1. International Association of Biomedical Gerontology 10 th Congress Queens College/Cambridge September 2003 T cell Replicative senescence: pleiotropic effects on human aging Rita B. Effros Dept of Pathology & Laboratory Medicine David Geffen School of Medicine at UCLA

2. Viral infections and aging l increased incidence and severity (influenza, RSV, HIV, SARS) l re-emergence of latent infections

3. Cytotoxic ( CD8) T cells > 10 18 different antigen receptors

4. Replicative senescence

6. Reduced apoptosis

7. Effect of repeated stimulation on telomerase

8. *

9. X Immunobiology: The Immune System in Health & Disease, 3 rd edition, by Janeway & Travers ( Current Biology Limited & Garland Publishing)

10. CD28-negative T cells  with age Boucher et al., Exp. Gerontol. 33:267, 1998 in CD4in CD8 Neonates NT NT Young adult (20-40) 4% 42% Elderly (70-90) 12% 79%

11. * CD28- T cells have shortened telomeres unable to proliferate resistant to apoptosis

12. Do senescent CD8 T cells affect other cell types and organ systems in vivo ?

13. CD8+ CD28- T cells l correlate with poor response to flu vaccine l suppress helper T cells l disease progression in ankylosing spondilitis l organ transplant patients-may suppress T cells that would reject the graft l correlate with osteoporotic fractures

14. REGULATION OF OC FORMATION AND FUNCTION Model REGULATION OF BONE RESORPTION Role of T cells T CELLS MONOCYTES ACTIVE OC STROMAL CELLS TGF  TNF  IL-6 PGE 2 GM-CSF M-CSF OC PRECURSORS TNF  TGF  Differentiation and activation Stimulatory Factors Inhibitory Factors RANKL OPG IL-1 TNF  RANKL (Modified from SAGE KE/ B.L. Riggs)

15. Effect of culture “age” on production of TNF alpha TNF  pg/ml 25164 Population Doublings

16. Production of “RANKL” by activated T cells (Receptor Activator for NFkB Ligand)

17. Production of RANKL by activated T cells RANKL ng/ml

18. Ectopic telomerase expression leads to lifespan extension of virus-specific CD8 T cells Telomere length stablization, prevents accumulation of p16, p21

19. Correction of senescence- associated cytotoxic defect

20. Replicative senescence l end stage of normal T cell differentiation l increased proportions in elderly l reduced anti-viral function l once generated, senescent CD8 T cells persist ? exert broad physiological effects l hTERT corrects only some of the defects associated with CD8 T cell senescence (CD28, compounds that  telomerase) l Reversal of T cell replicative senescence can improve both immune function and bone status

21. Collaborators and Support UCLA Xiaoming Zhu Hector ValenzuelaOtto Yang Mirabelle Dagarag Janis Giorgi Lucia Graham Roger Detels Tankdik EvazyanFarhad Parhami Geron Corporation Calvin Harley, Choy-Pik Chiu (UC BioSTAR, NIH,Plott Endowment, UCLA Center on Aging)