Experimental Gerontology 39 (2004) 637–644

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markers contributing to successful aging in

Elissaveta Anastasia Mihaylova, Milena Ivanova, Snejina Michailova, Kalina Penkova, Daniela Baltadjieva

Central Laboratory of Clinical Immunology, University Hospital Alexandrovska, 1 Georgy Sofiisky Str., 1431 Sofia, Bulgaria

Received 18 July 2003; received in revised form 4 August 2003; accepted 13 August 2003

Abstract

In order to clarify immunogenetic markers contributing to successful aging, HLA and cytokine gene profiles were analyzed in healthy elderly Bulgarians. Family segregation analysis was performed to define combined effect of haplotypes and immunophenotype profiles. The results of this study did not reveal any statisticaly significant allele and haplotype frequency differences between elderly and control group. In families with two generations longevity members we did not observed HLA alleles and haplotypes associated with autoimmunity. IL-10 genotype 21082G/A, 2819 C/C, 2592 C/C, related to the intermediate production, was positively associated, while genotype 21082A/A, 2819 C/T, 2592 C/A, related to the low level of production, was negatively associated with longevity in Bulgarians. This effect was modulated by IL-6 and IFNg genotypes associated with the low level of these pro-inflammatory cytokines. Immunophenotypic studies indicated lower relative and absolute numbers of CD3 þ 8 þ , CD8 þ 28 þ and CD8 þ 57 þ cells in elderly people. Analysis in familes showed that although most pronounced in the elderly group, lower numbers of CD8 þ T cells were also found in middle aged and young members of the families compared to the age matched controls. A progressive CD8 þ 28 þ cell subsets decline was seen with aging. In addition, we did not observed the ‘immune risk phenotype’ which is a marker of an increased inflammatory activity. Based on the results of this study, it seems reasonable to suggest that a combination of specific immunogenetic and immunophenotype profiles could contribute to the successful aging and to maintaining healthy status in elderly.

Keywords: Aging; HLA; Cytokine gene polymorphism; Lymphocyte subsets; Bulgarians

1. Introduction

individuals (Pawelec et al., 1997). The absolute number of CD4 þ and CD8 þ T cells decreases with age from 20 to 100 years (Doria and Frasca, 1997). In the elderly, the increase in the relative proportion of CD8 lymphocytes lacking CD28 has been recognized (Fagnoni et al., 1996; Nociari et al., 1999). An ‘immunological risk phenotype’ (low CD4 count, high CD8 count, decreased IL-2 production and mitogen responssivness together with CD28 negativity and CD57 positivity) has been found as predictive of shorter remaining life span in the very old population (Ferguson, 1995; Wikby et al., 1998; Olsson et al., 2000). Family segregation analysis has shown that CD4, CD8 and CD4/CD8 ratio are under genetic control (Amadori et al., 1995; Clementi et al., 1999). The level of immune responses as well as possibly longevity could be associated with genes regulating immune function (Modica et al., 1990). Although case-control data are still contro- versial (Caruso et al., 2000), it was suggested that longevity could be associated with MHC and cytokine gene polymorphisms. HLA alleles and haplotypes relevant

The human mean life span has been enhanced greatly since antiquity as a result of better health and living conditions. The average life span of the Bulgarian population is 71.8 years (68.5 years for male and 75.2 years for female). The majority of the population is between 25–64 years old (541%), 16.9 percent is between 64 and 95 years old, and a very small proportion (,0.05%) is 95 and 99 years old and centenarians.

Aging is a very complex process and longevity is a multifactorial trait, which is determined by genetic and environmental factors. Since it is too difficult to study aging as a whole, investigations try to focus on a specific physiological system that exhibits age-dependent functional changes. Immune remodeling and numerous changes in T-lymphocyte subset profiles were observed in elderly

* Corresponding author. Tel.: þ3592-9230-690; fax: þ3592-9230-496. E-mail address: immun@medun.acad.bg (E. Naumova).

E. Naumova et al. / Experimental Gerontology 39 (2004) 637–644

to susceptibility or resistance to infectious and autoimmune diseases (Dawkins et al., 1999; Thorsby, 1997) have been disscused. A positive association with longevity was found for HLA alleles DRB1*07, *11, *13 (Lagaay et al., 1991; Ivanova et al., 1998) and for the ancestral haplotype HLA- B8-DR3 (Proust et al., 1982; Rea and Middleton, 1994). Genetic diversity of pro- and anti inflammatory cytokines, that affects gene transcription causing variations in cytokine production might influence successful aging and longevity by modulating an individual’s response to life-threatening disorders (Bruunsgaard et al., 2001; Ershler and Keller, 2000; Volpato et al., 2001). IL-10 21082G involved in high-production of this anti-inflammatory cytokine is positively associated (Lio et al., 2002a,b), while IFN-g þ874 T (Lio et al., 2002a,b) and IL-6 2174G (Bonafe et al., 2001) allele involved in high production of these pro- inflammatory cytokines show negative gender specific association with longevity.