Contextual modifiers of healthspan, lifespan, and epigenome in mice under chronic social stress.
Contextual modifiers of healthspan, lifespan, and epigenome in mice under chronic social stress.
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DOI：
10.1073/pnas.2211755120
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发表时间：
2023-04-18
影响因子：
11.1
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中科院分区：
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对于暴露在慢性心理社会压力下的个人为什么会有更高的疾病风险和更低的存活率，人们的理解有限。这一领域的动物模型研究仍然有限。我们报告了迄今为止规模最大的关于终身社会压力对多个小鼠实验室品系的健康寿命、衰老相关疾病、表观基因组和寿命的影响的研究。低社会地位通常对人的一生不利，尽管特定社会地位的代价因压力而异。这些结果与通过肝脏DNA甲基化评估的相应表观遗传学变化有关。总体而言，我们的工作提供了生物学基础和临床前模型，以研究健康差距和加速老龄化的社会决定因素的影响。持续的生活压力和较低的社会经济地位是与老龄化有关的疾病和预期寿命下降的主要原因。实验性啮齿动物模型可以帮助确定潜在的机制，但很少有研究解决社会压力对衰老的长期后果。我们进行了一项随机研究，涉及300多只雄性小鼠，它们是常用的实验室品系(C57BL/6J、CD1和Sv129Ev)，被选为自发攻击梯度和应激脆弱性。小鼠被暴露在终身慢性心理社会应激方案中，以模拟衰老和疾病脆弱性的社会梯度。在我们的研究人群中，根据离散化的攻击性指数推断的低社会等级被发现对寿命有负面影响。然而，在低级别C57BL/6J、高级别Sv129Ev和中等级别CD1小鼠中，社会地位与遗传背景相互作用，分别具有较低的存活率，这意味着维持给定社会地位的成本因品系而异。机器学习线性判别分析发现，在当前数据集中，基线脱脂质量是小鼠遗传背景和社会排名的最重要预测因素。最后，品系和社会等级的差异与表观遗传学变化显著相关，在Sv129Ev小鼠中最显著，与排名较低的受试者相比，在高排名的受试者中最显著。总体而言，我们在一个与社会应激的行为学相关的啮齿动物模型中，将遗传背景和社会等级确定为影响衰老和寿命的关键背景因素，从而提供了一个临床前实验范式，以研究健康差异和加速老龄化的社会决定因素的影响。
There is limited understanding as to why individuals exposed to chronic psychosocial stress have a higher disease risk and lower survival. Research in animal models in this area is still limited. We report the largest study yet on the impact of lifelong social stress on healthspan, aging-associated diseases, epigenome, and lifespan in multiple mouse laboratory strains. Low social status was generally adverse for lifespan, although the cost of a given social rank varied across strains. These results were associated with corresponding epigenetic changes assessed via DNA methylation in the liver. Overall, our work provides a biological base and a preclinical model, to study the impact of social determinants of health disparities and accelerated aging. Sustained life stress and low socioeconomic status are among the major causes of aging-related diseases and decreased life expectancy. Experimental rodent models can help to identify the underlying mechanisms, yet very few studies address the long-term consequences of social stress on aging. We conducted a randomized study involving more than 300 male mice of commonly used laboratory strains (C57BL/6J, CD1, and Sv129Ev) chosen for the spontaneous aggression gradient and stress-vulnerability. Mice were exposed to a lifelong chronic psychosocial stress protocol to model social gradients in aging and disease vulnerability. Low social rank, inferred based on a discretized aggression index, was found to negatively impact lifespan in our study population. However, social rank interacted with genetic background in that low-ranking C57BL/6J, high-ranking Sv129Ev, and middle-ranking CD1 mice had lower survival, respectively, implying a cost of maintaining a given social rank that varies across strains. Machine learning linear discriminant analysis identified baseline fat-free mass as the most important predictor of mouse genetic background and social rank in the present dataset. Finally, strain and social rank differences were significantly associated with epigenetic changes, most significantly in Sv129Ev mice and in high-ranking compared to lower ranking subjects. Overall, we identified genetic background and social rank as critical contextual modifiers of aging and lifespan in an ethologically relevant rodent model of social stress, thereby providing a preclinical experimental paradigm to study the impact of social determinants of health disparities and accelerated aging.
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