Immune age and chronic disease: For whom is the clock ticking?

Many diseases associated with ageing are linked to the immune system. As we get older, our bodies have fewer immune cells to bring about healing. Our immune system is also less able to correct any defects in our body’s cells, triggering the development of various chronic diseases.

An international research team imagined the benefits of a system that could identify individuals most likely to develop ageing-related diseases, and then went on to create it. Using the blood immunome (the genes and proteins that make up the immune system) of 1 001 individuals aged 8-96 years, they developed a deep-learning method based on patterns of systemic age-related inflammation. The result of their work, an inflammatory clock of ageing (iAge), is described in the journal ‘Nature Aging’. The research was supported by the EU-funded PROPAG-AGEING project, and also received support from ADAGE, a project funded under the EU ERA-NET action JPco-fuND.iAge measures the inflammatory load, or number of inflammatory markers in blood or tissue. It predicts frailty, cardiovascular ageing, the likelihood of developing multiple chronic illnesses and the gradual deterioration of the body’s immune system as a result of natural ageing. The inflammatory clock is also associated with exceptional longevity in centenarians.

“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,” observes study senior author Dr David Furman of Stanford University School of Medicine, United States, in a ‘EurekAlert!’ news release. “Bringing biology to our completely unbiased approach allowed us to identify a number of metrics, including a small immune protein which is involved in age-related systemic chronic inflammation and cardiac aging. We now have means of detecting dysfunction and a pathway to intervention before full-blown pathology occurs.”

Dr Furman’s “small immune protein” is none other than the soluble chemokine CXCL9 that the study identified as the strongest contributor to iAge. “We showed that CXCL9 upregulates multiple genes implicated in inflammation and is involved in cellular senescence, vascular aging and adverse cardiac remodelling,” Dr Furman states. Silencing CXCL9 reverses the loss of function, inability to proliferate and distinctive phenotypes of arterial stiffness seen in ageing endothelial cells in both humans and mice.

Findings from the initial analysis were validated in an independent cohort of centenarians in the Framingham Heart Study. As reported in the news release, Dr Furman believes that the “age” of a person’s immune system is far more important than chronological age when it comes to health and longevity. “On average, centenarians have an immune age that is 40 years younger than what is considered ‘normal’ and we have one outlier, a super-healthy 105 year-old man (who lives in Italy) who has the immune system of a 25 year old,” he notes.

By assessing the cumulative physiological damage to a person’s immune system, iAge can be used to determine their risk of developing multiple chronic diseases. “Using iAge it’s possible to predict seven years in advance who is going to become frail,” remarks Dr Furman. “That leaves us lots of room for interventions.” PROPAG-AGEING (The continuum between healthy ageing and idiopathic Parkinson Disease within a propagation perspective of inflammation and damage: the search for new diagnostic, prognostic and therapeutic targets) ended in 2019.

For more information, please see:

PROPAG-AGEING project website