In athe distribution of HLA antigens between the study population and the control group, except for HLA-B40 and HLA-DR5. To ensure an ethnically homogeneous sample, nine elderly subjects of non-Caucasoid parentage were excluded. The study involved 964 subjects of 85 years and older and 2444 subjects of 20-35 years of age. The HLA typing was performed using standard lymphocytotoxicity and a two-color fluorescence test for class II antigens. The results showed statistically significant differences in HLA-B40 and HLA-DR5 frequency in females aged 85 years and over. The frequencies of homozygotes were not different between the young and old age groups. The study provides evidence that we are looking at two generations of the same population, with no indication of major demographic changes occurring during this century. Further studies on linkage of different HLA classes are needed to understand their association with life span, diseases, or aging processes.HLA frequencies were compared between different age groups (FIG.2). Gerkins et al., Macurova et al., and Converse and Williams reported an 18% increase in heterozygosity in the old age group. However, this finding was not confirmed in other studies. In our study, heterozygosity did not differ significantly compared to the young age group. It is intriguing that the differences in HLA frequency for both B40 and DR5 were more evident in females. This raises the question of whether this could be a key to understanding the difference in life expectancy between the sexes. However, further studies are needed to answer this question. This also leads us to consider the possibility of longevity genes being located outside the HLA region. With this in mind, the sex chromosome and even mitochondrial DNA could be proposed as possible sites. It has been postulated that the double X-chromosome is favorable for an extended length of life, possibly due to hormonal influence or an overcapacity of the immune system, provided by nature to ensure maximum reproductive success for females.

Our study did not detect a significant decrease in the frequency of established disease-associated HLA antigens such as B27, B8, and DR4 in the oldest age group. However, several arguments should be considered in this respect. Firstly, our control group consisted of blood donors selected on the basis of health criteria, which could result in a lower frequency of disease-associated HLA antigens than in the total population. Secondly, these HLA-associated disorders do not necessarily lead to an early death. On the other hand, this negative finding could emphasize the postulated advantage of these disease-associated HLA antigens for maintaining species survival.

Another study by Lagaay et al. reported similar findings with regards to autoimmune disease-associated HLA antigens in both young and old age groups selected on health criteria. This casts doubt on the significance of the Okinawa results or the strictness of the health criteria employed.

It is not clear at what age differences in HLA frequencies would show. Is it at middle age when diseases like cancer, cardiovascular disorders, and rheumatoid arthritis take their toll? Or is it in the oldest age group where beneficial longevity genes would become manifest? We are presently integrating the life expectancy curve into the data of HLA phenotype to investigate this question.

The idea of the existence of longevity genes is difficult to understand in the light of Darwin's theory of evolution. However, Hayflick has recently proposed an interesting theory on this topic. He suggests that parents would have a selective advantage in maintaining their physiological vigor after sexual maturation to ensure maximum parental fitness for survival of slowly maturing human progeny. The reserve capacity, present in virtually all organs, is the essential element in determining post-developmental longevity.