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Inflammatory Clock Measures ‘Universal’ Hallmark Of Aging

By Deborah Borfitz

July 15, 2021 | Systemic chronic inflammation—a universally strong signal of ill health associated with all nine hallmarks of aging and diseases that collectively represent the leading causes of disability and mortality worldwide—can now be measured by an inflammatory clock of aging (iAge) developed by investigators at the Stanford University School of Medicine and the Buck Institute for Research on Aging. It is the first “actionable clock” that predicts multimorbidity, frailty, immunological health, and chronic diseases of aging, according to David Furman, Ph.D., Buck Institute associate professor and director of its artificial intelligence (AI) platform. 

Furman is also co-founder of Stanford spinoff Edifice Health, born out of the Stanford 1000 Immunomes Project (KIP) endeavoring to define the biological basis of aging and disease using omics platforms and AI. The company is now marketing iAge to functional medicine (concierge) physicians and wellness clinics in the U.S. where between 12 and 14 million of the “worried well” self-pay for prevention-oriented healthcare. Pre-orders are being taken on the Edifice Health website.

Longer term, the plan is to get iAge approved by the U.S. Food and Drug Administration and obtain a billing code for the inflammatory age test from the Centers for Medicare & Medicaid Services while convincing payers that preventive medicine is important, says Furman. Healthcare in the country currently leans heavily toward symptom treatment rather than disease prevention. 

In a newly published study in Nature Aging (DOI: 10.1038/s43587-021-00082-y), Furman and his colleagues show that iAge tracks with multiple diseases as well as exceptional longevity. Utilizing deep learning in studies of the blood immunome of 1,001 people, they also identified a modifiable chemokine (CXCL9) associated with cardiac aging that could be used for early detection of age-related pathology and as a target for treatments.

Results from the initial analysis, which 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 that has been tracking health outcomes among thousands of individuals since 1948. Study results involving cardiac health were validated in a separate group of 97 extremely healthy adults (ages 25 to 90). 

While researchers are exploring disease-specific phenotypes, “the aging space is much more geared toward understanding the commonalities… and how those can predict multiple diseases simultaneously,” says Furman. Even if the world were cured of cancer today, it would only extend the lifespan of humans by two years because of all the other diseases they develop, he notes.

It was only a few years ago that multimorbidity was declared the number one priority for healthcare research by the Academy of Medical Sciences, Furman says. The associated issues include the greater amount of clinician time required to treat patients; the symptoms of one condition aggravating the symptoms, treatment, or medications of another condition; and polypharmacy increasing the risk of adverse medical outcomes. 

“We’re trying to solve the bigger problem, not just a single indication,” he stresses. 

Complex Equation 

The new study employed AI to boil data from participants in the KIP into a composite researchers call the inflammatory clock. The single-number score produced by iAge is based on levels of 50 immune-signaling proteins (cytokines) that were found to be the strongest predictors of inflammatory age, some of which are upregulated and others that are beneficially downregulated, says Furman. 

An individual’s iAge is high or low “depending on a complex equation,” he continues. 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."

Researchers also found a correlation between CXCL9 and results from pulse wave velocity testing (a measure of vascular stiffness), identifying people deemed healthy by available lab tests and clinical assessments who were likely to suffer from left ventricular hypertrophy and vascular dysfunction. 

Although CXCL9 on its own is insufficient to derive overall inflammatory load, he says, the small immune protein was found to be the strongest contributor to iAge. It is usually called into action to attract lymphocytes to the site of an infection but, as the researchers demonstrate, it also “upregulates multiple genes implicated in inflammation and is involved in cellular senescence, vascular aging, and adverse cardiac remodeling."

As covered in the Nature Aging paper, silencing CXCL9 reverses loss of function in aging endothelial cells in both humans and mice. But while the inflammatory profile of some people will show high CXCL9, the chemokine is absent in other immunotypes, Furman says.

The overall measurement approach is relatively straightforward, he says. Baseline inflammation levels for individuals in the KIP were first correlated with 10 diseases of aging they ether had or ultimately developed (150 people have been followed over the years), providing an accurate scoring system for multimorbidity. The analysis covered different physiological systems: cancer, cardiovascular, respiratory, gastrointestinal, urologic, neurologic, endocrine–metabolic, musculoskeletal, genital, reproductive, and psychiatric dysfunctions.

Notably, iAge can be used to predict seven years in advance who is going to become frail, Furman continues. The calculation was made by researchers on a subgroup of 29 older adults using a 2017 frailty score, based on the Timed Up and Go mobility test, which was regressed onto their iAge in 2010 and controlled for chronological age, sex, body mass index, and CMV (indicative of herpesvirus infection). 

Actionable Metrics 

Edifice Health launched three years ago and recently received an infusion of $12 million, enabling it to begin a study with 1,000 participants to test personalized interventions based on individual immunotypes, Furman says. In two previous double-blinded, placebo-controlled trials, the company showed iAge could be used to decrease inflammatory age and bring it to an optimal state. 

“Now, the question is can we in the mid- and long-term improve aging phenotypes,” he says. The new study intends to demonstrate not only that iAge can “move the needle,” but investigate the clinical implications of preventing various age-related conditions. 

The research team is using a laboratory about to be certified by Clinical Laboratory Improvement Amendments (CLIA), Furman adds. Certification will enable them to receive clinical samples and issue reports on the findings.

The availability of a single test for systemic inflammation is groundbreaking, says Furman, because it serves as a “universal” hallmark of aging unifying the current nine measures. "If you are 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. All nine of these hallmarks are, by and large, triggered by having systemic chronic inflammation in your body.” 

It has been known for about 120 years that the immune system protects against infection and disease, he says. But the theory that aging is associated with chronic inflammation emerged only 20 years ago and, up to now, there have been no reliable markers of inflammation. “Bringing biology to our completely unbiased approach allowed us to identify a number of metrics.”

Hemoglobin A1c is loosely connected to inflammation but at a level close to random chance, says Furman. The high-sensitivity C-reactive protein test has also been used for decades as a measure of inflammation to gauge the risk of cardiovascular events, but it has poor predictive power. Consequently, “savvy cardiologists” no longer favor such tests. 

The growing number of aging clocks hitting the market in recent years—some based on genetics and others on metabolism—may be good correlates of biological age, he says, but so what? “I do not want [merely] a clock. I want something that informs me about morbidity and mortality and that is what we have here.”