The general similarity of the pattern of HLA frequencies in the different age groups provides evidence that we are looking at two generations of the same population. Some of the previous studies reported differences in nearly all anti- gens tested at that time;" while in other studies'" the age-related differences appeared abruptly. This generates questions about the historic background and similarity of the study population and the control group, as Wainscoat el a1.25h ave pointed out. We have no indication that major demographic changes have oc- curred in our population during this century. This is illustrated by the gradual growth of the population and of the percentage of people over 85 years of age (FIG.3) . Neither did we find an abrupt or disproportionally large difference in HLA frequencies between different age groups (FIG.2 ).

Gerkins et al. Macurova et al." and Converse and Williams" report a ,I8 increase in heterozygosity in the old age group. This was not confirmed studies,'2-'5,20,22,I2n6 our study the heterozygosity was not different in as compared to the young age group.

The fact that the differences in HLA frequency both in B40 and in DR5 more evident in females is intriguing. Can we take this as a key to the ing of the difference in life expectancy between the sexes? It is clear that we cannot answer this question without further studies. This also brings us to

B40 Frequency(%) 30 25 20 15 10 5 0 Lelden Wales Copenhagen Paris Framlngham Prague Los Angeles Young old

FIGURE 2. The frequency (%) of HLA-B40 in the present study and in previously lished studies, in young and old age groups.

ANNALS NEW YORK ACADEMY OF SCIENCES

option of “longevity genes” being located outside the HLA region. With the association of the maternal age of death and the higher life expectancy for con- temporary women in mind, the sex chromosome and even mitochondria1 DNA could be proposed as a possible site. It has been postulated that the double X-chromosome is favorable for an extended length of life.27 This advantage can act through hormonal influence or by an overcapacity of the immune system, the latter provided by nature in order to ensure maximum reproductive success for the human female gender.

Our study did not detect a significant decrease in the frequency of established disease-associated HLA antigens, e.g., B27, B8, DR4, in the oldest age group. The following arguments should be considered in this respect: Firstly, our control group consists of blood donors who are selected on the basis of health criteria. This selection can cause the frequency of disease-associ-

100 80 60 1880 ‘90 1900 ‘10 ’20 ‘30 ‘40 ’50 ’60 ‘70 ‘80 ’83 ‘84 ‘85 ‘86 ’87 ‘88 Year = a &f88 Females Males 85+ Males 8 Females

FIGURE 3. The growth of the population of Leiden during this century is gradual. For the total population the number of males and females are plotted separately. For the inhabitants of 85 years and over males and females are pooled.

ated HLA antigens to be lower than in the total population. In other words our control group could be “too healthy.” The fact that in this particular age group the prevalence of disorders leading to rejection as blood donor will be low, and that relatives of diseased subjects can be expected to be especially motivated to enlist as blood donor, counters the argument that the control group may be too healthy. Moreover, we have checked the HLA frequencies of 134 cornea donors, 20-35 years of age, who can be considered a random sample of the population. The HLA pattern of the blood donors and the cornea donors did not differ (data

LAGAAY el al.: LONGEVITY & HEREDITY

example: insulin-dependent diabetes mellitus (IDDM) is associated HLA-DR3 or DR4. Individuals with those antigens, have a relative risk to IDDM which is 4 to 10 times higher than those lacking these antigens. The lence of IDDM in the population has been estimated to be approximately percent. A population-based study such as the present is not suitable to such minimal differences.

Thirdly, these HLA associated disorders do not necessarily lead to an early death. In the present study this is exemplified by subjects with well documented rheumatoid arthritis, who apparently survived while, or because, the disease process was burnt out.

On the other hand, this negative finding could emphasize the postulated ad- vantage of these disease-associated HLA antigens. After all, according to the principles of Darwin, these disease-associated HLA antigens would have become extinct, had they not been beneficial for the maintenance of the species.

al.:l o their study both the adult controls and the nona- and centenarians were healthy. This is remarkable in the light of the first point mentioned above: one would not expect a difference in autoimmune disease-associated HLA antigens if both young and old age groups are selected on health criteria. The fact that the difference is casts a doubt on the significance of the Okinawa results, or alternatively, on the strictness of the health criteria employed. To illustrate this critical remark, it is noteworthy that in the present population 54 (5.5%) out of 977 persons aged years or over were considered healthy according to the criteria described in the SENIEUR-protocol.28

It is not clear at what age the hypothetised differences in HLA frequencies would show. Is it at middle age, when diseases like cancer, cardiovascular disor- ders and rheumatoid arthritis take their toll? Or is it in the oldest age group, where the protecting, beneficial “longevity genes” would become manifest, as could be exemplified by the results of Takata et al.1° We are presently in the process of integrating the life expectancy curve into the data of HLA phenotype.