Graham Pawelec¹, Rita B. Effros², Calogero Caruso³, Ed Remarque ⁴, Yvonne Barnett⁵, Rafael Solana⁶

1 University of Tübingen, Tübingen, FRG, ² UCLA School of Medicine, Los Angeles, CA, USA , ³ Calogero Caruso, University of Palermo, Palermo, Italy , ⁴ Ed Remarque, University of Leiden, Leiden, Holland , ⁵ Yvonne Barnett, University of Ulster, Coleraine, Northern Ireland, ⁶ Rafael Solana, University of Córdoba, Córdoba, Spain

TABLE OF CONTENTS

1. Abstract

2. Introduction: What is immunosenescence?

3. Factors contributing to immunosenescence

3.1. Haematopoiesis
3.2. Thymus
3.3. Post-thymic aging

4. Alterations in T cell stimulation

4.1. Accessory cells
4.2. Costimulatory pathways

4.2.1. CD28
4.2.2. Other costimulators

4.3. T cell receptor signal transduction
4.4. Cytokine production and response

5. Clonal expansion after T cell activation

5.1. Culture models for immunosenescence: does the Hayflick Limit apply to normal T cells and if not, why not?
5.2. Does telomere attrition contribute to the replicative senescence of normal T cells?
5.3 Longevity of naive and memory cells
5.4 Activation-induced cell death and aging

6. Alterations in T cell subsets, repertoire and markers with aging

6.1. T cell subsets
6.2. T cell repertoire

7. Clinical relevance of immunosenescence

7.1. Infectious disease and cancer
7.2. Vaccination

8. Predictors of mortality and longevity

9. Possible approaches to interventionist manipulations

9.1. Vitamins and minerals; antioxidants
9.2. Hormones
9.3. Caloric restriction
9.4. Mutations and DNA repair
9.5. Stress

10. Perspectives

11. Acknowledgements

12. References

1. ABSTRACT

Deterioration of the immune system with aging ("immunosenescence") is believed to contribute to morbidity and mortality in man due to the greater incidence of infection, as well as possibly autoimmune phenomena and cancer in the aged. Dysregulation of T cell function is thought to play a critical part in these processes. Factors contributing to T cell immunosenescence may include a) stem cell defects, b) thymus involution, c) defects in antigen presenting cells (APC), d) aging of resting immune cells, e) disrupted activation pathways in immune cells, f) replicative senescence of clonally expanding cells. This review aims to consider the current state of knowledge on the scientific basis for and potential clinical relevance of those factors in immunosenescence.