Social Stress Leaves a Mark: Accelerated Brain Aging and Neuronal Senescence

A recent study published in Nature Aging, that was coordinated by Prof. Alessandro Bartolomucci member of Our Stress Network, reveals that chronic social stress can accelerate aging at the cellular level, particularly in the brain. Using preclinical mouse models, researchers exposed animals to two stress paradigms: chronic social subordination (involving exposure to aggression from dominant peers) and psychological restraint (a non-social stressor involving restricted movement). Remarkably, only social stress led to a significant accumulation of senescent cells, especially in neurons within the hippocampus and cortex—brain areas critical for memory, learning, and emotional regulation.

Senescent cells are damaged cells that stop dividing and secrete inflammatory molecules, contributing to chronic inflammation, tissue degeneration, and age-related diseases such as Alzheimer’s. Unexpectedly, the researchers found that neurons—cells typically considered post-mitotic—were the main targets of stress-induced senescence, as opposed to proliferative cells like microglia or astrocytes.

Social stress also increased markers of DNA damage and elevated expression of the protein p16, a key regulator of cellular aging. These effects were not limited to the brain: peripheral tissues such as blood and adipose tissue also showed increased signs of senescence, indicating widespread systemic impact.

To test possible interventions, the researchers used a genetically engineered mouse model that selectively eliminates p16-expressing cells. While this approach reduced DNA damage and inflammation markers, it did not reverse behavioral or physiological effects of stress, at least up to mid-life. This suggests that other types of senescent cells may be involved, or that some senescent cells might play protective roles under stress conditions.

This study provides significant insight into how chronic social stress can "get under the skin" and biologically accelerate aging. It highlights the importance of the social environment in shaping long-term health and opens new avenues for research into therapeutic strategies targeting stress-induced senescence and age-related diseases.

Lyons, C. E., Pallais, J. P., McGonigle, S., Mansk, R. P., Collinge, C. W.,  Yousefzadeh, M. J., Baker, D. J., Schrank, P. R., Williams, J. W., Niedernhofer, L. J., van Deursen, J. M., Razzoli, M., & Bartolomucci, A. (2025). Chronic social stress induces p16-mediated senescent cell accumulation in mice. Nature aging, 5(1), 48–64. https://doi.org/10.1038/s43587-024-00743-8

DOI: 10.21203/rs.3.rs-4004473/v1