image: The first actionable clock that highlights the critical role of the immune system in the aging process view more
Credit: James O'Brien for the Buck Institute
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. Utilizing deep learning, a form of AI, in studies of the blood immunome of 1001 people, researchers also identified a modifiable chemokine associated with cardiac aging which can be used for early detection of age-related pathology and provides a target for interventions. Results are published in Nature Aging.
"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 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. "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."
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.
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 driver's license. "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.
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."
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."
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"
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Citation: Deep Learning Identifies an Inflammatory Clock which Predicts Multimorbidity, Immunosenescence, Frailty and Cardiovascular Aging in Humans DOI: 10.1038/s43587-021-00082-y
Other Buck Institute collaborators include Yingxiang Huang, Annisa P. Grawe, and Khiem Nguyen. Additional co-authors include Nazish Sayed and Mark Davis, Stanford 1000 Immunomes Project, Stanford University School of Medicine, Stanford, CA; Francois Haddad and Joseph C. Wu, Stanford Cardiovascular Institute, Stanford University School of Medicine; Zuzana Krejciova-Rajaniemi and Vladimir Jojic, Edifice Health Inc., San Mateo, CA; Tianxiang Gao, Department of Computer Science, University of North Carolina, Chapel Hill, NC; Robert Tibshirani and Trevor Hastie, Department of Statistics and Department of Biomedical Data Science, Stanford University School of Medicine; Ayelet Alpert, Israel Institute of Technology, Haifa, Israel; Lu Cui, Department of Pathology, Stanford University School of Medicine; Tatiana Kuznetsova, KU Leuven Department of Cardiovascular Sciences, University of Leuven, Belgium; Yael Rosenberg-Hasson and Holden T. Maecker, Human Immune Monitoring Center, Stanford University School of Medicine; Rita Ostan, Interdepartmental Centre L. Galvani, University of Bologna, Bologna, Italy; Daniela Monti, Department of Experimental Clinical and Biomedical Sciences, University of Florence, Florence, Italy; Benoit Lehallier and Tony Wyss-Coray, Department of Neurology and Neurological Sciences, Stanford University School of Medicine; Shai Shen-Orr, Department of Immunology, Israel Institute of Technology, Haifa, Israel; and Cornelia L. Dekker, Division of Pediatric Infectious Diseases, Stanford University School of Medicine; Claudio Franceschi, Institute of Neurological Sciences of Bologna, Bologna, Italy; and Jose G. Montoya, Department of Medicine, Stanford University School of Medicine.
DISCLOSURES
David Furman and Mark M Davis are co-founders of Edifice Health Inc., a company that utilizes iAge.
Acknowledgments:
Support for study came from the Buck Institute for Research on Aging,
The Ellison Foundation, NIH grants U19 AI057229, U19 AI090019, K01 HL135455, P50AG047366, and NIH/NCRR CTSA award number UL1 RR025744. This work was also supported by grants from the European Union (EU) Horizon 2020 Project PROPAG-AGEING (grant 634821), the EU JPND ADAGE project, the Ministry of Education and Science of the Russian Federation Agreement (grant 074-02-2018-330). Additional funding came from the Stanford TRAM scholar award, the Paul F. Glenn Foundation and the NIH Stanford Alzheimer's Disease Research Center.
About the Buck Institute for Research on Aging
At the Buck, we aim to end the threat of age-related diseases for this and future generations. We bring together the most capable and passionate scientists from a broad range of disciplines to study mechanisms of aging and to identify therapeutics that slow down aging. Our goal is to increase human health span, or the healthy years of life. Located just north of San Francisco, we are globally recognized as the pioneer and leader in efforts to target aging, the number one risk factor for serious diseases including Alzheimer's, Parkinson's, cancer, macular degeneration, heart disease, and diabetes. The Buck wants to help people live better longer. Our success will ultimately change healthcare. Learn more at: https://buckinstitute.org
Journal
Nature Aging