Social isolation has been shown to be associated with inflammatory biomarker levels [1, 2]. Moreover, social isolation may lead to increased risk for cancer mortality . However, the impact of social isolation in women may differ from that in men, particularly in relation to inflammatory response and cancer mortality [6–9, 13]. In our analysis of 3,446 adult females based on a large, nationally representative survey, we found that socially isolated participants were more likely to have lower socioeconomic status, lower rates of physical activity, and higher rates of obesity and smoking. Lack of social connectedness was also associated with heightened levels of serum fibrinogen, but not CRP. Although Kaplan-Meier estimates indicated higher cancer mortality rates for participants with elevated fibrinogen levels, there was no statistically significant association between the two. Furthermore, there was no significant relationship between social isolation and cancer mortality after adjusting for demographic, socioeconomic, and behavioral risk factors.
In our study, we found a direct correlation between the degree of social isolation and fibrinogen levels. Similarly, the Framingham Offspring Study group by Kim et al. found elevated fibrinogen levels in those with less social connection . In addition, Nersesian et al. found high fibrinogen levels to be strongly associated with more socially isolated, middle-aged men and women . Prior studies have investigated the potential mechanisms underlying the relationship between social isolation and inflammation. This relationship may be mediated by increased psychological stress in isolated individuals, which is correlated with heightened inflammation [20–22]. Loneliness may activate the sympathetic nervous system and Hypothalamic Pituitary Adrenocortical (HPA) axis, both of which are critical components to the body’s stress response [23, 24]. Furthermore, dysregulation of the HPA-axis may be associated with chronic stress and subsequently higher inflammation levels . Researchers have also suggested that social isolation may result in heightened inflammatory sensitivity to biological and social stressors, resulting in elevated inflammation among isolated individuals .
Conversely, it is also possible that inflammation can induce social withdrawal. Raison and Miller suggest that inflammatory cytokines activate conservation and withdrawal behavior through the basal ganglia . More specifically, the inflammatory cytokines induce a “sickness behavior,” including social withdrawal, that provide an adaptive defense mechanism to protect against infection by avoiding exposures and conserving energy . Furthermore, the expression of the neuropeptide Y gene has been shown to be correlated with inflammation as well as social isolation and major depressive disorder [29–31].
Prior studies have shown a correlation between CRP and social integration [21, 32]. Similarly, in a New England regional study of over 2000 adults, these authors concluded that the least socially integrated individuals had a twofold or higher risk of elevated CRP levels compared to the most socially integrated . However, these studies evaluated social isolation and CRP among men and women. In contrast, prior studies have not shown a significant correlation between social isolation and CRP levels solely in women [2, 3]. Further studies are warranted to investigate the biological role of sex in the relationship between isolation and CRP level.
In this current report, elevated fibrinogen levels appeared to be associated with higher cancer mortality among women, though not statistically significant. However, on multivariate analysis, both CRP and fibrinogen were not independent predictors for cancer mortality. Similarly, Wulaningsih et al. was unable to demonstrate a significant association between CRP levels and cancer mortality in women, but the authors did find this relationship in their male cohort . In a study of over 10,000 women, Gathirua-Mwangi and colleagues also did not find a correlation between CRP and cancer mortality . The sex differences from these studies may be explained by the reported lower levels of cortisol levels in women in response to stress compared to men [11, 36, 37]. Kudielka and Kirschbaum showed that women under stress have less activation of the HPA-axis compared to men and thus have lower levels of inflammation . Furthermore, Taylor and colleagues reported that women are more likely to seek out social support in response to social stress, whereas men tend to exhibit a fight-or-flight stress response . Different biological responses to social stress between men and women may contribute to the statistically insignificant relationship between cancer mortality and inflammation in our female cohort.
While we found social isolation to be correlated with multiple potential risk factors for cancer, including heightened fibrinogen levels, increased obesity and smoking levels, as well as low physical activity and socioeconomic status, we found no association between social isolation and rate of cancer mortality. In contrast to our findings, Reynolds and Kaplan found higher rates of cancer mortality in socially isolated women in a regional sample of 6,848 adults . However, this study did not adjust for inflammation and physical activity. In a meta-analysis of 40 observational studies, Leigh-Hunt et al. found that social isolation was correlated with poor cardiovascular and mental health outcomes, but not cancer mortality . Thus, social isolation in relation to cancer mortality and its underlying mechanisms warrants further investigation.
Our results may not be generalizable due to the following limitations. Our sample was restricted to 1988–1994 due to the limited span of Social Network Index scores collected by NHANES. Due to the cross-sectional nature of our study, we were unable to offer insight into how changes over time in factors such as social isolation and inflammation impacted our participants’ health outcomes. In addition, we were unable to obtain information on cancer incidence, tumor type, stage of disease, treatment and survival time after diagnosis. The incidence and outcomes of certain cancers may be related to inflammation, while others may be predominantly related to other causes. For example, incidence and outcomes are largely related to carcinogens in smoking-related cancers. By including all cancer types, we may not be able to detect associations between certain subsets of malignancy and inflammation. Moreover, the surveys did not focus on factors related to social isolation such as feelings of loneliness, stress, or depression, which may affect cancer mortality. However, our report is a cross-disciplinary study that relates social behavior, immunology, and oncology. To our knowledge, this is one of the few studies that evaluated the impact of social isolation in women in relation to inflammatory markers and cancer mortality. Furthermore, we were able to perform our analysis in a multivariate model adjusting for important demographic, socioeconomic and behavioral factors.