1. Immunosenescence - Results of BELFRAIL (and INCIVAR) By Adriaensen Wim Department of Public Health and Primary Care, KU Leuven & UCL, Belgium

2. What is Immunosenescence?  Aging of the immune system  While all components of innate and adaptive immunity are changed with age, the clinical impact of these changes is not clear, and mechanisms of and markers for immunosenesenescence are controversial.  contribute to morbidity and mortality in the elderly  Increased incidence of infectious diseases, cancers, cardiovascular diseases and neurodegeneration.  Decreased response to vaccination

3. Hallmarks  The HALLMARKS of immunosenescence are: T-cell senescence Inflammageing or low grade chronic systemic inflammation  Inflammageing seems to underlie most of the age-related diseases (atherosclerosis, diabetes, osteoporosis, sarcopenia, etc) and seems to be related to mortality of all causes in older persons Lymf Naïve T- cell B cell Helpe r T-cel Cytotox ic T-cel APC Plasmacel CD8+ CD4+ Differentiation Cytokines

4. Longitudinal studies  BELFRAIL (started in 2008)  a population-based prospective cohort study of the very elderly in Belgium (80 years or older)  Investigate association of hallmarks of immunosenescence and functional performance or mortality  INCIVAR (started in 2012)  Community-based cohort study  Investigate consequence of immunosenescence: reduced Influenza vaccination response

5. Hallmark 1: Inflammageing

6. BELFRAIL - Inflammageing  Extensive set of serum inflammatory markers

7. IL-6 best mortality predictor Lesser extent: hCRP IL-10 IL-1β

8. IL-6 robust marker in very elderly  Can be 100 times as high as in adults  Good marker in this age-category  Was most robustly associated with both impaired global functioning (cross-sectional) and global functioning decline (longitudinal).  Elevated serum inflammatory markers could maybe summarize global functional burden, because inflammation may be a common underlying cause of physical and mental impairment or have a final common pathway.

9. Previous literature  Cytokine dysregulation is believed to play a key role in the remodeling of the immune responses and physiological changes.  IL-6, TNF-α and CRP have been found to be related or to predict physical disability, with IL-6 as the most robust predictor  Il-1b, IL-6, IL-8, TNF-α and CRP have been associated with cognitive decline and dementia  is not validated in very elderly individuals, not consistent  Ideal inflammatory markers of clinical relevance to predict GLOBAL functioning?

11. Cross-sectional: Global impairment

12. Longitudinal: Global decline

13. Hallmark 2: T-cell senescence

14. BELFRAIL : T-cell Senescence  Primarily in the CD8+ T-cell subset  filling up the immunological space with memory/effector cells.  Resistance to apoptosis  Telomere shortening  Shrinkage of the T-cell repertoire Ag YOUNG Antigen-inexperienced MIDDLE AGE Antigen-exposed ELDERLY Antigen-overexposed Naïve Polyclonal expansions Central Memory and Effector-Memory Oligoclonal expansion Late-stage Effector Memory

15. What causes these changes with age in immunity?  CMV infection is associated with accumulation of the most late-differentiated CD8 cells and decreased CD8+ naïve cells

16. Chronic CMV hypothesis

17. Immune Risk Profile  A set of bioparameters associated increased health risk  two geographically-limited Swedish longitudinal studies: OCTA and NONA studies  Non-institutionalised individuals aged > 85 years in very good health  associated with poor immune function:  CMV seropositivity  an inversed CD4/CD8 ratio  expansion of CMV specific CD8 memory cells (CD8+CD28-cells)  poor T-cell proliferative response  low levels of B cells

18. CD27-CD28- Most late- differentiated memory cells ”senescent” or ”terminally” differentiated CD45RA+CCR7+ (naive) CD27+CD28+ (memory) CD27+CD28- (memory) CD27-CD28+ (memory) Middle-aged Old, not IRP Old, IRP Wikby et al., 2006

19. Immune Risk Profile  IRP was found to be associated with high mortality at 2,4 and 6 years follow-up.

20. CD4/CD8 ratio  Surrogate marker CD4/CD8

21. R>5 - Naïve Dominated phenotype

22. Physical impairment when infected with CMV

23. Influenza Vaccination Response  About 90% of all influenza-related deaths occur among people aged at least 65 years  Protective antibody measures:  17-53% in persons aged > 65 years  70-90% in younger populations  Influenza vaccine efficacy is generally assessed based on measuring of the titer of anti-hemagglutinin  Altough T cell response and not humoral antibodies, control the infection and correlate better with protection against influenza in older person  INCIVAR study (Influence of CMV infection on Influenza vaccination response)  humoral – cellular response after seasonal vaccin  100 CMV- 100 CMV+ persons

24. Conclusions  Immunosenescence has large impact in the very elderly  Inflammageing  IL-6 as robust marker for global functioning and mortality  T-cell senescence  CD4:8 ratio as marker for functioning and mortality  CMV as driving force  Reduced vaccination response

25. Thank you for your attention! Acknowledgements: -Jean-Marie Degryse -Cathy Matheï -Gijs Van Pottelbergh -Bert Vaes -Pierre Wallemacq -Graham Pawelec -Evelyna Derhovanessian -Karin Hahnel