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International Association of Biomedical Gerontology 10 th Congress Queens College/Cambridge September 2003 T cell Rep

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.

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International Association of Biomedical Gerontology 10 th Congress Queens College/Cambridge September 2003 T cell Rep

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  1. International Association of Biomedical Gerontology 10th 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 Medicineat UCLA

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

  3. Cytotoxic ( CD8) T cells > 1018 different antigen receptors

  4. Replicative senescence

  5. Reduced apoptosis

  6. Effect of repeated stimulation on telomerase

  7. Effect of repeated stimulation on telomerase *

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

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

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

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

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

  13. REGULATION OF BONE RESORPTION Role of T cells REGULATION OF OC FORMATION AND FUNCTION Model T CELLS MONOCYTES Stimulatory Factors RANKL TNFa IL-1 TNFa Inhibitory Factors TNFa ACTIVE OC OC PRECURSORS Differentiation and activation OPG M-CSF RANKL RANKL IL-6 PGE2 GM-CSF TGFb TGFb STROMAL CELLS (Modified from SAGE KE/ B.L. Riggs)

  14. Effect of culture “age” onproduction of TNF alpha TNFa pg/ml 4 16 25 Population Doublings

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

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

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

  18. Correction of senescence-associated cytotoxic defect

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

  20. Collaborators and SupportUCLA Xiaoming Zhu Hector Valenzuela Otto Yang Mirabelle Dagarag Janis Giorgi Lucia Graham Roger Detels Tankdik Evazyan Farhad ParhamiGeron Corporation Calvin Harley, Choy-Pik Chiu (UC BioSTAR, NIH ,Plott Endowment, UCLA Center on Aging)

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