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Longevity and Heredity in Humans

Association with the Human Leucocyte Antigen Phenotypea

Association with the Human Leucocyte

A. M. LAGAAY,b J. D’AMARO,‘ G. J. LIGTHART,’ G. M. Th. SCHREUDER,cJ . J. van ROOD,‘ AND W. HIJMANS’

bSection of Gerontology und CDepurtrnento f Irnrnunohemutology University of Leiden

2300 RC Leiden, The Nerherlands

It is still not understood why some people live to be very old while others die at an earlier age from natural causes. There are several arguments supporting the hypothesis that genetic factors are important in this respect. Both average and maximum life span are fixed for each species. Between species and also between different strains within a species, average life span differs, as, for example, in different strains of mice reared under identical laboratory conditions. Smith and Walford’ have demonstrated that in mice the major histocompatibility complex (MHC) exerts a significant influence on life span. In mice, MHC is also associated with premature tumor incidence, a low immune response, less effective DNA- repair and autoimmune disease.24 These observations could be an indication of the existence of a “biological clock” which is governed by genetic factors.

Common knowledge has it that in the human species familial differences in longevity do exist and that these are at least partially accounted for by genetic factors: “longevity runs in the family.” Scientifically this has been studied by Abbott et al.’ who compared the parental age at death of subjects who died at different ages. There was a weak but significant trend for survival to increase with increasing age at death of the parent. This trend was more marked for the mater- nal age at death and more evident for males than for females. Palmore in the Dukes longitudinal study6 partly confirmed these observations. He found an influ- ence of the father’s age at death and again this was more evident in males. The mother’s age at death had no influence.

An important study from Sorensen et (I/. in Denmark7i ncludes 960 individuals who had been separated from their biologic parents in early childhood and had been reared by adoptive parents. In those who died prematurely, that is between 16 and 58 years of age, there was a significant correlation with the death of one of the biologic parents before the age of 50 (relative risk (RR) 1.71). There was no correlation with a premature death of one of the adoptive parents. The relative risk was higher regarding infectious (RR 5.8) or vascular (RR 4.5) causes of death. These findings may be interpreted as evidence for a genetic effect on the immune

LAGAAY et af.: LONGEVITY & HEREDITY

death from cancer of an adoptive parent before the age of 50 increased the rate of mortality among the adoptees fivefold. Death from cancer of a biologic parent had no detectable effect on the mortality of the adoptees.

HLA region is located on the short arm of the sixth chromosome. It codes for immunological repertoire in its broadest sense. A characteristic property is extreme polymorphism. In man several associations between HLA antigens disease exist with a relative risk which varies from 1.3 to 358.s Therefore, studied the HLA system for genes associated with longevity.

detect in the human species than in mice, since humans are an outbred population with an inherent genetic heterogeneity. In addition, there is no possibility to control other exogenous variables that may influence longevity. Even if ethnic and geographic matching between the study population and the control group is assured, a considerable genetic heterogeneity persists so that HLA types cannot be compared against a common background. For these reasons Walford et aL9 stated that it would be a more fruitful approach to do HLA typing in family studies or to determine the segregation of certain traits with haplotypes.

age groups is limited and their results are not uniform. It is essential that the study population and the young control group share the same genetic and geographic background and that both groups consist of large enough numbers for statistical analysis. The age difference between the two groups must be adequate, or age- brackets should be provided. Only some of the previous studies fulfill these re- quirements. In the following we will briefly review the most important findings from the literature.

Brief Literature Review

Recently, the Japanese group of Takata et al.'O-reporting on the oriental population of Okinawa, Japan-mentioned an extremely low frequency of HLA-DRw9 in nona- and centenarians as compared to younger age groups, and also a frequency of HLA-DR1 of 10.0 and 6.1% in the nona- and centenarians, respectively, while DRl was absent in the younger age groups. Since HLA-B40 is linked to DRw9 in the Japanese population, its frequency was decreased as well. Macurova et al. in Prague," described a marked difference in many antigens: a

In a well designed study, Yarnell et al. in Wales'*, also found a higher fre- quency of HLA-B40 in the old population. On the other hand, three studies in Caucasoid population^'^-'^ reported a slight decrease of HLA-B40 in the elderly. GreenbergI6 reported a decreased prevalence of HLA-B8 in women over 70 years of age as compared to men of the same age. He also found a decreased prevalence of the Al-B8 haplotype in this group as compared to both the young ages and men of the same age. Thompson et a1.l' noted an increase of the pheno- typic frequencies HLA-A29, B7 and B35 in 17 healthy centenarians in Kentucky, USA. One study20m entions a higher frequency of the A1 lCw7/B8/DR3 haplotype in highly aged males.

An increase in heterozygosity, mostly at the HLA-B locus, in older age groups been reported, but other studies have not confirmed this observation. 11,1s~19

ANNALS NEW YORK ACADEMY OF SCIENCES