A clinically meaningful metric of immune age derived from high-dimensional longitudinal monitoring

Nature Medicine

Volumn 25, Issue 3, 2019, Pages 487-495

  Alpert, Ayelet ^a   Pickman, Yishai ^a   Leipold, Michael ^b   Rosenberg Hasson, Yael ^b   Ji, Xuhuai ^b   Gaujoux, Renaud ^a,c   Rabani, Hadas ^a   Starosvetsky, Elina ^a   Kveler, Ksenya ^a   Schaffert, Steven ^b   Furman, David ^b   Caspi, Oren ^a,d   Rosenschein, Uri ^a,e   Khatri, Purvesh ^b   Dekker, Cornelia L ^b   Maecker, Holden T ^b   Davis, Mark M ^b,f   Shen Orr, Shai S ^a  

^a TECHNION ISRAEL INSTITUTE OF TECHNOLOGY   (Israel)

^b STANFORD UNIVERSITY SCHOOL OF MEDICINE   (United States)

^c CytoReason   (Israel)

^d Rambam Health Care Campus ^*  (Israel)

^e BNAI ZION MEDICAL CENTER   (Israel)

^f HOWARD HUGHES MEDICAL INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ADULT; AGED; AGING; ALL CAUSE MORTALITY; ARTICLE; CONTROLLED STUDY; FEMALE; HEART; HOMEOSTASIS; HUMAN; HUMAN TISSUE; IMMUNE STATUS; IMMUNE SYSTEM; MAJOR CLINICAL STUDY; MALE; MONITORING; OMICS; RISK ASSESSMENT; RISK FACTOR; STEADY STATE; IMMUNOLOGY; IMMUNOSENESCENCE; INDIVIDUALITY; LONGITUDINAL STUDY; LYMPHOCYTE; MIDDLE AGED; MORTALITY; MULTIVARIATE ANALYSIS; NORMAL HUMAN; PHENOTYPE; PROPORTIONAL HAZARDS MODEL; VERY ELDERLY; YOUNG ADULT;

CYTOKINE;

ADULT; AGED; AGED, 80 AND OVER; AGING; CYTOKINES; FEMALE; HEALTHY VOLUNTEERS; HUMANS; IMMUNOSENESCENCE; INDIVIDUALITY; LONGITUDINAL STUDIES; LYMPHOCYTES; MALE; MIDDLE AGED; MORTALITY; MULTIVARIATE ANALYSIS; PHENOTYPE; PROPORTIONAL HAZARDS MODELS; YOUNG ADULT;

EID: 85062635358     PISSN: 10788956     EISSN: 1546170X     Source Type: Journal    
DOI: 10.1038/s41591-019-0381-y     Document Type: Article

References (43)

1. Goronzy, J. J. & Weyand, C. M. Understanding immunosenescence to improve responses to vaccines. Nat. Immunol. 14, 428–436 (2013).
2. Deleidi, M., Jggle, M. & Rubino, G. Immune ageing, dysmetabolism and inflammation in neurological diseases. Front. Neurosci. 9, 172 (2015).
3. Dorshkind, K., Montecino-Rodriguez, E. & Signer, R. A. J. The ageing immune system: is it ever too old to become young again? Nat. Rev. Immunol. 9, 57–62 (2009).
4. Gruver, A. L., Hudson, L. L. & Sempowski, G. D. Immunosenescence of ageing. J. Pathol. 211, 144–156 (2007).
5. McElhaney, J. E. Influenza vaccine responses in older adults. Ageing Res. Rev. 10, 379–388 (2011).
6. Carr, E. J. et al. The cellular composition of the human immune system is shaped by age and cohabitation. Nat. Immunol. 17, 461–468 (2016).
7. Nikolich-Žugich, J. The twilight of immunity: emerging concepts in aging of the immune system. Nat. Immunol. 19, 10–19 (2018).
8. Ló Pez-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).
9. Franceschi, C. et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann. N. Y. Acad. Sci. 908, 244–254 (2000).
10. Shen-Orr, S. S. et al. Defective signaling in the JAK-STAT pathway tracks with chronic inflammation and cardiovascular risk in aging humans. Cell Syst. 3, 374–384.e4 (2016).
11. Furman, D. et al. Expression of specific inflammasome gene modules stratifies older individuals into two extreme clinical and immunological states. Nat. Med. 23, 174–184 (2017).
12. Orrù, V. et al. Genetic variants regulating immune cell levels in health and disease. Cell 155, 242–256 (2013).
13. Patin, E. et al. Natural variation in the parameters of innate immune cells is preferentially driven by genetic factors. Nat. Immunol. 19, 302–314 (2018).
14. Roederer, M. et al.The genetic architecture of the human immune system: a bioresource for autoimmunity and disease pathogenesis. Cell 161, 387–403 (2015).
15. Brodin, P. et al. Variation in the human immune system is largely driven by non-heritable Influences. Cell 160, 37–47 (2015).
16. Tsang, J. S. Utilizing population variation, vaccination, and systems biology to study human immunology. Trends Immunol. 36, 479–493 (2015).
17. Shen-Orr, S. S. & Furman, D. Variability in the immune system: Of vaccine responses and immune states. Curr. Opin. Immunol. 25, 542–547 (2013).
18. Brodin, P. & Davis, M. M. Human immune system variation. Nat. Rev. Immunol. 17, 21–29 (2017).
19. Kaczorowski, K. J. et al. Continuous immunotypes describe human immune variation and predict diverse responses. Proc. Natl Acad. Sci. USA 114, E6097–E6106 (2017).
20. Horvath, S. et al. An epigenetic clock analysis of race/ethnicity, sex, and coronary heart disease. Genome Biol. 17, 171 (2016).
21. Clegg, A., Young, J., Iliffe, S., Rikkert, M. O. & Rockwood, K. Frailty in elderly people. Lancet 381, 62167-62169 (2013).
22. Nakaya, H. I. et al. Systems analysis of immunity to influenza vaccination across multiple years and in diverse populations reveals shared molecular signatures. Immun ity 43, 1186–1198 (2015).
23. Bektas, A., Schurman, S. H., Sen, R. & Ferrucci, L. Aging, inflammation and the environment. Exp. Gerontol. 105, 10–18 (2018).
24. Pawelec, G. Immune parameters associated with mortality in the elderly are context-dependent: lessons from Sweden, Holland and Belgium. Biogerontology 19, 537–545 (2018).
25. Lin, Y. et al. Changes in blood lymphocyte numbers with age in vivo and their association with the levels of cytokines/cytokine receptors. Immun. Ageing 13, 24 (2016).
26. Strogatz, S. H. Nonlinear Dynamics and Chaos: With Applications to Physics, Biology, Chemistry, and Engineering (Studies in Nonlinearity) 1st edn (Addison-Wesley, Reading, Mass., 1994).
27. Furman, D. et al. Apoptosis and other immune biomarkers predict influenza vaccine responsiveness. Mol. Syst. Biol. 9, 659 (2013).
28. Merino, J. et al. Progressive decrease of CD8high+ CD28+ CD57– cells with ageing. Clin. Exp. Immunol. 112, 48–51 (1998).
29. Afzali, B. et al. CD161 expression characterizes a subpopulation of human regulatory T cells that produces IL-17 in a STAT3-dependent manner. Eur. J. Immunol. 43, 2043–2054 (2013).
30. Haghverdi, L., Büttner, M., Wolf, F. A., Buettner, F. & Theis, F. J. Diffusion pseudotime robustly reconstructs lineage branching. Nat. Methods 13, 845–848 (2016).
31. Shen-Orr, S. S. et al. Defective signaling in the JAK-STAT pathway tracks with chronic inflammation and cardiovascular risk in aging humans. Cell Syst. 3, 374–384.e4 (2016).
32. D’Agostino, R. B. et al. General cardiovascular risk profile for use in primary care: The Framingham Heart Study. Circulation 117, 743–753 (2008).
33. Barbie, D. A. et al. Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature 462, 108–112 (2009).
34. Horvath, S. DNA methylation age of human tissues and cell types. Genome Biol. 14, R115 (2013).
35. Marioni, R. E. et al. DNA methylation age of blood predicts all-cause mortality in later life. Genome Biol. 16, 25 (2015).
36. Waddington, C. H. The Strategy of the Genes. A Discussion of Some Aspects of Theoretical Biology. With an Appendix by H. Kacser (George Allen & Unwin, London, 1957).
37. Pawelec, G. Immune parameters associated with mortality in the elderly are context-dependent: lessons from Sweden, Holland and Belgium. Biogerontology 19, 537–545 (2018).
38. Ridker, P. M. et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 377, 1119–1131 (2017).
39. Blazkova, J. et al. Multicenter systems analysis of human blood reveals immature neutrophils in males and during pregnancy. J. Immunol. 198, 2479–2488 (2017).
40. Furman, D. et al. Systems analysis of sex differences reveals an immunosuppressive role for testosterone in the response to influenza vaccination. Proc. Natl Acad. Sci. USA 111, 869–874 (2014).
41. Furman, D. et al. Cytomegalovirus infection enhances the immune response to influenza. Sci. Transl. Med. 7, 281ra43 (2015).
42. Dai, H., Leeder, J. S. & Cui, Y. A modified generalized Fisher method for combining probabilities from dependent tests. Front. Genet. 5, 32 (2014).
43. Novershtern, N. Densely interconnected transcriptional circuits control cell states in human hematopoiesis. Cell 144, 296–309 (2011).