Graham Pawelec ¹, Ed Remarque ², Yvonne Barnett ³, Rafael Solana ⁴

1 University of Tübingen, Tübingen, FRG ², University of Leiden, Leiden, Holland ³, University of Ulster, Coleraine, Northern Ireland ⁴, University of Córdoba, Córdoba, Spain

Received 12/29/97 Accepted 1/5/97

3. WHAT IS IMMUNOSENESCENCE?

By most parameters measured either in the laboratory or in vivo, T cell function is decreased in elderly compared to young individuals. This perceived deterioration of immune responses is designated "immunosenescence" and is found in both long and short-lived species as a function of their age relative to life-expectancy rather than chronological time. Under certain special circumstances, immunosenescence may contribute to decreased pathology in elderly individuals, as in the lesser degree of acute rejection seen in clinical corneal and kidney transplantation [B. Bradley et al ., cited in (1)] and in murine models of systemic lupus erythematosis (2). However, under normal circumstances the effects of immunosenescence are likely to be primarily deleterious. There is increasingly good evidence that immunosenescence contributes to morbidity and mortality in man because of the greater incidence of infection, autoimmune phenomena and cancer in the aged. Most in vitro and in vivo tests of T cell function are depressed in elderly individuals (3), including even such very strong reactions as the rejection of allogeneic skin transplants (4). Moreover, prospective studies over the years have suggested a positive association between good T cell function in vitro and individual longevity (5-7). More recently, the first report of a Swedish longitudinal study of the very old has provided supportive data. Initially, data were collected on 102 donors aged 86 - 92. Two years later, 75 of these were still alive. A comparison of the two groups showed that non-survival was associated with the clustered parameters of poor T cell proliferative responses, high CD8 (cytotoxic/suppressor cell) cell fraction, and low CD4 (helper/delayed-type hypersensitivity [DTH] cell) and CD19 (B) cells. It was found that no single parameter was predictive for survival, but that a cluster of the above parameters was predictive (8). Other data illustrating the importance of the immune system in healthy aging come from studies on centenarians. By and large, unlike the "average" elderly, the healthy very elderly (centenarians) are found to have well-preserved immune functions, similar but not identical to, the "young" immune system (9).

Early observations on declining immune function with increasing age were made well over two decades ago, when it was reported that cytotoxic T cells were compromized in old mice (10). Since then many studies mostly performed in mice, rats and man but also including monkeys and dogs (11) have established that this immune decline is characterized in these diverse species by decreases in both humoral and cellular responses. The former may be a result of the latter, because observed changes both in the B cell germline encoded repertoire and the age-associated decrease in somatic hypermutation of the B cell antigen receptors (BCR) are now known to be critically affected by helper T cell aging (12). A basis for this may be the finding that a T cell product induces recombination-activating gene-1 (RAG-1) in athymic mice, which usually lack this in the bone marrow (BM) and therefore cannot rearrange BCR (13). Hence, the thymus is also necessary for B cell development, via its production of T cells and T cell-derived factors. In vivo, the T cell system of young and aged individuals is differently composed, particularly in terms of an increased proportion of memory cells in the aged. There is an overall decrease in mature CD3⁺ T cells with age (14-16), although this may not be a continuous process, with T cells decreasing until the third decade, then staying constant until the 7th, after which decreases are again observed (17). Reciprocally, increased numbers of apparently activated T cells (HLA-DR⁺, CD25⁺), as well as increased numbers of natural killer (NK) cells (18) are seen. It must be borne in mind that all these data in human are relevant only to peripheral cells; the situation in the lymphoid organs is unexplored, although it is known that in rats the effects of aging on numbers and types of cells in spleen and periphery are different (19). In some more recent experiments in mice both secondary lymphoid organs and blood lymphocyte subsets have been studied. Thus, Poynter et al . reported that the proportion of T cells bearing the NK marker NK-1 increases with age in mice in blood and secondary lymphoid organs and that these cells rapidly produced large amounts of IL 4 on stimulation (20). There are strong arguments for the extrathymic nature of such NK-1+ T cells (21), which may therefore increase in compensation for decreased thymic output of conventional T cells.

Apparently paradoxically, despite declining immune function, aging is also associated with increased autoimmune phenomena. Because not only autoantibodies in general, but also clearly pathogenic autoantibodies, are routinely generated during normal immune responses to foreign antigen in the healthy young, the requirement for peripheral control of potentially damaging autoreactivity is paramount (22). This could be dysregulated in aging. Thus, immunodeficiency on the one hand could be reconciled with increased autoimmunity on the other by postulating a compromized cellular regulatory activity with age. Data related to this point are controversial, but some are consistent with decreased cellular suppressive activity with age (23,24) or with increased resistance to suppressive influences in the aged (25). Decreased specific suppressor cell activity (26) in aged mice is associated with the appearance of MHC unrestricted T helper cells. The appearance of the same kind of MHC unrestricted helper activity has been observed in elderly humans (27), suggesting that altered suppression in aging may also occur in man. This has not been systematically investigated.

We believe that a better understanding of the causes of immunosenescence, particularly why a very small proportion of individuals successfully avoid it (currently about one person in 12,000 - 15,000 in developed countries has attained the age of 100), may offer the possibility of therapeutic intervention. Amelioration of the effects of dysregulated immune responses in the elderly may result in an enhancement of their quality of life, and significant reductions in the cost of medical care in old age. Whether an extension of healthy lifespan might theoretically follow is unknown and is not the main aim of this research, but is conceivable.