Social stress shortens lifespan in mice

Abstract

SummaryStress and low socioeconomic status in humans confer increased vulnerability to morbidity and mortality. However, this association is not mechanistically understood nor has its causation been explored in animal models thus far. Recently, cellular senescence has been suggested as a potential mechanism linking lifelong stress to age‐related diseases and shorter life expectancy in humans. Here, we established a causal role for lifelong social stress on shortening lifespan and increasing the risk of cardiovascular disease in mice. Specifically, we developed a lifelong chronic psychosocial stress model in which male mouse aggressive behavior is used to study the impact of negative social confrontations on healthspan and lifespan. C57BL/6J mice identified through unbiased cluster analysis for receiving high while exhibiting low aggression, or identified as subordinate based on an ethologic criterion, had lower median and maximal lifespan, and developed earlier onset of several organ pathologies in the presence of a cellular senescence signature. Critically, subordinate mice developed spontaneous early‐stage atherosclerotic lesions of the aortic sinuses characterized by significant immune cells infiltration and sporadic rupture and calcification, none of which was found in dominant subjects. In conclusion, we present here the first rodent model to study and mechanistically dissect the impact of chronic stress on lifespan and disease of aging. These data highlight a conserved role for social stress and low social status on shortening lifespan and increasing the risk of cardiovascular disease in mammals and identify a potential mechanistic link for this complex phenomenon.

Social dominance mediates behavioral adaptation to chronic stress in a sex-specific manner

“…Both objective and perceived SES impact human health, mortality, morbidity, and susceptibility to psychiatric disorders such as depression or anxiety (Farah, 2017;Freeman et al, 2016;Hoebel et al, 2017;McEwen and Gianaros, 2010;Shaked et al, 2016;Wetherall et al, 2019). These outcomes resemble findings related to social dominance in mice (Bartolomucci, 2007;Pallé et al, 2019;Razzoli et al, 2018). Intriguingly, some human studies have identified sex differences in the relationship between SES and stress-related psychopathologies (Kosidou et al, 2011;Mwinyi et al, 2017;Peplinski et al, 2018).…”

“…As a consequence, an individual's position in the dominance hierarchy has important consequences, including preferential access to food, shelter, and mates (Drews, 1993). Social rank within male hierarchies is also known to influence health, hormonal profile, brain function, metabolism and mortality (Pallé et al, 2019;Razzoli et al, 2018). For instance, subordinate individuals display increased anxiety-like behavior, a suppressed immune response, higher basal corticosterone levels, and reduced life span (Bartolomucci, 2007).…”

Chronic inflammation in the etiology of disease across the life span

“…Among the known endogenous causes of this phenotype are DNA damage, dysfunctional telomeres, epigenomic disruption, mitogenic signals and oxidative stress 56 . The non-endogenous contributors are thought to include chronic infections 57 , lifestyle-induced obesity 58 , microbiome dysbiosis 59 , diet 60 , social and cultural changes 61,62 and environmental and industrial toxicants 63 . The fact that differences exist in the extent to which older adults exhibit SCI 52,64 is thought to be indicative of inter-individual differences in exposure to these and other related pro-inflammatory factors, although studies documenting within-person associations between these risk factors and SCI are limited.…”

Social stress in female Columbian ground squirrels: density-independent effects of kin contribute to variation in fecal glucocorticoid metabolites

“…In social organisms, the interactions resulting from regular contact with related and unrelated animals may have profound effects on individual physiology, health, and fitness (Sapolsky 1992;Bartolomucci 2007;Razzoli et al 2018). Studies have highlighted both positive and negative effects of social interactions (or lack thereof) on individual metabolic rate (Stefanski and Engler 1998;Sloman et al 2000; Willis and Brigham 2007;Cao and Dornhaus 2008), immunity (Stefanski and Engler 1998;de Groot et al 2001), and oxidative stress (Nation et al 2008;Zhao et al 2013;Beaulieu et al 2014;Lardy et al 2016), as well as gene regulation and cellular maintenance (Kotrschal et al 2007;Tung et al 2012;Aydinonat et al 2014).…”