Why Is Loneliness Bad for Our Health?
Blood samples from over 42,000 people reveal social isolation and loneliness impact humans at the biological level.
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We humans are naturally social creatures – it’s a characteristic that brings joy and fulfillment to our lives but also supports our survival. Research continues to link social isolation and loneliness with an increased risk of developing conditions including coronary heart disease, stroke and obesity. How much social interaction we experience in our lives is now known to have a comparable influence over our risk of death as well-established factors, such as smoking or drinking alcohol. Yet, the World Health Organization estimates that 1 in 4 older adults experience social isolation, and 5–15% of adolescents experience loneliness.
As global health authorities explore measures to combat social isolation, scientists continue their work to understand the biological mechanisms that link loneliness with adverse health outcomes.
How does the feeling of loneliness or being socially isolated impact our cells? A new study, led by Dr. Jianfeng Feng, professor in Computer Science at the University of Warwick, turned to the proteome for answers. The study, published in Nature Human Behaviour, offers new insights into the biological mechanisms that could link loneliness and adverse health outcomes, such as cardiovascular disease and stroke.
What is the proteome?
The proteome refers to the complete set of proteins expressed in a cell, tissue or organism at any given time. Proteins are often nicknamed “cellular workhorses” due to their involvement in a wide range of cellular functions, including those that underpin both healthy and diseased states.
Can the proteome reveal why loneliness is bad for our health?
Prior to this research, a comprehensive proteome-wide association study – or PWAS – of social isolation and loneliness had not been conducted. Feng and colleagues utilized the UK BioBank – a large-scale biomedical database – to access blood samples from over 42,000 participants aged 40–69 years.
Social isolation and loneliness scores were calculated for each individual and a high-throughput proteomics platform from Olink was used to analyze the blood samples and identify any proteins associated with loneliness or social isolation.
Social isolation vs loneliness
When measuring social isolation, you might ask participants questions such as: how often do you have contact with friends or family? Do you live alone, or with a partner? Do you take part in any social activities? These are all objective measures. Loneliness, in contrast, is a feeling that someone experiences and is therefore a subjective measurement.“Olink is an antibody-based proteomic profiling platform and has been widely used in many cohort studies and clinical trials,” Dr. Chun Shen, a postdoctoral research fellow in the Department of Clinical Neurosciences at the University of Cambridge and the Institute of Science and Technology for Brain-Inspired Intelligence, told Technology Networks.
Loneliness has a proteome signature
After adjusting the data to account for sex, age, body mass index, ethnicity and socioeconomic background, 175 proteins were associated with social isolation and 26 proteins were associated with loneliness – 22 of these 26 were common across both.
A protein called growth differentiation factor 15, or GDF15 – which is involved in inflammatory processes – had the strongest association with social isolation. A protein called proprotein convertase subtilisin/kexin type 9, or PCSK9 – involved in cholesterol metabolism – showed the strongest association with loneliness.
Feng and colleagues explored the functional pathways of proteins associated with social isolation and loneliness. Shared pathways and enrichment in pathways such as cytokine–cytokine receptor interaction and antiviral processes were identified, in addition to links to type 2 diabetes, cardiovascular disease, stroke and risk of early death.
Next, they used mendelian randomization analysis to explore whether a causal relationship exists between social isolation and loneliness, and specific proteins. The expression of five proteins was deemed to be caused by loneliness – GFRA1, ADM, FABP4, TNFRSF10A and ASGR1.
The researchers extended their analysis to explore blood biomarkers and brain phenotypes associated with the expression of these proteins. All five demonstrated a connection with C-reactive protein, a biomarker of inflammation used in clinical practice. Higher levels of the protein ADM was associated with lower grey matter volume in the insula and the left caudate, brain structures related to interoception and emotional processing.
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Subscribe for FREE"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,” Feng said.
Confirming findings in wider cohorts
The proteins identified in this study provide clues as to why socially isolated or lonely people could be at a greater risk of poor health.
The researchers hope to repeat their work in larger cohorts based outside the UK, but it might not be easy: “We are indeed eager to validate our findings in the UK Biobank using independent datasets. However, social isolation and loneliness are not commonly measured, and we are still searching for an appropriate large-scale dataset,” Shen said. “We are planning to examine plasma protein levels in Chinese population data, which may potentially be used to confirm our findings in the future.”
It could be interesting to explore the proteome of loneliness in the context of extreme, mandatory social isolation, such as that experienced by the entire world during the COVID-19 pandemic. “The UK Biobank has collected additional Olink assay data for 2,000 participants, with samples taken both pre- and post-COVID. However, this data has not yet been released and is expected to become available in 2025,” Shen concluded.
Reference: Shen C, Zhang R, Yu J, Sahakian BJ, Cheng W, Feng J. Plasma proteomic signatures of social isolation and loneliness associated with morbidity and mortality. Nat Hum Behav. 2025. doi: 10.1038/s41562-024-02078-1
About the interviewee:
Dr Chun Shen is a postdoctoral research fellow at Fudan University, a visiting researcher at the Department of Clinical Neuroscience and an affiliated postdoc at Clare Hall.
