Buck Institute announces aging clock for immunosenescence

10th hallmark of aging? Buck claims actionable clock can predict immunological health and chronic diseases of aging; research highlights the critical role of the immune system in the aging process.

Researchers from the Buck Institute and Stanford University 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. Results are published in Nature Aging.

Longevity.Technology: Immunosenescence is making headlines at the moment (BioAge, Niedernhofer’s work at the University of Minnesota), as is inflammaging. This research and the resulting paper are exciting because they draw together so many key elements of longevity research, including these and multimorbidity, aging clocks and frailty.

An actionable aging clock and a metric for multimorbidity that can be used for the early detection of age-related clinical phenotypes and rolled out to clinics and perhaps with additional research to home-testing could vault longevity research into the next phase. Detection and prevention are, of course, the goals, rather than amelioration or cure.

Longevity.Technology reached out to David Furman, PhD, Buck Institute Associate Professor, Director of the 1001 Immunomes Project at Stanford University School of Medicine and senior author of the study to find out his feelings about the research results and what he thinks the next steps might be.

“These results are extremely exciting since to date the field has lacked accurate biomarkers to identify those at risk for chronic disease and accelerated aging. Our test for systemic chronic inflammation (or inflammaging) not only tracks with cardiovascular aging, but also correlates with a multitude of other diseases associated with aging including frailty and immunological decline. Most importantly, unlike genes, which you cannot change, the iAge test is largely actionable and because the immunological proteins affected here are mechanistically linked to accelerated vascular aging, targeting these could prevent or delay the most feared diseases associated with older age.

Buck aging inflammation
Aging inflammation. Source: James O’Brien for the Buck Institute

“We have recently finished two double-blinded randomized controlled trials and showed that we can “move the needle” and lower iAge using certain bioactive compounds identified using our AI pipeline. I think the most logical next step is to run a larger trial utilizing iAge to demonstrate that these novel compounds targeting iAge proteins are not only able to lower iAge, but also to improve aging-related clinical phenotypes.

Twelve years ago, we had a dream, a vision, we thought that deconstructing a human blood sample into dozens of thousands of components in large cohorts, and then using AI and Machine Learning to pinpoint the immunological basis of aging was one way towards the molecular interception of people at risk before disease kicks off. Today I am thrilled to be able to say that the era of precision medicine and preventative healthcare is here.”

Using deep learning, a form of AI, in studies of the blood immunome of 1001 people, the researchers also identified a modifiable chemokine associated with cardiac aging; this can be used for early detection of age-related pathology and provides a target for interventions [1].

“Standard immune metrics which can be used to identify individuals most at risk for developing single or even multiple chronic diseases of aging have been sorely lacking,” said Furman. “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. We now have means of detecting dysfunction and a pathway to intervention before full-blown pathology occurs [2].”

According to first author Nazish Sayed, MD, PhD, Assistant Professor of Vascular Surgery at Stanford Medicine, the study identified the soluble chemokine CXCL9 as the strongest contributor to iAge. Furman described it as 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,” adding that silencing CXCL9 reversed loss of function in aging endothelial cells in both humans and mice [2].

Larger implications for iAge

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. Furman says 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 driving licence. “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,” he said [2].

Study results involving cardiac health were also validated in a separate group of 97 extremely healthy adults (age 25–90 years of age) recruited from Palo Alto, California. Furman says 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 [2].”

Furman says the tool can be used to track someone’s risk of developing multiple chronic diseases by assessing the cumulative physiological damage to their immune system. For example, age-related frailty can be predicted by comparing biological immune metrics with information about how long it takes someone to stand up from a chair and walk a certain distance as well as their degree of autonomy and independence. “Using iAge it’s possible to predict seven years in advance who is going to become frail,” he said. “That leaves us lots of room for interventions [2].”

Highlighting the connection between immune health and aging

In 2013 a group of researchers studying aging identified nine “hallmarks” of the aging process. Age-related immune system dysfunction was not part of the mix. “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,” said Furman.

“If you’re 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. It’s clear that all of these nine hallmarks are, by and large, triggered by having systemic chronic inflammation in your body. I think of inflammation as the 10th hallmark [2].”

Image courtesy of James O’Brien for the Buck Institute

[1] https://www.nature.com/articles/s43587-021-00082-y
[2] https://www.eurekalert.org/pub_releases/2021-07/bifr-fac070821.php