Ben L. Pfeifer, M.D., Ph.D.
Director for Research and Development
Aeskulap-Hospital, Switzerland 2009
Experimental and clinical data show that ageing is associated with gradual deterioration of immune system function, generally referred to as immune-senescence. Compromised immunity not only contributes to decreased ability of the elderly to combat infectious disease, but also is responsible for their impaired response to vaccination, and probably increased occurrence of cancer.
Longitudinal studies have defined various progressive alterations in the aging immune system, whereby some functions are reduced; others remain unchanged or even up-regulated. It appears that the innate immune system is relatively preserved during aging in contrast to the more sophisticated, adaptive part of the immune system which exhibits profound changes, such as decline of absolute number of total T-cells (CD3+), decline of virgin T-cells (CD95-), increase in NK cells with well-preserved cytotoxic function, and reduction of B-cells. In particular, the exhaustion of virgin CD95- cells that are replaced by large clonal expansions of CD28- T-cells weakens the immune system function of the elderly, causing reduced defence against new antigenic challenges (viral, bacterial or neoplastic) ultimately impacting on human lifespan. This deterioration has been thought to be a consequence of thymic involution and chronic antigenic stimulation, most prominently from persistent infection with cytomegalovirus. Persistent infection is one of the driving forces for a chronic pro-inflammatory state associated with increases in type 1 (IL-2, IFN-gamma, TNF-alpha) and type 2 (IL-4,-6,-10) positive CD8+ T-cells conducive for various inflammatory pathologies of old age such as arteriosclerosis, dementia and cancer.
Cancer is generally considered a disease of old age. A dysfunctional immunity in the elderly contributes to compromised immune-surveillance leading to increased cancer incidence. The likelihood of developing some form of cancer, indeed, is increasing significantly after the age of 60 years. The lifetime risk of developing cancer is one in two for males and one in three for females. The overall cure rate for cancer is still below 50%. Metastatic cancer cannot be cured at all, today. It is estimated that deaths from cancer will continue to exceed even those from tuberculosis, malaria and AIDS combined. How effectively cancer cells can be controlled by the immune system is still controversial. There is clear evidence that tumour cells are immunogenic. A large number of immunotherapy trials for cancer patients demonstrate that antigen-presenting cells can be primed with tumour antigen in-vitro and in-vivo for better recognition by T-cells. However, even if a tumour is immunogenic, large amounts of specific cytotoxic T-cells will have to be recruited for a clinical significant immune response. This requirement of extreme clonal expansion can often not be fulfilled by the individual cancer patient, in particular, if the immune system is exhausted and immune-senescence has developed.
A good understanding as to how and why immune system function changes with age is essential for developing strategies to prevent immune-senescence and restore proper immune system function, thereby providing a basis for healthy longevity. Various such measures will be discussed.