A recent study in Nature Aging sheds light on how social stress accelerates the aging process at a cellular level. Researchers found that chronic social stress causes neurons in key brain regions to exhibit signs of senescence—a state where cells stop dividing and secrete inflammatory signals linked to aging-related diseases. This discovery adds to our understanding of how stress in the social environment might influence long-term health and the aging process.
The connection between life stress and health outcomes has long been established. Chronic stress can increase the risk of a range of aging-related diseases, including Alzheimer’s disease, cardiovascular problems, and type 2 diabetes. Yet, the mechanisms by which stress accelerates biological aging remain poorly understood.
The researchers aimed to address this gap by focusing on whether chronic social stress could trigger cellular senescence. While cellular senescence can serve protective functions, such as aiding in wound healing, its accumulation is linked to inflammation, tissue degradation, and diseases of aging.
“This research was inspired by a significant amount of work proving that life stress, social determinants, and low socio-economic status in particular, adversely affect health and accelerate aging in humans. However, the causal mechanisms are largely unknown and almost impossible to identify in humans,” said senior author Alessandro Bartolomucci, a professor and Ancel Keys Biomedical Scholar in Physiology and Metabolism at the University of Minnesota Medical School.
“One area of great interest to us was the possibility that life stress could accelerate aging by causing the accumulation of senescent cells. Senescent cells are known to adversely affect several aging-associated diseases, from atherosclerosis to Alzheimer’s and many others.”
The research team used preclinical models, specifically mice, to investigate the role of stress on senescent cells accumulation. Two distinct stress paradigms were used: social subordination stress, where subordinate mice were exposed to aggression from dominant mice, and psychological restraint stress, which limited the animals’ movement without a social component. Both stressors were administered over four weeks.
“My lab has worked for years on the development of mouse models of chronic stress, trying to determine how social versus psychological stressors can affect health and aging,” Bartolomucci explained. “Previous work found that social stressors—chronic social subordination in particular—adversely impact healthspan, cause several aging-associated diseases, and shorten lifespan. This chronic social subordination stress model can recapitulate certain aspects of the adverse impact of low socio-economic status on health.”
In their new study, the researchers found that social subordination stress led to the accumulation of senescent cells in key brain regions. Specifically, neurons in the hippocampus and cortex exhibited markers of senescence, including the expression of p16, a protein associated with cell cycle arrest and inflammatory signaling.
“One of the major surprises was that neurons—and not other cells like microglia or astrocytes (cells that divide and proliferate)—are the major, if not the only, target of stress-induced senescence,” Bartolomucci told PsyPost.
The researchers noted a stark difference between the effects of social stress and those of psychological restraint stress. While both stress models activated the body’s stress responses, only social stress consistently led to the accumulation of senescent cells in neurons. Compared to social stress, restraint stress resulted in fewer signs of senescence and appeared less impactful in terms of long-term biological consequences.
“Exposing mice to a psychological, non-social stress model increased in the brain only a small putative subpopulation of senescent cells—still ill-identified—showing an increased marker known as p21 but independent from p16,” Bartolomucci explained.
Another significant observation was that the DNA damage response seemed to be a primary driver of stress-induced senescence. In mice exposed to chronic social stress, the researchers found elevated levels of DNA damage markers. This damage likely triggers the cellular machinery responsible for activation of a senescence fate.
A particularly striking finding was the regional specificity of stress-induced senescence within the brain. Senescent cells were concentrated in the hippocampus and cortex but not in other brain regions typically associated with stress regulation, such as the hypothalamus or the amygdala. This suggests that chronic social stress impacts regions targeted by stress mediators rather than those responsible for initiating the stress response.
Interestingly, the researchers also discovered that the effects of chronic social stress on senescence were not limited to the brain. Peripheral tissues, including blood cells and adipose tissue, also exhibited increased markers of senescence. This suggests that the impact of social stress could potentially affect systemic health and contribute to aging-related diseases throughout the body. Longer exposure to social stress amplified these effects, indicating that the cumulative impact of stress over time could be particularly harmful.
The researchers attempted to mitigate these effects by targeting senescent cells for removal using a mouse model designed to clear cells expressing p16. While this intervention reduced the accumulation of DNA damage and some markers of inflammation, it did not fully reverse the physiological or behavioral effects of stress.
“Another surprise was that in spite of the beneficial effect of clearing p16-expressing cells on the accumulation of DNA damage and markers of senesce, the adverse effect of stress on behavior and physiology up to middle age (the maximum tested here) was not improved,” Bartolomucci said. “This suggests that either other senescent cells contribute to negative effects, or that these cells may also have protective effects under stress. Work is ongoing to discriminate.”
The study adds to the growing body of evidence linking chronic stress to aging at the cellular level, providing new insights into the mechanisms involved. Future research will aim to explore other biological pathways involved in stress and aging, such as oxidative damage and telomere damage. Researchers also hope that this research will inform the study of whether similar mechanisms are at play in humans and to test interventions that could mitigate the harmful effects of stress on aging.
“This finding may have significant implications in understanding how stress ‘gets under the skin’ and inform the many clinical trials focusing on the role of senescent cells and other biological mechanisms in aging and healthspan,” Bartolomucci explained. “Overall, we expect that in the long term this research may yield fundamental new insights into how stress can adversely affect biological mechanisms of aging, and to what extent manipulating these mechanisms can confer resilience to stress-induced adverse health effects.”
The study, “Chronic social stress induces p16-mediated senescent cell accumulation in mice,” was authored by Carey E. Lyons, Jean Pierre Pallais, Seth McGonigle, Rachel P. Mansk, Charles W. Collinge, Matthew J. Yousefzadeh, Darren J. Baker, Patricia R. Schrank, Jesse W. Williams, Laura J. Niedernhofer, Jan M. van Deursen, Maria Razzoli & Alessandro Bartolomucci
