Loneliness linked to higher risk of heart disease and stroke and susceptibility to infection

Researchers from the UK and China drew this conclusion after studying proteins from blood samples taken from over 42,000 adults recruited to the UK Biobank. Their findings are published today in the journal Nature Human Behaviour.

Social relationships play an important role in our wellbeing. Evidence increasingly demonstrates that both social isolation and loneliness are linked to poorer health and an early death. Despite this evidence, however, the underlying mechanisms through which social relationships impact health remain elusive.

One way to explore biological mechanisms is to look at proteins circulating in the blood. Proteins are molecules produced by our genes and are essential for helping our bodies function properly. They can also serve as useful drug targets, allowing researchers to develop new treatments to tackle diseases.

A team led by scientists at the University of Cambridge, UK, and Fudan University, China, examined the ‘proteomes’ – the suite of proteins – in blood samples donated by over 42,000 adults aged 40-69 years who are taking part in the UK Biobank. This allowed them to see which proteins were present in higher levels among people who were socially isolated or lonely, and how these proteins were connected to poorer health.

The team calculated social isolation and loneliness scores for individuals. Social isolation is an objective measure based on, for example, whether someone lives alone, how frequently they have contact with others socially, and whether they take part in social activities. Loneliness, on the other hand, is a subjective measure based on whether an individual feels lonely.

When they analysed the proteomes and adjusted for factors such as age, sex and socioeconomic background, the team found 175 proteins associated with social isolation and 26 proteins associated with loneliness (though there was substantial overlap, with approximately 85% of the proteins associated with loneliness being shared with social isolation). Many of these proteins are produced in response to inflammation, viral infection and as part of our immune responses, as well as having been linked to cardiovascular disease, type 2 diabetes, stroke, and early death.

The team then used a statistical technique known as Mendelian randomization to explore the causal relationship between social isolation and loneliness on the one hand, and proteins on the other. Using this approach, they identified five proteins whose abundance was caused by loneliness.

Dr Chun Shen from the Department of Clinical Neurosciences at the University of Cambridge and the Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, said: “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.

Professor Jianfeng Feng from the University of Warwick said: "There are more than 100,000 proteins and many of their variants in the human body. AI and high throughput proteomics can help us pinpoint some key proteins in prevention, diagnosis, treatment and prognosis in many human diseases and revolutionise the traditional view of human health.

"The proteins we’ve identified give us clues to the biology underpinning poor health among people who are socially isolated or lonely, highlighting why social relationships play such an important part in keeping us healthy.”

One of the proteins produced in higher levels as a result of loneliness was ADM. Previous studies have shown that this protein plays a role in responding to stress and in regulating stress hormones and social hormones such as oxytocin – the so-called ‘love hormone’ – which can reduce stress and improve mood.

The team found a strong association between ADM and the volume of the insula, a brain hub for interoception, our ability to sense what's happening inside our body – the greater the ADM levels, the smaller the volume of this region. Higher ADM levels were also linked to lower volume of the left caudate, a region involved in emotional, reward, and social processes. In addition, higher levels of ADM were linked to increased risk of early death.

Another of the proteins, ASGR1, is associated with higher cholesterol and an increased risk of cardiovascular disease, while other identified proteins play roles in the development of insulin resistance, atherosclerosis (‘furring’ of the arteries) and cancer progression, for example.

Professor Barbara Sahakian from the Department of Psychiatry at the University of Cambridge said: “These findings drive home the importance of social contact in keeping us well. More and more people of all ages are reporting feeling lonely. That’s why the World Health Organization has described social isolation and loneliness as a ‘global public health concern’. We need to find ways to tackle this growing problem and keep people connected to help them stay healthy.”

The research was supported by the National Natural Sciences 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.

Reference
Shen, C et al. Plasma proteomic signatures of social isolation and loneliness associated with morbidity and mortality. Nat Hum Behav; 3 Jan 2025; DOI: 10.1038/s41562-024-02078-1