title: Defective Signaling in the JAK-STAT Pathway Tracks with Chronic Inflammation and Cardiovascular Risk in Aging Humans.
abstract: Chronic inflammation, a decline in immune responsiveness, and reduced cardiovascular function are all associated with aging, but the relationships among these phenomena remain unclear. Here, we longitudinally profiled a total of 84 signaling conditions in 91 young and older adults and observed an age-related reduction in cytokine responsiveness within four immune cell lineages, most prominently T cells. The phenotype can be partially explained by elevated baseline levels of phosphorylated STAT (pSTAT) proteins and a different response capacity of naive versus memory T cell subsets to interleukin 6 (IL-6), interferon α (IFN-α), and, to a lesser extent, IL-21 and IFN-γ. Baseline pSTAT levels tracked with circulating levels of C-reactive protein (CRP), and we derived a cytokine response score that negatively correlates with measures of cardiovascular disease, specifically diastolic dysfunction and atherosclerotic burden, outperforming CRP. Thus, we identified an immunological link between inflammation, decreased cell responsiveness in the JAK-STAT pathway, and cardiovascular aging. Targeting chronic inflammation may ameliorate this deficiency in cellular responsiveness and improve cardiovascular function.
authors.affiliation: Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Division of Systems Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Shai S
authors.initials: SS
authors.lastname: Shen-Orr
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute of Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: David
authors.initials: D
authors.lastname: Furman
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute of Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Kidd
authors.affiliation: Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Francois
authors.initials: F
authors.lastname: Hadad
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Human Immune Monitoring Center, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Lovelace
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Human Immune Monitoring Center, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Ying-Wen
authors.initials: YW
authors.lastname: Huang
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Human Immune Monitoring Center, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Yael
authors.initials: Y
authors.lastname: Rosenberg-Hasson
authors.affiliation: Division of Pediatric Infectious Diseases, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Sally
authors.initials: S
authors.lastname: Mackey
authors.affiliation: Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Fatemeh A Gomari
authors.initials: FA
authors.lastname: Grisar
authors.affiliation: Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel.
authors.forename: Yishai
authors.initials: Y
authors.lastname: Pickman
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute of Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA; Human Immune Monitoring Center, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Holden T
authors.initials: HT
authors.lastname: Maecker
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Yueh-Hsiu
authors.initials: YH
authors.lastname: Chien
authors.affiliation: Institute of Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA; Division of Pediatric Infectious Diseases, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Cornelia L
authors.initials: CL
authors.lastname: Dekker
authors.affiliation: Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Wu
authors.affiliation: Division of Systems Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: atul.butte@ucsf.edu.
authors.forename: Atul J
authors.initials: AJ
authors.lastname: Butte
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute of Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: mmdavis@stanford.edu.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Davis
mesh_terms: D000375:Aging; D002318:Cardiovascular Diseases; D016207:Cytokines; D006801:Humans; D007249:Inflammation; D007371:Interferon-gamma; D010766:Phosphorylation; D012307:Risk Factors; D050791:STAT Transcription Factors; D015398:Signal Transduction
chemical_list: D016207:Cytokines; D050791:STAT Transcription Factors; D007371:Interferon-gamma
keywords: aging; cardiovascular; cytokine responses; immune monitoring; immune signaling; immunosenescence; inflammaging; systems immunology