Loneliness Impacts Health by Diminishing Protein Levels

Quality social relationships are essential to an individual's well-being. Conversely, loneliness and social isolation are harmful. Recent studies have shown that they are linked to morbidity and mortality, just like risk factors such as smoking and obesity! But how can our social relationships influence our physiology? Researchers found that loneliness increased the levels of several proteins involved in inflammatory mechanisms.

Loneliness and social isolation are more common than we think and affect people of all ages. It is estimated that 25% of older people and 5 to 15% of adolescents suffer from it. Numerous research shows that these conditions severely impact health, quality of life and longevity. “ The effect of social isolation and loneliness on mortality is comparable to that of other well-known risk factors such as smoking, obesity and physical inactivity », Underlines the World Health Organization.

Loneliness and social isolation are in fact associated with a 50% increase in the risk of dementia and a 30% increase in the risk of cardiovascular disease or stroke. These conditions also lead to a 25% increased risk of dying prematurely. Experimental studies have shown that social interactions can alter physiology, notably by impacting the sympathetic nervous system, the hypothalamic-pituitary-adrenal axis (involved in our response to stress) and the immune system. Despite these findings, the biology underlying the link between social relationships and health remains largely unknown.

The proteome of 42,000 individuals scrutinized

Given the influence of social relationships on health, scientists are now interested in the biological processes responsible for this influence. One way to explore these biological mechanisms is to observe proteins circulating in the blood. As end products of gene expression, they are essential for the proper functioning of our body. They also often serve as therapeutic targets in the case of numerous diseases.

So a team led by researchers from the University of Cambridge, UK, and Fudan University, China, set out to examine the proteome of a large cohort of individuals. Initially, the objective was to identify proteomic profiles associated with social isolation and loneliness. Next, it was a question of elucidating how proteomic alterations contribute to this association. The results of this research have just been published in the journal Natural Human Behavior.

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This study is based on data from more than 42,000 individuals taken from the UK Biobank, aged 40 to 69 years. Among them, 9.3% considered themselves socially isolated and 6.4% felt alone. Note that the two conditions are different. Social isolation is an objective measure. It takes into account, for example, whether a person lives alone, the number of their contacts, their social activities, etc. Loneliness, on the other hand, is a subjective measure. It is based on whether a person feels alone or not.

During a median follow-up of almost 14 years, 2695 participants developed cardiovascular disease, 892 developed dementia, 1703 developed type 2 diabetes, 1521 developed depression, 983 developed stroke, and 4255 were deceased. To carry out their analysis, the team had individual data on 2920 plasma proteins.

Proteins produced in cases of inflammation and viral infection

After adjusting for ethnicity, education level, household income, smoking, alcohol consumption and body mass index, the researchers identified 175 proteins associated with social isolation and 26 proteins associated with loneliness! They specify that 22 proteins were common to both conditions.

The team identified 179 proteins with a significant association with social isolation and/or loneliness. Credits: Shen et al., Nature Human Behavior (2025)

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The majority of identified proteins showed a positive association. This means that a greater abundance of these proteins led to a higher risk of social isolation or loneliness. Our bodies produce many of these proteins in response to inflammation and as part of immune responses. They play a role in cardiovascular disease, type 2 diabetes, stroke and premature death.

The team reports that GDF15 showed the strongest association with social isolation. We know that this protein is involved in cancers, inflammation and cardiovascular diseases. A high level of GDF15 would be a marker of risk of death and serious cardiac events. The PCSK9 protein showed the strongest association with loneliness. It is a key protein for regulating cholesterol metabolism.

Only four proteins emerged as protective factors against social isolation and one against loneliness.

Certain brain regions “reduced” by loneliness

Once the link was confirmed, the causal relationship between isolation/loneliness and proteins remained to be explored. The researchers found that none of the proteins appeared to cause either condition. In contrast, loneliness significantly influenced the levels of five proteins. Among them, ADM, which plays a role in the stress response and in the regulation of “social” hormones such as oxytocin.

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To explore the relationship between the identified proteins and general physical functions, the researchers studied their associations with other blood biomarkers and brain volume. They report that cystatin C – a biomarker of kidney function – showed the strongest association with all five proteins. Additionally, they all showed robust connections with C-reactive protein (CRP) – a substantial biomarker of systemic inflammation.

At the brain level, the data revealed a significant association between four proteins and the volumes of certain brain regions (the insula, the caudate nucleus and the frontal cortex). These areas are essential for interoception (our ability to perceive the state of our body), as well as emotional and social processes. A high level of ADM was associated with reduced gray matter volumes in the insula and left caudate nucleus.

Maintain social interactions to be healthy

The researchers then investigated the associations between proteins linked to social isolation and loneliness and the incidence of morbidity and mortality. They considered five diseases whose association with social relationships is well documented: cardiovascular disease, dementia, type 2 diabetes, depression and stroke.

After adjusting for various confounding factors, the results revealed that 90% of the 179 proteins identified were associated with mortality and more than 50% were linked to type 2 diabetes, cardiovascular disease and stroke. Only 6.6% of them were associated with dementia.

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GDF15 emerged as the main protein associated with increased risk of all diseases and mortality, excluding type 2 diabetes. High levels of ADM led to increased risk of early death. An association also appeared between the ASGR1 protein and higher cholesterol levels and an increased risk of cardiovascular disease. Other identified proteins play a role in the development of insulin resistance, atherosclerosis and cancer progression.

This is the first study describing robust and comprehensive plasma proteomic signatures associated with social isolation and loneliness. The results thus support the idea that social relationships indirectly influence morbidity and mortality. It therefore appears essential to maintain quality social contacts to be in good health.

“ More and more people of all ages report feeling alone. […] We need to find ways to combat this growing problem and keep people connected to help them stay healthy », concludes Barbara Sahakian, professor in the department of psychiatry at the University of Cambridge and co-author of the study.