The Ticking Clock of Aging

by Amanda Chase, PhD
July 12, 2021

Aging is a gradual, time-dependent process that includes the onset of age-related diseases. Unfortunately, aging is associated with increased health problems, including, but not limited to, cardiovascular health. Aging can cause changes in the heart and blood vessels that increase a person’s risk of developing heart disease or heart failure, which significantly decreases quality of life. Although it is a natural process we all face, there is not a good understanding of the how, why, or rate of aging. Recently, more attention has been put towards not only understanding the aging process, but also how to lessen the associated aging diseases, including cardiovascular disease.

While the immune system is well known to play a critical role in maintaining human health and protection against infections, it has more recently become clear that components of the immune system are chronically elevated in aged individuals and are associated with an increased incidence of cardiovascular disease and others. Therefore, what if inflammation plays a critical role in regulating aging? And what if there could be a way for physicians to detect age-related disease early to allow more preventative care?

A team of researchers from two institutions, Nazish Sayed, MD, PhD (Assistant Professor at Stanford Cardiovascular Institute and Division of Vascular Surgery) and Yingxiang Huang, PhD (co-first author) and corresponding author David Furman PhD (Associate Professor at Buck Institute for Research on Aging and Director of the Stanford 1000 Immunomes Project), utilized artificial intelligence to address both questions. They identified a protein that was associated with increased inflammation that could be used to indicate healthy versus unhealthy aging. Their findings from this international team were recently published in Nature Aging. Artificial intelligence refers to the use of large amounts of information or data to find recurring patterns and trends. Machine learning takes those large amounts of data and helps create a model based on that sample data to allow predictions to be made based on new data. Here, the researchers obtained blood from a group of 1001 subjects and analyzed the samples on several different platforms.

Study design. 1001 subjects (age 8-96) were recruited, and blood samples were collected. The Stanford Human Immune Monitoring Center performed several standard procedures to analyze the specimens. Clinical characterization was assessed via questionnaires for 902 participants, and comprehensive cardiovascular phenotyping was conducted for 97 healthy young and older adults. The iAge metric was derived from these data.

With that large amount of data, they then used machine learning to look for patterns of age-related inflammation. They developed an inflammatory clock of age-related chronic inflammation (iAge) that can predict important aging characteristics, including multiple morbidities, frailty, and cardiovascular aging. Uniquely, iAGE was associated with exceptional longevity in an independent cohort of individuals over one hundred years of age (centenarians). iAge has the important potential to be used as a diagnostic tool to identify those at risk for both non-communicable and infectious disease, as well as to identify healthy older adults at risk for early cardiovascular aging.

Interestingly, a major contributor to the inflammatory clock was a protein called CXCL9. This protein is a cytokine: a protein that is involved in regulating immune cell migration, differentiation, and activation. CXCL9 could be considered an immune biomarker for chronic age-related inflammation to serve as a metric of healthy vs unhealthy aging. A biomarker is a characteristic that can be measured and evaluated as a sign of a normal biological process. For example, blood pressure and cholesterol levels could be considered biomarkers for cardiovascular disease. As CXCL9 is mainly produced by aging endothelium, it is an optimal biomarker for chronic age-related inflammation and for levels of cardiovascular aging.

CXCL9 has previously been shown to be elevated in hypertension and in patients with left ventricular dysfunction. Here, the research team was able to validate CXCL9 as an indicator of cardiovascular pathology, independent of age, and could be used to predict subclinical levels of cardiovascular aging in otherwise healthy individuals. In fact, CXCL9 was shown to be the master regulator of vascular function, suggesting that future therapies targeting CXCL9 could prevent age-related deterioration of the vascular system, and possibly other physiological systems, to decrease age-related health problems.

Illustration. Artist depiction of Cardiovascular Inflammaging showing the immunological fire throughout humans as the body faces all sorts of challenges.

Other authors from this international team included Khiem Nguyen, Zuzana Krejciova-Rajaniemi, Anissa P. Grawe, Tianxiang Gao, Robert Tibshirani, Trevor Hastie, Ayelet Alpert, Lu Cui, Tatiana Kuznetsova, Yael Rosenberg-Hasson, Rita Ostan, Daniela Monti, Benoit Lehallier, Shai S. Shen-Orr, Holden T. Maecker, Cornelia L. Dekker, Tony Wyss-Coray, Claudio Franceschi, Vladimir Jojic, François Haddad, José G. Montoya, Joseph C. Wu, and Mark M. Davis.  Support for the conduct of these studies was from The Buck Institute for Research on Aging, the Ellison Foundation, National Institutes of Health (NIH) U19 AI057229, U19 AI090019, NIH/NCRR CTSA award number UL1 RR025744 and K01 HL135455. Additional funding included grants from the EU Horizon 2020 Project PROPAG-AGEING (grant 634821), the EU JPND ADAGE project, the Ministry of Education and Science of the Russian Federation Agreement (agreement no. 075-15-2020-808), Stanford TRAM scholar award, Stanford Alzheimer’s Disease Research Center P50AG047366 and the Paul F. Glenn Foundation.

Nazish Sayed, MD, PhD