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Longevity and Heredity in Humans: Association with the Human Leucocyte Antigen Phenotype

A. M. LAGAAY, J. DAMARO, G. J. LIGTHART, G. M. Th. SCHREUDER, J. J. van ROOD, AND W. HIJMANS

Section of Gerontology and Department of Immunohematology, University of Leiden, 2300 RC Leiden, The Netherlands

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 lifespan are fixed for each species. Between species and also between different strains within a species, average lifespan differs, as 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 lifespan. 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 indicate the existence of a biological clock governed by genetic factors.

Common knowledge has it that familial differences in longevity exist in humans and that these are at least partially accounted for by genetic factors: longevity runs in the family. Abbott et al. studied this scientifically by comparing the parental age at death of subjects who died at different ages [6]. 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 maternal age at death and more evident for males than for females. Palmore in the Dukes longitudinal study partly confirmed these observations [7]. He found an influence 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 al. in Denmark includes 960 individuals who had been separated from their biological parents in early childhood and reared by adoptive parents [8]. 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 biological 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 system.

The 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 and disease exist with a relative risk which varies from 1.3 to 358 [25]. Therefore, we studied the HLA system for genes associated with longevity.

Detecting these genes in humans is more difficult than in mice since humans are an outbred population with inherent genetic heterogeneity. In addition, there are no possibilities 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, considerable genetic heterogeneity persists so that HLA types cannot be compared against a common background. For these reasons, Walford et al. 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.

Previous studies on associations between HLA antigens and longevity in different age groups are 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 requirements. In the following, we will briefly review the most important findings from the literature.

Recently, the Japanese group of Takata et al. 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 nona- and centenarians, respectively, while DR1 was absent in younger age groups. Since HLA-B40 is linked to DRw9 in the Japanese population, its frequency was decreased as well [10]. Macurova et al. in Prague described a marked difference in many antigens [11].