Background: There is strong evidence that an individual's genetic background is an important predisposing factor to longevity. In the present study, we analyzed the frequency of HLA class I, class II, as well as the TNF- -308 polymorphism that may be related to an increased lifespan in a healthy elder Mexican Mestizo population.

Results: HLA typing was performed by polymerase chain reaction sequence-specific oligonucleotide (PCR SSO) reverse dot blot. The TNF- -308 polymorphism was assessed by PCR restriction fragment length polymorphism. A significantly increased frequency of HLA-DRB1*11 was found in elderly women, whereas this allele was not present in elderly males. The TNF2 allele was also increased in the elder group when compared to young controls. The frequencies of the remaining alleles tested were not statistically different among groups.

Conclusion: These data suggest an ethnicity-independent tendency of HLA-DRB1*11 in elder females to increase lifespan and a possible role of the TNF2 allele with the successful remodeling of senescent immune system.

Background: Class III genes are associated with old age. Thus, longevity has been shown to be related to the selection of HLA alleles or haplotypes, being the more frequently associated with A1 B8 Cw7 DR3 in Caucasians [3, 4], the increased or decreased frequency of HLA-B40 [5-7], and the augmented frequency of HLA-DR11 in elder women in Caucasian as well as in Japanese populations [8, 9] among other alleles. Immunogenetic studies in aged, healthy Mexican Mestizo population have not yet been performed.

Aging is associated with a complex remodeling of the immune system often in the direction of apparently decreased immune competence. However, it has been proposed that longevity is related to optimal function of the immune system because some genetic determinants for successful aging might reside in those polymorphisms of genes that regulate immune responses e.g. major histocompatibility complex (MHC) [1, 2]. The studies of lifespan in humans have resulted in different and even controversial associations of HLA class I, class II, and DRB1*0404 being the more frequent in the young group, being these alleles not statistically significant. Mexican Mestizo individuals have a proportion of 56% Native American Indian genes, 40% Caucasian genes, and 4% African genes [10]. Mestizo population represents a complex mixture of European and American native inhabitants and constitute the core of the Mexican population. This complex genetic process began in the 16th century and has been expanded during the course of time and continues to be a dynamic process, e.g., African population inhabited the Americas almost 200 years later. On the other hand, aged people in the Mexican population have increased from a life expectancy of 63 years in the 1970s up to 70 years nowadays.

When the differences between aged males and females were analyzed, a decreased frequency of HLA-DRB1*11 in males was found when compared to females because no one in the former group had HLA-DRB1*11 (p = 0.002; OR = 0.18; CI 95% = 0.060.53; p = 0.024 by Bonferroni's correction). On the other hand, when elderly males were compared to young males for HLA-DRB1*11, a diminished frequency was found although not statistically significant when Bonferroni's correction was applied. The high-resolution typing showed a decreased frequency of the HLA-DRB1*1101 allele in elderly females when compared to the other HLA-DRB1*11 alleles from young women and again this difference was not significant by Bonferroni's correction.

Healthy elderly people show a pro-inflammatory phenotype with increased levels of cytokines such as TNF- [11]. The TNF- gene is located within the HLA class III region. This cytokine is involved in tissue remodeling, epithelial cell barrier permeability, macrophage activation, recruitment of inflammatory infiltrate, and up-regulation of adhesion molecules, among other functions. TNF- also determines the strength, effectiveness, and duration of local and systemic inflammatory responses [12].

Our data must be balanced against the small number of subjects studied. However, we found that interestingly, no old man had HLA-DRB1*11, which may suggest that survival being gender-dependent [15, 16]. This finding for Mexican Mestizo women is in agreement with previous reports in different populations, which might indicate that the contribution of this allele to an increase in lifespan is independent of ethnicity [8].

The TNF- promoter contains numerous polymorphic sites, which are possible targets for transcription factors. The polymorphism at position -308 is defined by the substitution of a G byIn evolutionary terms, the ethnic group known as Mexican Mestizo is a recent one, barely 500 years old. This lapse is certainly not enough to establish allele selection or modify completely the structure of previous haplotypes by the genetic admixture process that could account for changes in certain HLA clusters of Mexican natives. On the other hand, infectious diseases imported by conquerors have indeed influenced the selection of HLA repertoire in our region. The cultural and socio-economic conditions of our geographical zone (Mexico and Central America) have contributed to a marked increase in life expectancy, particularly over the last 50 years, although this is still far removed from that of developed countries. It is worth mentioning that the mean age of our study group is at least 10 years greater than the current life expectancy for Mexico and, hence, they represent the oldest population who have enjoyed successful aging within our country.

Methods

Subjects