Immune responses generally decline with age. However, the dynamics of this process at the individual level have not been characterized, hindering quantification of an individual’s immune age. Here, we use multiple ‘omics’ technologies to capture population- and individual-level changes in the human immune system of 135 healthy adult individuals of different ages sampled longitudinally over a nine-year period. We observed high inter-individual variability in the rates of change of cellular frequencies that was dictated by their baseline values, allowing identification of steady-state levels toward which a cell subset converged and the ordered convergence of multiple cell subsets toward an older adult homeostasis. These data form a high-dimensional trajectory of immune aging (IMM-AGE) that describes a person’s immune status better than chronological age. We show that the IMM-AGE score predicted all-cause mortality beyond well-established risk factors in the Framingham Heart Study, establishing its potential use in clinics for identification of patients at risk.
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Source code is available from the corresponding author upon reasonable request.
Frequencies of gated cellular populations for the snapshot and ongoing data sets are in Supplementary Tables 3 and 5, respectively. Adjusted frequencies for the ongoing data set are in Supplementary Table 6. Subjects’ identities were shuffled to protect their privacy. Raw fcs files of the ongoing data set used for both cellular phenotyping and phospho-flow analysis were deposited into the Immport website (http://www.immport.org/immport-open/public/home/home) and can be downloaded using the following accession codes stratified by year: SDY212 (2008), SDY312 (2009), SDY311 (2010), SDY112 (2011), SDY315 (2012) and SDY478 (2013). Raw gene expression .CEL files for years 2011–2012 were deposited into the Immport website and can be downloaded using the following accession codes stratified by year: SDY112 (2011) and SDY315 (2012). Raw and processed gene expression data for years 2013–2015 are available in the GEO website (https://www.ncbi.nlm.nih.gov/geo/) through the following accession numbers: GSE123696 (2013), GSE123687 (2014) and GSE123698 (2015). Longitudinal clinical data of the participants are available in Supplementary Table 13, with the same shuffling of subjects’ identities used for cellular frequency data. DMAP gene expression data are publicly available on the GEO website (accession number GSE24759). Gene expression and methylation data from the Framingham Heart Study are available through dbGaP (study identifier phs000007). Phenotypic data are similarly available using the following accession codes: gender and age at exam 8 (pht003099); smoking status, blood pressure and blood pressure treatment (pht000747); HDL, total cholesterol and fasting glucose (pht000742); diabetes treatment (pht000041). Cardiovascular disease status at exam 8 and all-cause mortality during follow-up time were derived from the files ‘survival and follow-up status for cardiovascular events' (pht003316) and ‘survival – all cause mortality' (pht003317), respectively.
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We thank M. G’Sell for statistical analysis advice, O. Barak, B. Kidd, F. Haddad and members of the Shen-Orr lab for illuminating discussions; the clinical and administrative staff at the Stanford-Lucille Packard Children’s Hospital Vaccine Program; members of the Stanford Human Immune Monitoring Center for help with assay measurements; and D. Cohen for computational support. 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 M.M.D.; and from the Israeli Science Foundation (grant 1365/12), Rappaport Institute and Kolk family awards to S.S.S.-O. The project was supported by National Institutes of Health (NIH)/National Center for Research Resources Clinical and Translational Science Awards to Stanford University (UL1 RR025744). This trial is registered at http://www.clinicaltrials.gov as NCT01827462. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.