify socio-behavioral intervention strategies to increase resilience. The R61 – development, proof-of-concept phase has 2 Aims. Aim 1 will identify social factors affecting the pace of aging by using a randomized design that manipulates social connectedness, social stability and social stress. We will also develop quantitative assessment tools relevant for aging research. Aim 2 will develop a “comprehensive aging index”, an algorithm which is based on quantifiable behavioral, physical and physiological changes over the lifecourse. The R33 – implementation phase has 2 Aims. Aim 3 will determine whether social rank, social instability and/or social deprivation affect lifespan in male and female mice and will implement the algorithm to predict longevity based on data collected during the lifecourse. Aim 4 will implement behavioral strategies designed to increase resilience, including social rank reversal, social integration and cognitive stimulation/environmental enrichment. At its completion, this project will develop novel experimental paradigms and assessment tools with far reaching impact to the field. It will also generate an unprecedented new knowledge on how social factors affect health trajectories and aging, and which aging process is amenable to intervention versus those that are not amenable to intervention.

概括 人类在健康和老龄化方面存在明显的社会梯度；社会联系越大， 社会经济地位（SES）越低，过多疾病的负担和死亡率就越低。始终如一，缺乏 社会支持不足和社会经济地位低是健康的主要负面决定因素，增加了患病率 和/或预测疾病的发作。不幸的是，疾病往往只有在老年时才会显现出来。 治疗选择和生物学灵活性是有限的。此外，社会背景对衰老的因果作用是 很难确定，需要一个实验设计，其中社会因素可以被随机化来推断 因果关系，这是不道德的，而且在人类中通常是不可行的。社会的进化保守作用 健康和衰老的决定因素（SDoHA）以及在社会中进行随机实验设计的能力 哺乳动物，提供了将人类观察到的结果反向翻译到其他动物的机会。尤其， 使用实验小鼠来研究社会因素对衰老的影响有几个优点，包括： 与其他哺乳动物相比，其寿命相对较短，从而能够完成长寿研究 合理的时间范围；对社会行为变量进行意向治疗随机化设计的能力； 它们能够接受复杂的基因操作。然而，SDoHA 的作用常常被忽视。 使用小鼠进行生物医学衰老研究，因此缺少人类衰老的关键组成部分。本次活动的目标 项目目标是：（i）开发适合雄性和雌性小鼠衰老研究的严格的社会行为模型； (ii) 开发创新评估工具和总结全球减值的“综合老龄化指数” 在行为、身体功能和生理学方面，以及可以预测功能损伤和寿命的，(iii) 确定影响衰老过程中个体差异的社会因素，最后（iv）确定社会行为 增强复原力的干预策略。 R61 – 开发、概念验证阶段有 2 个目标。目的 1 将通过使用操纵社会的随机设计来确定影响衰老速度的社会因素 连通性、社会稳定性和社会压力。我们还将开发相关的定量评估工具 衰老研究。目标2将开发“综合老化指数”，这是一种基于可量化的算法 生命历程中的行为、身体和生理变化。 R33 – 实施阶段有 2 个目标。 目标 3 将确定社会地位、社会不稳定和/或社会剥夺是否影响男性和女性的寿命。 雌性小鼠将实施算法，根据生命历程中收集的数据来预测寿命。 目标 4 将实施旨在提高弹性的行为策略，包括社会排名逆转、社交 整合和认知刺激/环境丰富。该项目完成后将开发出新颖的 对该领域产生深远影响的实验范式和评估工具。它还会生成一个 关于社会因素如何影响健康轨迹和衰老以及哪些衰老会产生前所未有的新知识 适合干预的过程与不适合干预的过程不同。