The findings suggest increased activity of the sympathetic nervous system – responsible for the “fight or flight” response – may overstimulate development of inflammatory white blood cells in the bone marrow. At the same time it may decrease the production of antiviral proteins, reducing the body’s ability to fight infections.

However, at this stage this is still just a hypothesis. The study has not directly demonstrated that people who are socially isolated are more likely to become ill or die earlier and the immune system played a key role.

Loneliness and social isolation can be complex emotions, and it may be difficult to pin down a single causative factor. It could be a cycle where people with a chronic disease may be less motivated to socialise with others, increasing the sense of isolation, and so on.

Many people in the UK – particularly older adults – can be lonely and socially isolated. But there are ways to combat loneliness, both byseeking help if you are lonely and by helping lonely and isolated people in your community.   

Where did the story come from?

The study was carried out by researchers from the University of California and the University of Chicago, with financial support provided by the US National Institutes of Health.

It was published in the peer-reviewed scientific journal PNAS on an open-access basis, so it is free to read online or download as a PDF.

The UK media’s reporting of the research was generally accurate, but could have benefited from making it clearer that we don’t know whether these findings provide the whole answer.

Also, although this study looks at a previously observed concept, it hasn’t demonstrated that people who are lonely or isolated are more likely to become ill or die earlier.  

What kind of research was this?

This laboratory study in humans and rhesus macaque monkeys aimed to investigate the cellular effects of loneliness. Various studies have already linked social isolation in humans to chronic disease and mortality, though the possible biological mechanism behind this has remained poorly understood.

In humans, feeling socially isolated can involve feeling threatened and being hyperalert. Humans evolved to live in groups with other humans, so prolonged isolation may, on an unconscious level, trigger feelings of profound unease about potential threats: if all of your tribe has suddenly vanished, you could be in a lot of trouble.

Animal models have shown the response to a threat involves signalling from the sympathetic nervous system (SNS) – responsible for the “fight or flight” response – to the bone marrow, where new blood cells are produced.

SNS signalling is thought to increase the activity of “pro-inflammatory” genes, which stimulate the development of early-stage myeloid blood cells in the bone marrow. These myeloid cells give rise to various types of white blood cells (involved in fighting infection), as well as red blood cells and platelets.

It is thought increased myeloid stimulation could contribute to inflammation-related chronic diseases. Meanwhile, while increasing the activity of pro-inflammatory genes, SNS signalling is thought to decrease the activity of genes involved in the production of antiviral immune proteins.

This process is called the conserved transcriptional response to adversity (CTRA) and is associated with specific gene activity, known as CTRA gene expression. This study aimed to find further evidence of the possible links between perceptions of social isolation and sympathetic nervous system effects on the myeloid cells and the CTRA.       

What did the research involve?

The research involved groups of humans and rhesus macaques, and looked at how perceived isolation was associated with measures of immune blood cells and CTRA gene expression.

The human study involved 141 people taking part in the Chicago Health, Aging and Social Relations Study (CHASRS). About a quarter of these people perceived themselves to be highly socially isolated, based on their scores on a loneliness scale during the first five years of the study.

The current research involved blood samples collected from these people during study years 5 to 10. The researchers looked at white blood cell count and CTRA gene expression. Urine samples were also collected to measure the “fight or flight” hormones adrenaline and noradrenaline, and the stress hormone cortisol.

The researchers looked at the association between these biological measures and the score on the loneliness scale, taking account of various potential confounding factors, including age, gender, marital status, income and lifestyle factors.

The macaques were classified to have low, intermediate or high social isolation based on their assessed sociability and behaviours that indicated they felt threatened. Researchers similarly took urine and blood samples from these animals examining stress hormones, white blood cells and gene expression. 

What were the basic results?

The researchers found people with perceived social isolation had an average 6.5% increase in the activity of genes making up the CTRA profile. After additional adjustment for stress, depression and level of social support, isolation was associated with a 12.2% increase in the activity of CTRA genes. Social isolation was also associated with increased levels of white blood cells involved in the inflammatory response.

Similar results were found in macaques – those perceived as socially isolated demonstrated higher CTRA gene activity, with up-regulation of “pro-inflammatory” genes and down-regulation of genes involved in the production of antiviral immune proteins.

This was also demonstrated as an impaired response when the macaques were experimentally infected with simian immunodeficiency virus (SIV), a type of virus that affects primates.

Both humans and macaques with perceived social isolation also demonstrated increased urinary levels of the hormone noradrenaline. 

How did the researchers interpret the results?

The researchers concluded that their study shows socially isolated people have elevated sympathetic nervous system activity, which is associated with activation of the CTRA gene profile.

This is characterised by up-regulation of pro-inflammatory genes and down-regulation of genes involved in the production of antiviral proteins.  

Conclusion

People who are lonely and socially isolated have often been suggested as being at higher risk of illness, disease and early death. This study has aimed to further explore the possible biological mechanisms behind this.

The findings suggest it may involve the “fight or flight” response overstimulating the development of inflammatory white blood cells in the bone marrow, while decreasing the production of antiviral proteins. The idea is this altered immune and inflammatory response could therefore contribute to the increased disease risk.

But this is only a hypothesis. Though the research in animals has suggested socially isolated macaques may be more susceptible to viral infection, this study has not proved that socially isolated humans are more likely to become ill or die earlier.

It also does not confirm this is the only biological mechanism by which social isolation may confer an increased disease risk in humans. Feelings of loneliness and social isolation can be complex emotions that may be influenced by many personal, health and life circumstances.

For example, a person may have a chronic disease that has caused them to become more withdrawn, depressed and socially isolated. This chronic disease may then cause an increased mortality risk, rather than being a direct effect of the social isolation.

As such, there may be several contributing factors involved in a cycle and it can be difficult to pin down a single causative factor – isolation, for example – directly leading to the outcome, such as disease or early death.

However, what is fairly apparent from this and previous research is that, whatever the biological mechanism(s) that may be behind it, loneliness and social isolation do seem to be associated in some way with disease and illness.

If you are feeling isolated and lonely, there are a range of organisations that can help you reconnect with people. Volunteer work can also be an effective way of meeting new people, as well as boosting your self-esteem and wellbeing.

Read more about how to combat feelings of loneliness.