Variations in Innate Immune Cell Subtypes Correlate with Epigenetic Clocks, Inflammaging and Health Outcomes

Advanced Science, vol. 12, pp. e05922

Abstract

Epigenetic clocks in blood have shown promise as tools to quantify biological age, displaying robust associations with morbidity and all-cause mortality. Whilst the effect of cell-type heterogeneity on epigenetic clock estimates has been explored, such studies have been limited to studying heterogeneity within the adaptive immune system. Much less is known about whether heterogeneity within the innate immune system can impact epigenetic clock estimates and their associations with health outcomes. Here, we apply a high-resolution DNAm reference panel of 19 immune cell-types, including young and adult monocyte, natural killer, and neutrophil subsets, demonstrating how shifts within these innate subtypes display associations with epigenetic clock acceleration, inflammaging, and all-cause mortality. The associations of monocyte heterogeneity with inflammation are further validated using transcriptomic and metabolomic data. Additionally, a non-negligible fraction of nucleated red blood cell-like cells in circulation is found to associate with inflammaging, markers of dysfunctional erythropoiesis, and is a major risk factor for all-cause mortality. These results extend findings obtained within the adaptive immune system to innate immune and erythrocyte-like cells, demonstrating how heterogeneity within these other blood cell compartments is also associated with inflammaging, epigenetic clocks, and health outcomes.

Authors 16

1. Xiaolong Guo

   Shanghai Institute of Nutrition and Health · University of Chinese Academy of Sciences

   Affiliation as printed

   Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences Chinese Academy of Sciences 320 Yue Yang Road Shanghai 200031 China

   Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai, 200031 China

2. Andrea Aparicio

   Brigham and Women's Hospital · Harvard University

   Affiliation as printed

   Channing Division of Network Medicine Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston MA 02115 USA

   Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115 USA

3. Kirsten Seale
   Affiliation as printed

   TruDiagnostics 881 Corporate Dr Lexington KY 40503 USA

   TruDiagnostics, 881 Corporate Dr, Lexington, KY, 40503 USA

4. Qingwen Chen

   Brigham and Women's Hospital · Harvard University

   Affiliation as printed

   Channing Division of Network Medicine Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston MA 02115 USA

   Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115 USA

5. Anne Richmond

   Institute of Genetics and Cancer · University of Edinburgh

   Affiliation as printed

   Centre for Genomic and Experimental Medicine Institute of Genetics and Cancer University of Edinburgh Edinburgh EH4 2XU UK

   Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, EH4 2XU UK

6. Zhaozhen Du

   Shanghai Institute of Nutrition and Health · University of Chinese Academy of Sciences

   Affiliation as printed

   Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences Chinese Academy of Sciences 320 Yue Yang Road Shanghai 200031 China

   Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai, 200031 China

7. Shijie Zheng

   Pfizer (United States)

   Affiliation as printed

   Pfizer Research & Development, Pfizer Inc. Groton Connecticut CT06340 USA

8. Esteban Ballestar

   Josep Carreras Leukaemia Research Institute · East China Normal University

   Affiliation as printed

   Epigenetics and Immune Disease Group Josep Carreras Leukaemia Research Institute (IJC) Badalona Barcelona 08916 Spain

   Epigenetics in Inflammatory and Metabolic Diseases Laboratory Health Science Center (HSC) East China Normal University (ECNU) Shanghai 200241 China

   Epigenetics and Immune Disease Group, Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, 08916 Spain

   Epigenetics in Inflammatory and Metabolic Diseases Laboratory, Health Science Center (HSC), East China Normal University (ECNU), Shanghai, 200241 China

9. Charlotte A. M. Cecil

   Erasmus MC · Erasmus MC - Sophia Children’s Hospital

   Affiliation as printed

   Department of Child and Adolescent Psychiatry/Psychology Sophia's Children Centre Erasmus MC Rotterdam 3015 CN The Netherlands

   Department of Child and Adolescent Psychiatry/Psychology, Sophia's Children Centre, Erasmus MC, Rotterdam, 3015 CN The Netherlands

10. Bastiaan T. Heijmans Aachen Department of Biomedical Data Sciences

    Leiden University Medical Center

    Affiliation as printed

    Department of Biomedical Data Sciences Leiden University Medical Center Einthovenweg 20 Leiden 2333 ZC The Netherlands

    Department of Biomedical Data Sciences, Leiden University Medical Center, Einthovenweg 20, Leiden, 2333 ZC The Netherlands

11. Steve Horvath
    Affiliation as printed

    Altos Labs Cambridge CB21 6GP UK

    Altos Labs, Cambridge, CB21 6GP UK

12. Varun B. Dwaraka corresponding
    Affiliation as printed

    TruDiagnostics 881 Corporate Dr Lexington KY 40503 USA

    TruDiagnostics, 881 Corporate Dr, Lexington, KY, 40503 USA

13. Jessica Ann Lasky-Su corresponding
    Affiliation as printed

    TruDiagnostics 881 Corporate Dr Lexington KY 40503 USA

    TruDiagnostics, 881 Corporate Dr, Lexington, KY, 40503 USA

14. Ryan C. Smith corresponding

    Brigham and Women's Hospital · Harvard University

    Affiliation as printed

    Channing Division of Network Medicine Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston MA 02115 USA

    Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115 USA

15. Riccardo E. Marioni corresponding

    Institute of Genetics and Cancer · University of Edinburgh

    Affiliation as printed

    Centre for Genomic and Experimental Medicine Institute of Genetics and Cancer University of Edinburgh Edinburgh EH4 2XU UK

    Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, EH4 2XU UK

16. Andrew Erich Teschendorff corresponding

    Shanghai Institute of Nutrition and Health · University of Chinese Academy of Sciences

    Affiliation as printed

    Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences Chinese Academy of Sciences 320 Yue Yang Road Shanghai 200031 China

    Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai, 200031 China