@article{4e9e5ca1a7c94defb4311dd2d45e38ff,
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.",
keywords = "aging, cardiovascular, cytokine responses, immune monitoring, immune signaling, immunosenescence, inflammaging, systems immunology",
author = "Shen-Orr, {Shai S.} and David Furman and Kidd, {Brian A.} and Francois Hadad and Patricia Lovelace and Huang, {Ying Wen} and Yael Rosenberg-Hasson and Sally Mackey and Grisar, {Fatemeh A.Gomari} and Yishai Pickman and Maecker, {Holden T.} and Chien, {Yueh hsiu} and Dekker, {Cornelia L.} and Wu, {Joseph C.} and Butte, {Atul J.} and Davis, {Mark M.}",
note = "Funding Information: We thank A. Alpert, E. Starosvetsky, A. Morgan, N. Kotecha, P. Khatri, R. Kafri, S. Kim, R. Tibshirani, J. Goronzy, C. Weyand, and U. Rosenschien for illuminating discussions; J. Ptacek and G. Nolan for invaluable help with the cytokine response assays; research nurses S. Swope, C. Walsh, and S. Cathey, clinical research associates K. Spann, A. Gutierrez, and R. Fleischman, administrative associate T. Quan, and medical assistant/phlebotomist M. Ugur at the Stanford-LPCH Vaccine Program; A. Skrenchuk and B. Oskotsky for computational support; and the Hewlett Packard Foundation and Lucile Packard Children{\textquoteright}s Hospital for computational resources. This work was supported in part by grants from the Ellison Medical Foundation, Howard Hughes Medical Institute, and National Institute of Allergy and Infectious Diseases (U19 AI057229 and U19 AI090019 to MMD and Bioinformatics Support Contract HHSN272201200028C to A.J.B.; BWF IRSA 1015009 and AHA 13EIA14420025 to J.C.W.), as well as Clinical and Translational Science Award 5UL1 RR025744 for the Stanford Center for Clinical and Translational Education and Research (Spectrum) from the National Center for Research Resources, National Institutes of Health. This trial is registered at http://www.clinicaltrials.gov as NCT01827462. S.S.S.-O. was supported in part by The Israeli Science Foundation (grant 1365/12). F.H. is supported by the Stanford Cardiovascular Institute. D.F. received support from the Stanford Center on Longevity. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: {\textcopyright} 2016",
year = "2016",
month = oct,
day = "26",
doi = "10.1016/j.cels.2016.09.009",
language = "English",
volume = "3",
pages = "374--384.e4",
journal = "Cell Systems",
issn = "2405-4712",
publisher = "Cell Press",
number = "4",
}