Association between longevity and cytokine gene polymorphisms. A study in Sardinian centenarians

Giovanni Mario Pes1, Domenico Lio2, Ciriaco Carru1, Luca Deiana1, Giovannella Claudio Franceschi4,5, Luigi Ferrucci5, Fabiola Oliveri5, Letizia Scola2, Antonio Crivello2, Giuseppina Candore2, Giuseppina Colonna-Romano2, and Calogero Caruso2

1Chair of Clinical Biochemistry, University of Sassari, Sassari, 2Study Group on Immunosenescence, Department of Pathobiology and Biomedical Methodologies, University of Palermo, Palermo, 3Medicine Unit, Padova Hospital, Padova, Italy, 4Department of Experimental Pathology, University Bologna, Bologna, 5Istituto Nazionale di Riposo e Cura per Anziani, Ancona and Firenze, Italy

analyzed according to gender. Conclusions: These data indicate that gene polymorphisms of cytokines playing a major regulatory role in the inflammatory response do not affect life expectancy in the Sar- dinian population. Thus, cytokine/longevity associ- ations have a population-specific component, being affected by the population-specific gene pool as well as by gene-environment interactions, behaving as survival rather than longevity genes.

ABSTRACT. Background and aims: Human longevity seems to be directly correlated with optimal functioning of the immune system, suggesting that some genetic determinants of longevity reside in those polymorphisms for the immune system genes which regulate immune-inflammatory responses, in particular cytokine gene polymorphisms. The fre- quency of –174C single nucleotide polymorphism (SNP) in the promoter region of the interleukin(IL)- 6 gene is increased in Italian male centenarians. Moreover, the frequency of –1082G SNP at the 5’ flanking region of the IL-10 gene coding sequence is increased among male centenarians, and that of +874A SNP at the interferon (IFN)-γ gene was found more frequently in female centenarians. These find- ings indicate that different alleles at different cy- tokine gene codings for pro- (IL-6, IFN-γ) or anti-in- flammatory (IL-10) cytokines may affect the indi- vidual life-span expectancy, influencing the type and intensity of immune-inflammatory responses against environmental stressors. Methods: In the pre- sent study, we analyzed these IL-6, IL-10 and IFN-γ gene polymorphisms in 112 (36 male, 76 female) centenarians from the island of Sardinia, whose population shows a genetic background quite dif- ferent from that of mainland Italy, as well as in 137 sixty-year-old controls from the same geographic area. Results: No significant differences were ob- served on analyzing IL-6, IL-10 and IFN-γ polymor- phism frequencies among centenarians and con-

INTRODUCTION

Human longevity is the result of several interacting factors including genetic, environmental and behav- ioral components (1). Several studies indicate that hu- man longevity is inextricably linked with optimal func- tioning of the immune system (2). However, the prob- lem arises as to whether people live longer because of “good” immune function, or whether they possess good immune function because other factors have en- abled them to survive longer (3). Thus, to understand better the role of the immune system in longevity, we must search for immunogenetic markers of longevity (2, 3). Cytokine dysregulation is believed to play a key role in the proposed remodeling of the immune-in- flammatory responses accompanying old age and, by regulating the type and magnitude of the immune re- sponse in the elderly, may play a pivotal role in aging and survival (2-6). More interestingly, some data indicate

Key words: Centenarians, cytokines, immunogenetics, longevity, polymorphisms. Correspondence: C. Caruso, MD, Gruppo di Studio sull’Immunosenescenza, Dipartimento di Biopatologia e Metodologie Biomediche, Corso Tukory 211, 90134 Palermo, Italy. E-mail: marcoc@unipa.it Received May 19, 2003; accepted in revised form October 13, 2003.

Received May 19, 2003; accepted in revised form October 13, 2003.

that the lack of ability to control systemic inflammation is a good marker of immunological risk phenotype (2, 3, 7).

registry of local parish archives, social security docu- ments, and the testimony of a first-degree relative. One hundred and thirty-seven 60-year-old (±1 year) healthy controls (68 men, 69 women), without clinical symp- toms of immune-inflammatory diseases, were randomly selected from the inhabitants of the same province. This age was chosen based on the consideration that, at this age, both men and women have less than 1% proba- bility of becoming centenarians (19). Written informed consent for enrolling in the study and for personal da- ta management was obtained from all subjects accord- ing to Italian law. Blood specimens were collected in tripotassium EDTA sterile tubes and immediately stored at -70°C. Genomic DNA was stored at -20°C for ge- netic analysis.