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Lack of association between human longevity and polymorphisms of IL-1 cluster, IL-6, IL-10  and TNF- genes in Finnish nonagenarians

Xiu-Yun Wang a,b, Mikko Hurme b, Marja Jylha¨ a,

a Department of Gerontology, School of Public Health, Uni(cid:1)ersity of Tampere, FIN-33014 Tampere, Finland

b Department of Microbiology and Immunology, Medical School, of Tampere and Tampere Uni(cid:1)ersity Hospital, Tampere, Finland

Abstract

accompanied by immune deterioration and dysregulation of cytokines. Increased IL-6 1B, 0 | concentration in vivo and enhanced IL-6, IL-1 , and TNF- production in vitro have been reported in healthy elderly people. Cytokine gene polymorphisms have been demonstrated to be associated with cytokine production both in vivo and in vitro, and with some diseases. Thus, gene polymorphisms of cytokine may play a role in longevity by modulating an individual’s responses to life-threatening disorders. Cytokine gene polymorphisms at IL1A− 889, IL1B+3953, IL1B−511, IL1RN VNTR, IL6−174, IL10−1082, and TNFA−308 were genotyped in 250 Finnish nonagenarians (52 men and 198 women) and in 400 healthy blood donors (18–60 years) as controls. No statistically significant differences were found in lo,  the genotype distributions, allelic frequencies and A2+ carrier status of IL-1 , IL-1 , “01 | IL-1RA, IL-6, IL-10, and TNF- genes between nonagenarians and younger controls within Finnish population, nor between male and female nonagenarians. No differences emerged between nonagenarians and younger controls by comparing different IL-1 gene cluster haplotypes. Thus, there is no evidence of an association of IL-1 complex, IL-6, IL-10, and aeed TNF- gene polymorphisms with longevity, alone or in combination. © 2001 Elsevier Science Ireland Ltd. All rights reserved.

Keywords: Longevity; Cytokine; Gene polymorphism

0047-6374/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S0047-6374(01)00338-4

1. Introduction

Over the last few years, there has been an increasing interest in research on the molecular and biochemical basis of aging. The role of genetics in determining life span is complex and paradoxical (Finch and Tanzi, 1997). Some genes can affect longevity by modulating an individual’s responses to life-threatening disorders, while others by regulating maximum life spans (MLS) as an intrinsic physiological trait (Finch and Tanzi, 1997; Scha¨chter, 1998).

longevity. Since a genetic component for human longevity has long been postulated (Abbott et al., 1974), scattered data have been gained from the association studies aimed at identifying such loci. So far, five genes implicated in longevity have been defined: HLA-DR (Proust et al., 1982; Akisaka et al., 1997), APOE (Scha¨chter et al., 1994; Kervinen et al., 1994; Zhang et al., 1998), APOB (Kervinen et al., 1994; De Benedictis et al., 1997), ACE (Scha¨chter et al., 1994; Faure-Delanef et al., 1998), and PAI-1 (Mannucci et al., 1997), although there have still been contradictory reports on APOE (Bader et al., 1998), APOB (Scha¨chter et al., 1994) and ACE (Agerholm-Larsen et al., 1997). In addition, unlike the gene polymorphisms men- tioned above, it has been reported that there is no evidence of an association of either WRN (the Werner syndrome gene) polymorphism (Castro et al., 1999), or NAT2, GSTM1 and CYP2D6 loci (Muiras et al., 1998) with longevity.

It has been believed that aging is associated with immune deterioration (Venka- traman and Fernandes, 1997). In humans and in animals, an age-dependent decline in immunocompetence has been demonstrated with major alterations concerning functional changes of cell-mediated immunity (Rea et al., 1996; Miller, 1996). It has been suggested that the age-related increased incidence of infective disease, cancer, autoimmune diseases and degenerative diseases could be related to generalized reduction in immunocompetence (Rea et al., 1996).

Cytokines have gained much attention in the study of ageing because they possess immunomodulatory function. Many cytokines, for instance IL-1, IL-6, =O | TNF- are deeply involved in the pathogenesis of most age-related diseases, such as atherosclerosis, fibrosis, osteoporosis (Fagiolo et al., 1993), Alzheimer’s disease (Ershler, 1993), and coronary heart disease (Mendall et al., 1997). Furthermore, it has been suggested that dysregulation of cytokines may be partly responsible for the increased morbidity and mortality rates in the elderly (Harris et al., 1999). The cytokine interleukin-6 (IL-6) has been aptly called ‘the cytokine for gerontologists’ (Ershler, 1993). Normally the levels of IL-6 in serum are low in absence of inflammation. In healthy elderly people, increased IL-6 concentration has been found not only in plasma (Wei et al., 1992), and intracellularly in T cells (O’Ma- hony et al., 1998), but also in vitro production by peripheral mononuclear cells after mitogen stimulation (Fagiolo et al., 1993). Enhanced in vitro production of  “oh other pro-inflammatory cytokines, IL-1 and TNF- from mononuclear cells after mitogen stimulation has also been reported (Fagiolo et al., 1993; Born et al., 1995). It has now been demonstrated that the cytokine genes are polymorphic. The IL-1

It has now been demonstrated that the cytokine genes are polymorphic. The lo, 1p, complex codes for at least four proteins: IL-1 , IL-1 , IL-1 receptor