An inflammatory aging clock (iAge) based on deep learning tracks multimorbidity, immunosenescence, frailty and cardiovascular aging.

Journal: Nature aging
PMID:

Abstract

While many diseases of aging have been linked to the immunological system, immune metrics capable of identifying the most at-risk individuals are lacking. From the blood immunome of 1,001 individuals aged 8-96 years, we developed a deep-learning method based on patterns of systemic age-related inflammation. The resulting inflammatory clock of aging (iAge) tracked with multimorbidity, immunosenescence, frailty and cardiovascular aging, and is also associated with exceptional longevity in centenarians. The strongest contributor to iAge was the chemokine CXCL9, which was involved in cardiac aging, adverse cardiac remodeling and poor vascular function. Furthermore, aging endothelial cells in human and mice show loss of function, cellular senescence and hallmark phenotypes of arterial stiffness, all of which are reversed by silencing CXCL9. In conclusion, we identify a key role of CXCL9 in age-related chronic inflammation and derive a metric for multimorbidity that can be utilized for the early detection of age-related clinical phenotypes.

Authors

  • Nazish Sayed
    Stanford 1000 Immunomes Project, Stanford University School of Medicine, Stanford, CA, USA.
  • Yingxiang Huang
    Buck Artificial Intelligence Platform, the Buck Institute for Research on Aging, Novato, CA, USA.
  • Khiem Nguyen
    Buck Artificial Intelligence Platform, the Buck Institute for Research on Aging, Novato, CA, USA.
  • Zuzana Krejciova-Rajaniemi
    Edifice Health Inc., San Mateo, CA, USA.
  • Anissa P Grawe
    Buck Artificial Intelligence Platform, the Buck Institute for Research on Aging, Novato, CA, USA.
  • Tianxiang Gao
    Department of Computer Science, University of North Carolina, Chapel Hill, NC, USA.
  • Robert Tibshirani
    Department of Statistics, Stanford University , Stanford, California 94305, United States.
  • Trevor Hastie
    Department of Statistics, Stanford University, Stanford, CA 94305, USA.
  • Ayelet Alpert
    Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel.
  • Lu Cui
    Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
  • Tatiana Kuznetsova
    3 Research Unit Hypertension and Cardiovascular Epidemiology KU Leuven Department of Cardiovascular Sciences University of Leuven Belgium.
  • Yael Rosenberg-Hasson
    Human Immune Monitoring Center, Stanford University, Stanford, CA 94304.
  • Rita Ostan
    Interdepartmental Centre L. Galvani (CIG), Alma Mater Studiorum, University of Bologna, Bologna, Italy.
  • Daniela Monti
    Department of Experimental Clinical and Biomedical Sciences, Mario Serio, University of Florence, Florence, Italy.
  • Benoit Lehallier
    Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California.
  • Shai S Shen-Orr
    Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. shenorr@technion.ac.il.
  • Holden T Maecker
    Molecular Biology and Biochemistry Department, Simon Fraser University, Burnaby, BC V5A 1S6, Canada, Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC V5Z 1L3, Canada, Department of Neurology, University at Buffalo School of Medicine and Biomedical Sciences, Buffalo, NY 14203, USA, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA, Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA, Center for Human Immunology, Autoimmunity and Inflammation, National Institutes of Health, Bethesda, MD 20892, USA, School of Dental Medicine, University at Buffalo, NY 14214-8006, USA, J. Craig Venter Institute, La Jolla, CA 92037, USA, Department of Pathology, University of California, San Diego, CA 92093, USA.
  • Cornelia L Dekker
    Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94304.
  • Tony Wyss-Coray
    Department of Neurology and Neurological Sciences, Stanford University, Stanford, California, USA.
  • Claudio Franceschi
    Institute of Information Technologies, Mathematics and Mechanics, Lobachevsky University, Nizhny, Russia.
  • Vladimir Jojic
    Edifice Health Inc., San Mateo, CA, USA.
  • Francois Haddad
    Division of Cardiovascular Medicine (F.H.), in the Department of Medicine, Stanford University, CA.
  • José G Montoya
    Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
  • Joseph C Wu
  • Mark M Davis
    Institute of Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA 94304.
  • David Furman
    Stanford 1000 Immunomes Project, Stanford University School of Medicine, Stanford, CA, USA.