Researchers develop inflammatory age clock that predicts frailty and mortality

Researchers at the Stanford University School of Medicine and the Buck Institute for Research on Aging have built an inflammation-based aging clock that can accurately assess the risk of illness and mortality. The work was published in Nature Aging on July 12, 2021, and was funded by the Stanford Alzheimer’s Disease Research Center, the Ellison Foundation, the Buck Institute for Research on Aging, and the National Institutes of Health. While the number of candles we have blown tells our chronological age, it does not always reflect the rate at which our bodies age. “Every year, the calendar tells us we’re a year older. But not all humans age biologically at the same rate. You see this in the clinic — some older people are extremely disease-prone, while others are the picture of health,” said Dr. David Furman, the study’s senior author. Dr. Furman is also an associate professor at the Novato, California-based Buck Institute for Research on Aging and director of the Artificial Intelligence Platform at the same institute. The discrepancy between chronological and biological age, according to Dr. Furman, can be linked to immune function. The human immune system is a complex network of cells and proteins that work to defend the body against infections. It maintains a record of every pathogen it has conquered so it can identify and promptly destroy the microbe if it attacks the body again. Immune functioning is based on a quick, intense, localized, short-term, resist-and-repair response called acute inflammation. This is ‘good inflammation’ that does its job and wanes within days. However, as we grow older, a different type of bodywide, ‘bad inflammation’ starts to kick in. This is the infamous low-grade, constant, and systemic chronic inflammation that triggers organ damage and increases vulnerability to diseases such as heart attack, stroke, cancer, and neurodegeneration. Before this particular study, researchers had no way to assess a person’s inflammatory status to predict clinical problems and identify ways of staving them off. A study conducted between 2009 and 2016 drew blood samples from more than 1000 participants and subjected them to a barrage of analytical tests. The researchers’ goal was to determine levels of immune-signaling proteins known as cytokines, the status of various immune cells in response to stimuli, and gene activity in these cells. The new study used artificial intelligence to crunch down all this data to a composite that researchers now refer to as an ‘inflammatory clock’. The team noted that the strongest predictors of inflammatory age were about 50 cytokines (immune-signaling proteins). Physical tests conducted on participants whose blood had been drawn 7 years earlier showed that inflammatory age was superior to chronological age in predicting frailty. Dr. Furman and his team also obtained and examined blood samples from an ongoing study highlighting long-lived people in Bologna, Italy. The researchers established that some of the older people had an inflammatory age about 40 years younger than their calendar age. One individual who was 105 years old had an inflammatory age of 25. This helped cement the understanding that a younger inflammatory age could be linked to increased healthspan and lifespan. In further analysis, the researchers found that levels of a cytokine secreted by certain immune cells to draw other immune cells to a site of infection increase dramatically after the age of 60. This cytokine, identified as CXCL9, had a more powerful impact on the inflammatory age score than other factors. High inflammatory age scores – and CXCL9 levels – were tied to increased risk for cardiovascular disease. Laboratory experiments using mice and human cells showed that reducing levels of CXCL9 restored youthful function of endothelial cells, which are the main component in blood vessel walls. This demonstrated that inhibiting CXCL9 could help decrease susceptibility to cardiovascular disease. “Our inflammatory aging clock’s ability to detect subclinical accelerated cardiovascular aging hints at its potential clinical impact. All disorders are treated best when they’re treated early,” added Dr. Furman. The team’s work demonstrated the concept of an inflammatory clock that shows how strong your immune system is and predicts how soon you’re likely to develop frailty. These findings could be used as a launchpad for creating interventions that could help increase health and lifespan.