·        Researchers developed an aging clock based on inflammation patterns from the blood of 1,001 individuals aged 8 to 96 years.
·        The resulting inflammatory clock of aging (iAge) tracks for multiple diseases and frailty.
·        iAge also predicts cardiovascular disease and exceptional longevity in centenarians.

For over a hundred years, the immune system has been recognized for its essential role in maintaining human health. But only in the past few decades has it become apparent that compounds linked to inflammation are often chronically elevated in aged individuals and people with age-related diseases like cancer, neurodegenerative disorders, and cardiovascular disease. So, can patterns of inflammatory components in the blood be interpreted like fortune-tellers do tea leaves to inform us of our biological age — the actual age of our cells instead of our age in years — and whether we’re at risk of age-related diseases?

That’s precisely what Nazish Sayed and colleagues from Stanford University School of Medicine did — they generated an aging clock called iAge based on inflammation patterns in the blood. Not only can this aging clock track with a person’s total number of age-related diseases (multimorbidity), frailty, and exceptional longevity, iAge can assess cardiovascular disease risk in otherwise healthy individuals. In their article published in Nature Aging, the authors propose that iAge can be used as a companion diagnostic to inform physicians about a patient’s overall health status.

Patterns of inflammatory compounds predict age and frailty

Between 2007 and 2016, blood samples were drawn from 1,001 ambulatory participants aged 8 to 96 years recruited at Stanford University for two studies: one on aging and vaccination and another on chronic fatigue syndrome. The blood samples from these participants were profiled for all sorts of immune and inflammatory molecules.

​​Using sophisticated computational methods, Sayed and colleagues constructed a metric for age-related chronic inflammation that could summarize an individual’s cumulative inflammatory burden. This metric, which the authors called iAge, was then put to the test for its ability to predict age and frailty — which it did pretty well.

After establishing that the inflammatory burden reflected in the iAge score was correlated with chronological age — as iAge scores increased, so did age — Sayed and colleagues also assessed the importance of iAge in age-related functional deterioration. When iAge was used to examine older adults over seven years from 2010 to 2017, they found that iAge from 2010 was predictive of frailty score in 2017. Notably, compared to chronological age, the link between iAge to frailty score was significantly stronger.

“Using iAge it’s possible to predict seven years in advance who is going to become frail. That leaves us lots of room for interventions,” Senior author David Furman, Ph.D., Buck Institute Associate Professor, Director of the 1001 Immunomes Project at Stanford University School of Medicine, commented in a press release.

(Sayed et al., 2021 | Nature Aging) The inflammatory clock of aging (iAge) tracks with age and frailty. a, Using 50 circulating immune proteins, Sayed and colleagues derived iAge to predict chronological age. c, For a subset of older adults, frailty was assessed in 2017 using a modified frailty score. iAge measured in 2010 predicted the frailty score seven years in advance. 

Centenarians have a low inflammatory burden

Next, Sayed explored the relationship between iAge and longevity by looking at a cohort of 37 individuals from Bologna, Italy: 19 were centenarians and 18 controls 50 to 79 years old. Thirteen out of 19 (68%) centenarians had low iAge scores, whereas only 31% (6 out of 19) were in the high-rank group. In contrast, 77% (14 out of 18) of controls in the high rank versus 23% in the low-rank group. This indicates that regardless of chronological age, iAge is predictive of exceptional 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,” said Furman.

Chronic inflammation is linked to age-related disease

Since multimorbidity has become the gold standard in aging research as it represents the accumulation of physiological damage in an individual and is a top priority for global health, Sayed and colleagues tested if multimorbidity correlated with iAge. To do so, they analyzed diseases of 10 different physiological systems, including cancer, cardiovascular, and psychiatric dysfunctions.

As older adults in this study (>60 years old) presented with more age-related diseases, the iAge score increased. Collectively, these results highlight the critical role of inflammation in the accumulation of physiological damage during aging and show that the inflammatory clock is a metric for overall health linked to multiple diseases associated with aging.

“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,” said Furman. “We now have means of detecting dysfunction and a pathway to intervention before full-blown pathology occurs.”

(Sayed et al., 2021 | Nature Aging) The inflammatory clock of aging (iAge) tracks multimorbidity and extended longevity. iAge was significantly correlated with multimorbidity in the older population analyzed (>60 years old). Ten age-related diseases were selected to characterize the clinical significance of iAge. The items studied included different diseases and physiological systems: cancer, cardiovascular, respiratory, gastrointestinal, urologic, neurologic, endocrine–metabolic, musculoskeletal, genital–reproductive, and psychiatric. All these disease features were binary. e, The inflammatory index (rank cAge minus rank iAge) was compared between a healthy group of older adults (age-range 50–79 years) and centenarian participants (age-range 99–107 years). Centenarians were overrepresented in individuals with low iAge index (protective), whereas the control older adults were over-represented in individuals with high iAge index.

What’s more, this clock identified those at risk for early cardiovascular aging within healthy older adults with no clinical or laboratory evidence of cardiovascular disease.

“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.”

The 10th Hallmark of Aging

This isn’t the first and only tool used to determine age. There are nine well-established hallmarks of aging: (1) genomic instability, (2) shortening telomere length, (3) epigenetic modifications, (4) loss of proteostasis, (5) deregulated nutrient sensing, (6) mitochondrial dysfunction, (7) cellular senescence, (8) stem cell exhaustion and (9) altered intracellular communication, have all been shown to be linked to sustained systemic inflammation.

“It’s clear that all of these nine hallmarks are, by and large, triggered by having systemic chronic inflammation in your body,” concluded Furman. “I think of inflammation as the 10th hallmark.”

But one of the limitations of biological clocks, in general, is that they do not directly provide the mechanism by which they work. While it is possible to infer causality between aging and these hallmarks, individual biomarkers selected from biological aging clocks need to be experimentally tested to elucidate the underlying mechanism. That’s one of the strong suits of this article, as Sayed and colleagues showed there was a strong link between elevated iAge and inadequate short-term immune responses.

Furman thinks that the iAge most certainly trumps the chronological information derived from a birth certificate or driver’s license when it comes to health and longevity.

“It’s becoming clear that we have to pay more attention to the immune system with age, given that almost every age-related malady has inflammation as part of its etiology.”

Nevertheless, it will be interesting to see how iAge matches up with existing aging clocks based off these hallmarks of aging. Some of the notable aging clocks use all sorts of characteristics, from those using a wide array of biological modalities to facial features. The current standard efforts have mostly been exploring each modality in isolation. Future attention would benefit from combining modalities to provide a more holistic resolution to the aging process.