iAge: detecting your immune age

A recent study has developed and tested an ‘inflammatory clock’ – named iAge – that can be used to determine someone’s immune age.

The researchers from the Buck Institute and Stanford University (both CA, USA), who developed this method to determine immune age, believe it can help predict multimorbidity, frailty, immunosenescence and cardiovascular aging well in advance of symptom onset. This could allow for successful early interventions, while also providing an insight into potential targets to treat age-related conditions.

Senior author on the study, David Furman (Buck Institute), explained the source of his motivation for this project, stating that, “standard immune metrics which can be used to identify individuals most at risk for developing single or even multiple chronic diseases of aging have been sorely lacking.”

To develop the clock to resolve this issue, the team examined the blood immunome – the collection of genes and proteins that make up the immune system – of 1001 people between the ages of 2–96 years old. Correlating patterns of systemic age-related inflammation in this cohort with the biomarkers and molecules of the immunome present in their blood, the team was able to develop the deep learning method, iAge.

During the development of iAge, the team identified a chemokine, known as CXCL9, as the greatest predictor of immune age. CXCL9 typically localizes at the site of an infection, attracting lymphocytes to join them there to destroy the invading pathogen. However, the team identified further implications of the molecule. “We showed that CXCL9 upregulates multiple genes implicated in inflammation and is involved in cellular senescence, vascular aging and adverse cardiac remodeling,” noted Furman.

What’s more, silencing of CXCL9 led to aging endothelial cells of humans and mice retrieving some of the function lost due to aging.

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While it is now well-known that the gut microbiome is linked with human health, research into its impact on aging has provided inconsistent results. Now, results from a cohort of over 9000 individuals, suggests the gut microbiome does indeed impact aging.

The team validated the deep learning system in a group of centenarians and all-cause mortality participants from the Framingham Heart Study. In this validation, they repeatedly found that immune age was a much greater predictor of health than actual age. The group who had been healthy enough to make it into their 100s were found to have an immune age 40 years lower than the predicted ‘normal’.

Further validations concerning heart health were conducted in a group of 97 extremely healthy individuals. Comparing CXCL9 levels and pulse wave velocity tests results, which indicate an individual’s vascular stiffness, the team identified a correlation between the two. Silencing of CXCL9 again led to a reverse in the display of phenotypes of arterial stiffness in human and mice endothelial cells.

The team believes that these results indicate that iAge has the ability to monitor someone’s risk of developing chronic, inflammation-related diseases. Combining measurements of functional capabilities, like how long it takes to stand from a chair, with iAge measurements, enabled researchers to predict the onset of frailty. “Using iAge it’s possible to predict seven years in advance who is going to become frail. That leaves us lots of room for interventions,” remarked Furman.

The capabilities of this method, alongside the spotlight shone by this study on the role that inflammatory molecules play in the development of age-related conditions, have left Furman clamoring for the immune system to be added to the nine “hallmarks” of aging:

“It’s becoming clear that we have to pay more attention to the immune system with age, given that almost every age-related malady has inflammation as part of its etiology. If you’re chronically inflamed, you will have genomic instability as well as mitochondrial dysfunction and issues with protein stability. Systemic chronic inflammation triggers telomere attrition, as well as epigenetic alterations. It’s clear that all of these nine hallmarks are, by and large, triggered by having systemic chronic inflammation in your body. I think of inflammation as the 10th hallmark.”