HLA, aging, and longevity: A critical reappraisal

Despite a large number of studies, available data do not allow at present t o reach definitive and clear conclusions on role of HLA on longevity, owing to major methodological problems, such as serological and molecular typing of different loci, insufficient sample sizes, different inclusion criteria and age cut-off, inappropriate mixing of data referred to people from 58 t o over 100 years of age, inappropriate control matching, and neglected cons ideration of sex-related effects and the different genetic make-up of studi ed populations. However, within this confused scenario, some data emerge. F irst, two studies that do not fit the biases above discussed show that some HLA alleles are associated with longevity. However, some of these alleles may confer an increased risk to undergo a variety of diseases. Second, long evity may be associated with an increased homozygosity at HLA loci. Third, an intriguing association between longevity and the 8.1 ancestral haplotype (AH), which has been proven to be associated with a variety of immune dysf unctions and autoimmune diseases, apparently emerges. This association appe ars to be a sex-specific (males) longevity contributor, and it is particula rly interesting, taking into account that a type 2 (early infancy) --> type 1 (adulthood) --> type 2 (aging) shift of cytokine profile occurs lifelong , and that individuals bearing this haplotype show a type 2 immune responsi veness (note that type 1 cytokines mainly enhance cellular responses, where as type 2 cytokines predominantly enhance humoral responses). On the whole, the (sex specific) association of longevity with alleles or haplotypes of several genes related to risk factors for a variety of diseases (cardiovasc ular diseases, cancer), including HLA alleles and haplotypes, is not unexpe cted on che basis of previous studies on the genetics of longevity in cente narians. This association can be interpreted under the perspective of a wel l known evolutionary theory of aging (antagonistic pleiotropy), This theory predicts that the same gene (or allele or haplotype) can have different ro les (positive or negative) in different periods of the life span. Thus, the 8.1 AH should exert a positive effect during the infancy and aging but not in adulthood, when, indeed it is associated to susceptibility to a variety of diseases. Human Immunology 61, 942-949 (2000). (C) American Society for Histocompatibility and Immunogenetics, 2000. Published by Elsevier Science Inc.