NEW YORK – An international team led by members of Stanford University's Stanford 1000 Immunomes Project has uncovered inflammation-related markers of aging, including an interferon-related inflammatory chemokine called CXCL9 that appears to influence everything from vascular aging and cardiac remodeling to cellular senescence.
"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," senior author David Furman, director of the Stanford 1000 Immunomes Project and a researcher affiliated with the Buck Institute for Research on Aging, Edifice Health, and Stanford University, said in a statement. "We now have means of detecting dysfunction and a pathway to intervention before full-blown pathology occurs."
The team reasoned that the immune system — particularly inflammation patterns — could hold clues to the variation that has been observed in biological aging between individuals, with some developing disease or frailty relatively early on and others remaining remarkably healthy well into old age.
As they reported in Nature Aging on Monday, the researchers used deep learning to put together an "inflammatory clock of aging," dubbed iAge. That predictive tool was based on measurements of age-related chronic inflammation gleaned from blood gene expression, serum cytokine, and cell subpopulation profiles for 1,001 individuals between the ages of 8 and 96 years old, they explained, along with their cellular and serum responses to cytomegalovirus, or CMV, infection and other stimuli.
"Given the well-established importance of chronic inflammation for many human diseases and the lack of standard measures, we used deep-learning methods on blood immune biomarkers to construct a metric for age-related chronic inflammation (iAge)," they wrote, noting that the tool "predicts important aging phenotypes and provides insights into the mechanisms leading to vascular aging."
For their analyses, the investigators tapped into blood samples collected from 339 male and 662 female participants in longitudinal studies on aging and other conditions over nearly a decade, from 2007 to 2016. Among the participants were dozens of centenarians from Bologna in Italy.
Along with tests aimed at detecting dozens of cytokines, chemokines, and growth factors, the team did gene expression profiling on whole blood or peripheral blood mononuclear cell samples, CMV testing, and assays aimed at characterizing cell type frequencies, responses to cytokine stimulation, and more.
With these data, the researchers focused on a set of immune cytokines that could be used to predict participants' biological, or inflammatory, age — a metric that lined up with everything from age-related disease to frailty in the study cohort and in available data from the Framingham Heart Study.
"Using iAge it's possible to predict seven years in advance who is going to become frail," Furman noted. "That leaves us lots of room for interventions."
In the very long-lived study participants, levels of the age-related cytokines were markedly lower than expected, the team noted, with inflammatory ages for centenarians appearing decades younger than their chronological ages.
When researchers dug into the inflammatory aging signatures further, they found that CXCL9 appeared to play an outsized role in the biological aging process. In several endothelial cell lines developed using donor fibroblast samples and induced pluripotent stem cells generated from them, for example, they found that CXCL9 knockdown with short hairpin RNAs extend the formation of tubular networks linked to angiogenesis over time, suggesting the chemokine can contribute to aging and vascular health.
"[W]e demonstrate that CXCL9 is a master regulator of vascular function and cellular senescence, which indicates that therapies targeting CXCL9 could be used to prevent age-related deterioration of the vascular system and other physiological systems as well," the authors concluded.