Loneliness and Social Isolation Leave a Mark on the Blood

Social isolation and loneliness have long been linked to adverse health outcomes, including cardiovascular disease (CVD), diabetes, and premature death. However, the biologic underpinnings of these associations remain unclear.

Leveraging data from more than 40,000 UK Biobank participants, researchers found that loneliness and social isolation can leave a mark on the body at the molecular level. They identified a number of proteins associated with social isolation and loneliness, many of which were prospectively linked to adverse health outcomes during follow-up.

“We know that social isolation and loneliness are linked to poorer health, but we’ve never understood why. Our work has highlighted a number of proteins that appear to play a key role in this relationship, with levels of some proteins in particular increasing as a direct consequence of loneliness,” lead author Chun Shen, PhD, with the University of Cambridge, Cambridge, England, and Fudan University, Shanghai, China, said in a statement.

The study was published online on January 3 in Nature Human Behavior.

Causal Links?

Social relationships play a key role in well-being. Yet in an increasingly digital and fast-paced world, feelings of loneliness and isolation have become common.

“The World Health Organization (WHO) has found that social isolation and loneliness are widespread, with one in four older people experiencing social isolation and 5%-15% of adolescents feeling lonely,” corresponding author Barbara J Sahakian, DSc, FMedSci, PhD, with the University of Cambridge, told Medscape Medical News. “For this reason, the WHO has declared social isolation and loneliness a global public health concern.”

There is increasing evidence linking social isolation and loneliness to illness and death. As previously reported by Medscape Medical News, Sahakian and colleagues found in an earlier study that social isolation in older people carried a 26% increased risk of developing dementia.

To investigate the potential underlying biologic processes, the investigators analyzed blood samples and behavioral data from 42,062 adults (mean age, 56 years; 52% women) in the UK Biobank.

Among the total cohort, about 9% reported being socially isolated and about 6% felt lonely. During a median follow-up of nearly 14 years, 2695 developed CVD, 892 developed dementia, 1703 developed type 2 diabetes, 1521 developed depression, 983 suffered a stroke, and 4255 died.

In models adjusted for relevant cofactors, 175 proteins were associated with social isolation, and 26 proteins were associated with loneliness.

Co-expression network analysis revealed overlapping pathways between social isolation and loneliness, suggesting shared biologic mechanisms. Roughly 85% of the proteins associated with loneliness were shared with social isolation, the study team reported.

More than half of these proteins were prospectively associated with major adverse health events, such as CVD, stroke, type 2 diabetes, and mortality, over 14 years, the researchers noted.

The proteins found to be significantly associated with loneliness and social isolation have also been implicated in inflammation and antiviral and immune responses, they pointed out.

In addition, Mendelian randomization analysis suggested a causal relationship between loneliness and five specific proteins expressed in the brain: GFRA1, ADM, FABP4, TNFRSF10A, and ASGR1. Individuals who reported being lonely tended to have higher levels of these proteins than peers who did not feel lonely.

These five proteins showed broad associations with other blood biomarkers, as well as volumes in brain regions involved in interoception and emotional and social processes, the investigators reported. The proteins also partly mediated the relationship between loneliness and CVD, stroke, and mortality.

Clinical Implications

Commenting on the findings for Medscape Medical News, Dilip V. Jeste, MD, director of the Global Research Network on Social Determinants of Mental Health and Exposomics, and president-elect of the World Federation for Psychotherapy, noted that this is the first study showing “robust and comprehensive plasma proteomic signatures associated with loneliness and social isolation.”

“Comprehending the biology underlying the impact of social relationships on health, particularly the peripheral changes preceding disease, may provide new opportunities for targeted prevention and for effective intervention,” Jeste said.

He cautioned that further investigations in “larger, more powerful datasets will be needed to determine whether the observed associations are due to causality rather than pleiotropy. Future validation in an independent dataset is essential.”

In terms of clinical practice, assessing, managing, and preventing loneliness in all age groups is critical, Jeste said.

“It is necessary to ask about loneliness in almost every patient seen in clinical practice, just as we ask about smoking history in everyone.”

Sahakian agreed. “This is where social prescribing by doctors can help,” she said.

“They can link people who are lonely up with local community activities that have a social element to them. Volunteering for charities is also good for positive social interactions or joining a cycling group or walking group or other exercise activity, which involves others, such as team sports,” Sahakian said. “This will help reduce loneliness and build social support systems, which reduce the impact of stress.”

This research was supported by the National Natural Science Foundation of China, China Postdoctoral Science Foundation, Shanghai Rising-Star Program, National Key R&D Program of China, Shanghai Municipal Science and Technology Major Project, 111 Project, Shanghai Center for Brain Science and Brain-Inspired Technology, and Zhangjiang Lab. The authors declared no competing interests. Jeste had no relevant disclosures.