OPEN ACCESS International Journal of Molecular Sciences ISSN 1422-0067 www.mdpi.com/journal/ijms

Possible Role of −374T/A Polymorphism of RAGE Gene in Longevity

Interdepartimental Center for Research in Molecular Medicine (CIRMC), University of Via Taramelli

, Pavia

, Italy; E-Mails: sara-

@tiscali.it (S.B.); roxvieste@hotmail.it

Department of Cardiology, Istituiti Clinici di Pavia e Vigevano University Hospital, Via Parco Vecchio

, Pavia

, Italy; E-Mails: anna.mcolonna@gmail.com (A.C.); betty.matrone@gmail.com (B.M.); johnny

@hotmail.it (E.M.B.); g.pelissero@grupposandonato.it (G.P.)

IRCCS San Donato Hospital, San Donato Milanese

, Italy

Received: 9 October 2013; in revised form: 11 November 2013 / Accepted: 15 November Published: 21 November 2013

improvements in health and longevity. The survival of elderly people has improved significantly and thus centenarians are becoming the fastest growing population group. Environmental, genetic, and accidental factors have influenced the human life span. Researchers have gained substantial evidence that advanced glycation end products may play an important role in the processes of physiological aging. The aim of the present study was to investigate any differences in the frequencies of −374T/A polymorphism in subjects aged >90 years and in middle-aged individuals. We observed association between the A allele and genotype homozygous for this allele (AA) with a longer life expectancy in the male population. In particular, there was a prevalence of AA genotype and A allele in long-living subjects and a prevalence of the allele T in middle-aged subjects, indicating a possible protective role of the allele A to aging. In conclusion, our results support the hypothesis that longevity is the result of a good functioning of the immune system and a presumable hyper-expression of variants of anti-inflammatory genes of immunity. The differences in the genetic regulation of inflammatory processes may influence the presence of age-related disorders.

1. Introduction

During the last decades, demographic and social changes have resulted in improvements in health and longevity. The survival of elderly people has improved significantly and thus centenarians are becoming the fastest growing population group [1]. Environmental, genetic, and accidental factors influenced the human life span [2]. The numerous researches on genes involved in oxidative stress, lipid and glucose metabolism, inflammation, DNA damage and repair, axis of growth hormone and insulin-like growth factor [3] are still conflicting; it may be suggested that the combination of numerous fixed genetic variants will be necessary for someone to achieve exceptional longevity [4]. International research has focused its attention on centenarians as excellent study models for biological

Researchers have gained substantial belief that advanced glycation end products (AGEs) may play an important role in the processes of physiological aging [6]. AGEs could be involved either through the formation of free radicals, or through molecular interaction with their specific surface receptor (RAGE) [7]. The recruitment of the receptor RAGE by AGE leads to an increase in oxidative stress inducing also a state of endothelial cell activation [8]. Upon binding with its ligands, RAGE quickly becomes over-expressed and becomes part of a positive-loop feedback mechanism that results in a destabilizing effect on homeostasis phone [9].

The −374T/A RAGE promoter polymorphism leads to reduced binding of a nuclear factor to regulatory element of the RAGE gene promoter. Transcription factor binding assays revealed that introduction of the −374 A allele cause the abolition of a nuclear protein binding site, supporting role of these polymorphisms in affecting RAGE transcriptional repression [10]. The aim of the present study was to investigate any differences in the frequencies of polymorphism in subjects aged ≥90 years and in middle-aged individuals.

2. Results

The characteristics of subjects included in the study were listed in Table 1. The population in study consists of 254 Caucasian subjects (170 women and 84 men): subjects aged ≥90 years included in the Long-living Group (n = 119) and subject aged 18 to <80 years were used as Group (n = 135). The age of long-living subjects group ranged between 90 and 106 (mean ± deviation: 93 ± 3). The mean age of the control group was 62 ± 10.

Levels of total cholesterol and glucose were significantly higher in subject aged ≥90 years (p = 0.0029 and p = 0.01 respectively). HDL cholesterol and triglycerides levels were not significantly different between cases and controls. As regards the cardiovascular risk factor, we found no differences in hypertension frequencies but we found that subjects having ever smoked was significantly lower in people more than 90 years old compared to controls (4% versus 19%, p < 0.01).

Subjects with ≥90 years Subjects with <80 years p Value (n = 119) (n = 135) Age, years 93 ± 3 62 ± 10 <0.0001 Male, n (%) 28 (24%) 56 (41%) NS Hypertension, n (%) 36 (30%) 41 (30%) NS Smoking, n (%) 15 (4%) 26 (19%) <0.01 Total Cholesterol (mg/dL) 183 ± 33 147 ± 59 0.0029 Triglycerides (mg/dL) 97 ± 18 138 ± 11 NS HDL Cholesterol (mg/dL) 44 ± 14 50 ± 21 NS Glucose (g/dL) 104 ± 30 90 ± 21 0.01

The genotypic and allelic distributions of the −374 T/A polymorphism are reported in Table 2. The distributions of the frequencies of each genotype are in agreement with those predicted by the Hardy-Weinberg equilibrium. In our study, we did not find significant differences between middle-aged individuals and the long-living group.

2. −374T/A genotype and allele frequencies in middle-aged and long-living subjects.

Middle-aged individuals Subjects with ≥90 years RAGE −374T/A p Value (n = 135) (n = 119) Genotype AA 29 (21%) 29 (24%) NS AT 67 (50%) 54 (45%) NS TT 39 (36%) 36 (30%) NS Allele A 125 (46%) 112 (47%) NS T 145 (54%) 126 (53%)