Immune Aging Clock Identifies CXCL9 as a Target to Suppress Age-Related Inflammation
Researchers are increasingly making use of machine learning approaches in order to produce measures of biological age, known as clocks, derived from weighted combinations of biological data: epigenetic status, protein levels, transcript levels, and so forth. In most such clocks, it is unclear as to how the underlying processes of aging act to produce the identified epigenetic marks or differences in protein levels. Researchers here build a protein-based clock that is restricted to immune system signaling molecules that are found in blood samples. Working backwards from the proteins identified as being important to the clock, they note one that can be suppressed to potentially reverse some of the inflammatory aspects of age-related immune dysfunction.
Researchers have created an inflammatory clock of aging (iAge) which measures inflammatory load and predicts multi-morbidity, frailty, immune health, cardiovascular aging and is also associated with exceptional longevity in centenarians. The study identified the soluble chemokine CXCL9 as the strongest contributor to iAge. It is a small immune protein that is usually called into action to attract lymphocytes to the site of an infection. "But in this case we showed that CXCL9 upregulates multiple genes implicated in inflammation and is involved in cellular senescence, vascular aging, and adverse cardiac remodeling. Silencing CXCL9 reversed loss of function in aging endothelial cells in both humans and mice."
Results from the initial analysis, which also included information from comprehensive clinical health assessments of 902 individuals, were validated in an independent cohort of centenarians and all-cause mortality in the Framingham Heart Study. According to the researchers, when it comes to health and longevity, the "age" of one's immune system most certainly trumps the chronological information that can be derived from a driver's license. "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 has the immune system of a 25 year old."
Study results involving cardiac health were also validated in a separate group of 97 extremely healthy adults (age 25 - 90 years of age). Researchers found a correlation between CXCL9 and results from pulse wave velocity testing, a measure of vascular stiffness. "These people are all healthy according to all available lab tests and clinical assessments, but by using iAge we were able to predict who is likely to suffer from left ventricular hypertrophy (an enlargement and thickening of the walls of the heart's main pumping chamber) and vascular dysfunction."