Abstract
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.
Original language | English (US) |
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Article number | e2211755120 |
Journal | Proceedings of the National Academy of Sciences of the United States of America |
Volume | 120 |
Issue number | 16 |
DOIs | |
State | Published - Apr 18 2023 |
Bibliographical note
Funding Information:ACKNOWLEDGMENTS. Supported by NIH/NIA R01AG043972, R61 AG078520, Minnesota partnership for Biotechnology and Molecular Genomic #18.4, Fesler-Lampert Chair in Aging Studies and Department of Integrative Biology and Physiology, University of Minnesota, Grant Accelerator Program, to A.B. We wish to thank J. Tung and R. Campbell for statistical advice on an earlier version of the manuscript, W. Zhou for invaluable advice on Sensible Step-wise Analysis of DNA Methylation (SeSAMe) use and methylation data handling, C. Erickson, J. McCallum, N. Spielman, R. Mansk and S. McGonigle for their help with the study, and the staff of the Research Animal Resources at the University of Minnesota for animal care. We also acknowledge the support of the University of Minnesota Genomics Center (SCR_012413) and the Minnesota Supercomputing Institute.
Publisher Copyright:
Copyright © 2023 the Author(s). Published by PNAS. This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
Keywords
- aging
- epigenetic
- social determinants of health
- social status
- strain differences
PubMed: MeSH publication types
- Journal Article
- Research Support, Non-U.S. Gov't
- Research Support, N.I.H., Extramural