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

10. PREDICTORS OF MORTALITY AND LONGEVITY

Lifespan is influenced by genetic makeup, most clearly demonstrated so far for the association between longevity and MHC type in mice (300) and possibly humans (301-303). One mechanism accounting for this association may be a relationship between MHC alleles and rate of thymic involution (304). The lifespan of allophenic mice produced from a long-lived and a short-lived strain (305) is positively correlated with the proportion of lymphocytes derived from the long-lived strain, showing the importance of the immune system to overall lifespan (306), perhaps via the effect of mature T cells on maintenance of the thymic environment alluded to above. The association may be by way of susceptibility to lymphomas: it has been shown that mice which have higher levels of memory cells, lower levels of naive cells and lower proliferative responses at 6 months of age retain these patterns in later life, and that in genetically heterogeneous populations, mice with this phenotype have significantly shorter lifespans caused by an increased incidence of lymphomas (307). However, more recent data indicate that it may not be that death is caused exclusively by lymphomas in this system, because the CD4 memory correlation holds regardless of whether the mice died of lymphoma, fibrosarcoma, mammary carcinoma or other terminal disease (308). In inbred mouse strains, the vigor of T cell responses in old mice is influenced by MHC type, with those mice possessing "low responder" phenotypes succumbing at an earlier age than those with "high responder" phenotypes, mostly due to their increased susceptibility to lymphomas (309). Increased levels of IL 6 in old mice may play a role in the increased occurrence of lymphoma (310). Therefore, the mechanism of the genetic association of MHC with lifespan in mice may be a reflection of decreased immunosurveillance against lymphoma or other tumors, as a result of immunosenescence. Mice genetically selected for high antibody responses are found to have longer lifespans, and this is also associated with lower incidence of lymphoma (311). On the other hand, mice selected for high or low T cell responses to PHA also have lower and higher lymphoma incidences respectively, but do not differ in longevity; whereas mice selected for resistance to chemical carcinogenesis show altered tumor incidence and longevity without corresponding alterations in immunity (311). What these results may mean in longer-lived, less tumor-prone species like man is unclear.

There are certainly also other genetic influences on immune responsiveness, upon which the effects of aging may be superimposed, that must be taken into account. For example, the CD4:CD8 ratio, which is also affected by age, is different in males and females and in family segregation analysis has been shown to be under genetic control (312). The MHC type of the individual may also affect the absolute numbers of lymphocytes in the periphery; for example, it has been reported that HLA-B8, DR3-haplotype-bearing donors have lower levels of peripheral lymphocytes than other donors, possibly because of increased levels of spontaneous apoptosis (313). It may be interesting to note that this HLA-B8, DR3 haplotype was one of those found very rarely in a recent study of elderly Greeks (in 1.6% of SENIEUR elderly versus 10% of young controls, ref. 303). Several groups are searching for genetic markers of longevity, and some data are now beginning to appear, eg. the finding that a particular allele, C2, of the proto-oncogene transcription factor ETS-1 is represented at significantly higher levels in the elderly compared to teenagers (314). The relevance to mammalian aging of the recently defined mutations in "gerontogenes" in roundworms and other invertebrate species is unclear, but will be an exciting area of investigation (315).

In most aging studies in human, individuals > 60 years are commonly considered "old". Longitudinal studies are required to establish the critical changes within the immune system and what may be associated with "healthy aging". Nowhere is this clearer than in the study of centenarians, who may be considered to be that very small proportion of successfully aged individuals. An examination of healthy centenarians would show whether immunological aging is divorced from overall physiological aging. Were the immune system to be senescent despite health in these individuals, this would indicate the lack of importance of immunity for healthy aging. Not surprisingly, healthy centenarians are found to have well-preserved immune functions, much more similar to the "young" immune system than the average situation for less extremely old donors. Thus, as summarized by Franceschi (9), T cell proliferative responses are well-maintained (albeit taking place more slowly), the T cell repertoire still contains all Vß families, hematopoiesis is maintained, autoantibodies are absent, and interestingly, there is a high level of lymphocyte genomic stability (low spontaneous breaks etc., which otherwise are thought to increase with age in average, non-centenarian, donors (316). There were some data suggesting that healthy centenarians represented a group with the best retention of thymic structure and function and that these individuals were also characterized by lower DNA damage (52).