ViroGates A/S : Social isolation in mid-adulthood is associated with elevated suPAR

Background: A meta-analysis reveals a 25-30% increased risk of mortality associated with social isolation, loneliness, and living alone (Holt-Lunstad et al., 2015). Based on an evolutionary theory hypothesis by Cacioppo et al. (2006), loneliness, characterized as a negative emotional state arising from perceived shortcomings in social relationships, is seen as an adaptive response to social disconnection. This response is thought to prepare individuals to confront an unsafe environment without the support of family and friends. The hypothesis suggests that loneliness may induce changes in immune functioning, enhancing an individual's ability to combat infections in the event of injury.

Methods: This study included three populations: The TRIAGE Study Cohort, The Dunedin Study Cohort and Environmental Risk Longitudinal Twin Study Cohort. The researchers measured social isolation and loneliness based on patients: living alone, level of childhood isolation and loneliness. The inflammation was measured based on 3 markers of systemic inflammation: C-reactive protein (CRP), interleukin-6 (IL-6), and a newer inflammation marker, soluble urokinase plasminogen activator receptor (suPAR).

Results: The study answered 4 questions:

• Is living alone associated with inflammation in acutely admitted medical patients?

In the TRIAGE Study, acutely admitted medical patients who were living alone had significantly higher median levels of CRP (5.8 mg/L vs. 4.8 mg/L), IL-6 (9.3 pg/mL vs. 7.3 pg/mL), and suPAR (5.2 ng/mL vs. 4.2 ng/mL) compared with patients who were not living by themselves.

• Is childhood social isolation longitudinally associated with inflammation in adulthood?

Participants who had experienced childhood social isolation or age-38 loneliness had higher CRP, IL-6, and suPAR at age 45, after controlling for sex (and age by design). The associations between childhood social isolation or age-38 loneliness with elevated age-45 suPAR held after controlling for childhood SES, and age-45 BMI, smoking, concurrent depression, and anti-inflammatory medication. In contrast to suPAR, childhood social isolation or age-38 loneliness were not significantly associated with age-45 CRP or IL-6 levels when controlling for age-45 BMI and smoking or further for additional covariates.

• Is adult loneliness cross-sectionally associated with inflammation?

After controlling for sex, participants who were lonelier at age 45 had higher suPAR levels at age 45, but not CRP or IL-6. The association with suPAR remained significant after controlling for childhood SES, and age-45 BMI, smoking, and concurrent depression. Further controlling for use of anti-inflammatory medication did not change any of the results.

• Do social isolation and loneliness have a multiplicative effect?

No significant social isolation × loneliness interactions were observed for the three inflammation markers, in either the Dunedin or the E-Risk samples.

Conclusions: Examining various age groups across multiple cohorts, this study investigated how social isolation and loneliness relate to different markers of inflammation. The results highlight a more consistent association between social isolation and inflammation compared to loneliness, underscoring the need for a clear distinction between these concepts in research. Moreover, the study suggests that the impact of childhood social isolation on inflammation becomes more evident in mid-adulthood rather than in young adulthood. Notably, the use of suPAR, a marker of chronic inflammation, appears to be a reliable indicator of the inflammatory consequences of social isolation, as supported by the study's findings