Advertisement

Immune Parameters Associated with Mortality in Longitudinal Studies of Very Old People Can Be Markedly Dissimilar Even in Apparently Similar Populations

  • Graham PawelecEmail author
  • David Goldeck
Chapter
Part of the Healthy Ageing and Longevity book series (HAL, volume 10)

Abstract

While challenging, only longitudinal studies can pinpoint biomarkers dynamically associated with a selected outcome. In human studies of ageing, this challenge is particularly onerous, both in terms of the time required and the outcome selected. While recognizing the limitations of our approach, taking the most robust and unequivocal outcome (all-cause mortality), and taking a very old population as the starting point, we have sought to define peripheral blood “immune signatures” predicting incipient mortality. Studies in overtly similar populations in Sweden, Belgium and The Netherlands reveal certain constellations of immune biomarkers associated with all-cause mortality in people >80 years of age. Unexpectedly, however, these “immune risk profiles” are different in the different populations. Thus, it is unlikely that it will be possible to identify “one-size-fits-all” biomarkers of ageing in different populations, at least when solely focusing on parameters of immunity.

Keywords

Immunosenescence Longitudinal studies Immune signatures Immune risk profile Cytomegalovirus Inflammaging Biomarker of aging Mortality 

Notes

Acknowledgements

The author’s own work was most recently supported by grants from the Deutsche Forschungsgemeinschaft (DFG PA 361/22), the Bundesministerium für Bildung und Forschung (BMBF 16SV5536K), the European Commission (FP7 LIP F2-2011-259679, IDEAL), and an unrestricted educational grant from the Croeni Foundation.

References

  1. Adriaensen W, Derhovanessian E, Vaes B, Van Pottelbergh G, Degryse JM, Pawelec G et al (2015) CD4:8 ratio >5 is associated with a dominant naive T-cell phenotype and impaired physical functioning in CMV-seropositive very elderly people: results from the BELFRAIL study. J Gerontol A Biol Sci Med Sci 70(2):143–154.  https://doi.org/10.1093/gerona/glu018. PubMed PMID: 24568932CrossRefPubMedGoogle Scholar
  2. Adriaensen W, Pawelec G, Vaes B, Hamprecht K, Derhovanessian E, van Pottelbergh G et al (2017) CD4:8 ratio above 5 is associated with all-cause mortality in CMV-seronegative very old women: results from the BELFRAIL study. J Gerontol A Biol Sci Med Sci 72(9):1155–1162.  https://doi.org/10.1093/gerona/glw215. PubMed PMID: 27927759CrossRefPubMedGoogle Scholar
  3. Alam I, Goldeck D, Larbi A, Pawelec G (2013) Aging affects the proportions of T and B cells in a group of elderly men in a developing country–a pilot study from Pakistan. Age (Dordr) 35(5):1521–1530.  https://doi.org/10.1007/s11357-012-9455-1. PubMed PMID: 22810104; PubMed Central PMCID: PMCPMC3776124CrossRefGoogle Scholar
  4. Bertram L, Bockenhoff A, Demuth I, Duzel S, Eckardt R, Li SC et al (2014) Cohort profile: the Berlin aging study II (BASE-II). Int J Epidemiol 43(3):703–712.  https://doi.org/10.1093/ije/dyt018. PubMed PMID: 23505255CrossRefPubMedGoogle Scholar
  5. Cao Dinh H, Bautmans I, Beyer I, Mets T, Onyema OO, Forti LN et al (2018) Association between immunosenescence phenotypes and pre-frailty in older subjects: does cytomegalovirus play a role? J Gerontol A Biol Sci Med Sci.  https://doi.org/10.1093/gerona/gly135. PubMed PMID: 29924317CrossRefGoogle Scholar
  6. Collerton J, Martin-Ruiz C, Davies K, Hilkens CM, Isaacs J, Kolenda C et al (2012) Frailty and the role of inflammation, immunosenescence and cellular ageing in the very old: cross-sectional findings from the Newcastle 85+ Study. Mech Ageing Dev 133(6):456–466.  https://doi.org/10.1016/j.mad.2012.05.005. PubMed PMID: 22663935CrossRefPubMedGoogle Scholar
  7. Colonna-Romano G, Buffa S, Bulati M, Candore G, Lio D, Pellicano M et al (2010) B cells compartment in centenarian offspring and old people. Curr Pharm Des 16(6):604–608. PubMed PMID: 20388070CrossRefGoogle Scholar
  8. Derhovanessian E, Maier AB, Beck R, Jahn G, Hahnel K, Slagboom PE et al (2010) Hallmark features of immunosenescence are absent in familial longevity. J Immunol 185(8):4618–4624.  https://doi.org/10.4049/jimmunol.1001629. PubMed PMID: 20855876CrossRefPubMedGoogle Scholar
  9. Derhovanessian E, Maier AB, Hahnel K, Zelba H, de Craen AJ, Roelofs H et al (2013) Lower proportion of naive peripheral CD8+ T cells and an unopposed pro-inflammatory response to human Cytomegalovirus proteins in vitro are associated with longer survival in very elderly people. Age (Dordr) 35(4):1387–1399.  https://doi.org/10.1007/s11357-012-9425-7. PubMed PMID: 22661297; PubMed Central PMCID: PMCPMC3705124CrossRefGoogle Scholar
  10. Formiga F, Ferrer A, Padros G, Cintra A, Pujol R (2014) Inverted CD4:CD8 ratio is not associated with three-year mortality in a sample of community-dwelling oldest old: the OCTABAIX immune study. J Nutr Health Aging 18(4):425–428.  https://doi.org/10.1007/s12603-013-0403-2. PubMed PMID: 24676325CrossRefPubMedGoogle Scholar
  11. Fulop T, Witkowski JM, Pawelec G, Alan C, Larbi A (2014) On the immunological theory of aging. Interdiscip Top Gerontol 39:163–176.  https://doi.org/10.1159/000358904. PubMed PMID: 24862019CrossRefPubMedGoogle Scholar
  12. Goldeck D, Larsen LA, Christiansen L, Christensen K, Hamprecht K, Pawelec G et al (2016) Genetic Influence on the Peripheral Blood CD4+ T-cell Differentiation Status in CMV Infection. J Gerontol A Biol Sci Med Sci 71(12):1537–1543.  https://doi.org/10.1093/gerona/glv230. PubMed PMID: 26755680CrossRefPubMedGoogle Scholar
  13. Hadrup SR, Strindhall J, Kollgaard T, Seremet T, Johansson B, Pawelec G et al (2006) Longitudinal studies of clonally expanded CD8 T cells reveal a repertoire shrinkage predicting mortality and an increased number of dysfunctional cytomegalovirus-specific T cells in the very elderly. J Immunol 176(4):2645–2653. PubMed PMID: 16456027CrossRefGoogle Scholar
  14. Huppert FA, Pinto EM, Morgan K, Brayne C (2003) Survival in a population sample is predicted by proportions of lymphocyte subsets. Mech Ageing Dev 124(4):449–451. PubMed PMID: 12714252CrossRefGoogle Scholar
  15. Jagger A, Shimojima Y, Goronzy JJ, Weyand CM (2014) Regulatory T cells and the immune aging process: a mini-review. Gerontology 60(2):130–137.  https://doi.org/10.1159/000355303. PubMed PMID: 24296590; PubMed Central PMCID: PMCPMC4878402CrossRefPubMedGoogle Scholar
  16. Lagaay AM, van Asperen IA, Hijmans W (1992) The prevalence of morbidity in the oldest old, aged 85 and over: a population-based survey in Leiden, The Netherlands. Arch Gerontol Geriatr 15(2):115–131. PubMed PMID: 15374369CrossRefGoogle Scholar
  17. Leng SX, Xue QL, Tian J, Walston JD, Fried LP (2007) Inflammation and frailty in older women. J Am Geriatr Soc 55(6):864–871.  https://doi.org/10.1111/j.1532-5415.2007.01186.x. PubMed PMID: 17537086CrossRefPubMedGoogle Scholar
  18. Mathei C, Vaes B, Wallemacq P, Degryse J (2011) Associations between cytomegalovirus infection and functional impairment and frailty in the BELFRAIL Cohort. J Am Geriatr Soc 59(12):2201–2208.  https://doi.org/10.1111/j.1532-5415.2011.03719.x. PubMed PMID: 22092044CrossRefPubMedGoogle Scholar
  19. Mathei C, Adriaensen W, Vaes B, Van Pottelbergh G, Wallemacq P, Degryse J (2015) No relation between CMV infection and mortality in the oldest old: results from the Belfrail study. Age Ageing 44(1):130–135.  https://doi.org/10.1093/ageing/afu094. PubMed PMID: 25026957CrossRefPubMedGoogle Scholar
  20. Ndumbi P, Gilbert L, Tsoukas CM (2015) Comprehensive evaluation of the immune risk phenotype in successfully treated HIV-infected individuals. PLoS ONE 10(2):e0117039.  https://doi.org/10.1371/journal.pone.0117039. PubMed PMID: 25647167; PubMed Central PMCID: PMCPMC4315523CrossRefPubMedPubMedCentralGoogle Scholar
  21. Nikolich-Zugich J (2018) The twilight of immunity: emerging concepts in aging of the immune system. Nat Immunol 19(1):10–19.  https://doi.org/10.1038/s41590-017-0006-x. PubMed PMID: 29242543CrossRefPubMedGoogle Scholar
  22. Olsson J, Wikby A, Johansson B, Lofgren S, Nilsson BO, Ferguson FG (2000) Age-related change in peripheral blood T-lymphocyte subpopulations and cytomegalovirus infection in the very old: the Swedish longitudinal OCTO immune study. Mech Ageing Dev 121(1–3):187–201. PubMed PMID: 11164473PubMedGoogle Scholar
  23. Pawelec G (2017) Does the human immune system ever really become “senescent”? F1000Res 6.  https://doi.org/10.12688/f1000research.11297.1. PubMed PMID: 28868129; PubMed Central PMCID: PMCPMC5553082CrossRefGoogle Scholar
  24. Pawelec G (2018) Immune parameters associated with mortality in the elderly are context-dependent: lessons from Sweden, Holland and Belgium. Biogerontology 19(6):537–545.  https://doi.org/10.1007/s10522-017-9739-z. PubMed PMID: 29185165CrossRefPubMedGoogle Scholar
  25. Pawelec G, Derhovanessian E, Larbi A, Strindhall J, Wikby A (2009) Cytomegalovirus and human immunosenescence. Rev Med Virol 19(1):47–56.  https://doi.org/10.1002/rmv.598. PubMed PMID: 19035529CrossRefPubMedGoogle Scholar
  26. Pellicano M, Larbi A, Goldeck D, Colonna-Romano G, Buffa S, Bulati M et al (2012) Immune profiling of Alzheimer patients. J Neuroimmunol 242(1–2):52–59.  https://doi.org/10.1016/j.jneuroim.2011.11.005. PubMed PMID: 22153977CrossRefPubMedGoogle Scholar
  27. Pellicano M, Buffa S, Goldeck D, Bulati M, Martorana A, Caruso C et al (2014) Evidence for less marked potential signs of T-cell immunosenescence in centenarian offspring than in the general age-matched population. J Gerontol A Biol Sci Med Sci 69(5):495–504.  https://doi.org/10.1093/gerona/glt120. PubMed PMID: 23974207CrossRefPubMedGoogle Scholar
  28. Plonquet A, Bastuji-Garin S, Tahmasebi F, Brisacier C, Ledudal K, Farcet J et al (2011) Immune risk phenotype is associated with nosocomial lung infections in elderly in-patients. Immun Ageing 8:8.  https://doi.org/10.1186/1742-4933-8-8. PubMed PMID: 21961997; PubMed Central PMCID: PMCPMC3203033CrossRefPubMedPubMedCentralGoogle Scholar
  29. Simanek AM, Dowd JB, Pawelec G, Melzer D, Dutta A, Aiello AE (2011) Seropositivity to cytomegalovirus, inflammation, all-cause and cardiovascular disease-related mortality in the United States. PLoS ONE 6(2):e16103.  https://doi.org/10.1371/journal.pone.0016103. PubMed PMID: 21379581; PubMed Central PMCID: PMCPMC3040745CrossRefPubMedPubMedCentralGoogle Scholar
  30. Spyridopoulos I, Martin-Ruiz C, Hilkens C, Yadegarfar ME, Isaacs J, Jagger C et al (2016) CMV seropositivity and T-cell senescence predict increased cardiovascular mortality in octogenarians: results from the Newcastle 85+ study. Aging Cell 15(2):389–392.  https://doi.org/10.1111/acel.12430. PubMed PMID: 26696322; PubMed Central PMCID: PMCPMC4783336CrossRefPubMedGoogle Scholar
  31. Strindhall J, Nilsson BO, Lofgren S, Ernerudh J, Pawelec G, Johansson B et al (2007) No immune risk profile among individuals who reach 100 years of age: findings from the Swedish NONA immune longitudinal study. Exp Gerontol 42(8):753–761.  https://doi.org/10.1016/j.exger.2007.05.001. PubMed PMID: 17606347CrossRefPubMedGoogle Scholar
  32. Vaes B, Pasquet A, Wallemacq P, Rezzoug N, Mekouar H, Olivier PA et al (2010) The BELFRAIL (BFC80 +) study: a population-based prospective cohort study of the very elderly in Belgium. BMC Geriatr 10:39.  https://doi.org/10.1186/1471-2318-10-39. PubMed PMID: 20565795; PubMed Central PMCID: PMCPMC2906485CrossRefPubMedPubMedCentralGoogle Scholar
  33. Wikby A, Johansson B, Ferguson F, Olsson J (1994) Age-related changes in immune parameters in a very old population of Swedish people: a longitudinal study. Exp Gerontol 29(5):531–541. PubMed PMID: 7828662CrossRefGoogle Scholar
  34. Wikby A, Ferguson F, Forsey R, Thompson J, Strindhall J, Lofgren S et al (2005) An immune risk phenotype, cognitive impairment, and survival in very late life: impact of allostatic load in Swedish octogenarian and nonagenarian humans. J Gerontol A Biol Sci Med Sci 60(5):556–565. PubMed PMID: 15972602CrossRefGoogle Scholar
  35. Xia X, Chen W, McDermott J, Han JJ (2017) Molecular and phenotypic biomarkers of aging. F1000Res 6:860.  https://doi.org/10.12688/f1000research.10692.1. PubMed PMID: 28663789; PubMed Central PMCID: PMCPMC5473407CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of ImmunologyUniversity of TübingenTübingenGermany
  2. 2.Health Sciences North Research Institute of CanadaSudburyCanada
  3. 3.Second Department of Internal MedicineUniversity of TübingenTübingenGermany

Personalised recommendations