Experimental Gerontology 39 (2004) 1095–1100

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specific association of genetic variation in peroxisome proliferator-activated receptor (PPAR)g-2 with longevity

Michelangela , Massimiliano , Maria Rosaria , Emilia , Fabiola Olivierib , Francesca Marchegianib , Claudio Franceschib , Giuseppe Paolissoa,*

aDepartment of Geriatric Medicine and Metabolic Diseases, VI Divisione di Medicina Interna, II University of Piazza Miraglia 2, I-80138 Naples, Italy

bDepartment of Experimental Pathology, University of Bologna, via S. Giacomo 12, 40126 Bologna,

Received 21 November 2003; received in revised form 19 March 2004; accepted 23 March 2004

Long-lived subjects have been shown to have peculiar anthropometric features (i.e. lower body mass index (BMI)) and metabolic parameters (i.e. improved insulin sensitivity). Life style and a genetic background potentially protective against the age-related metabolic derangement might contribute to such a particular phenotype.

Peroxisome proliferator-activated receptor (PPAR)g-2 is an important regulator of adipose tissue metabolism, insulin sensitivity and inflammatory response. Thus, the potential role of genetic variability at Pro/Ala loci of PPARG gene on longevity was studied in 222 long- lived subjects and 250 aged subjects.

We found a different Pro/Ala genotype frequency distribution between long-lived and aged men subjects, long-lived men having an increased frequency of Pro/Ala genotype (20 vs 8.5%); no differences was found when allele and genotype distribution of Pro/Ala gene polymorphism were analyzed in the two age group of women. Interestingly, subjects with Pro/Ala polymorphism had significantly lower BMI than Ala/Ala and Pro/Pro polymorphism.

In conclusion, our study demonstrated that paraoxonase Pro/Ala gene polyporphism is associated with human longevity. Such an effect is probably due to the effect of Pro/Ala polymorphism on body composition and appears to be gender specific. q 2004 Elsevier Inc. All rights reserved.

Keywords: PPARg; Pro12Ala gene polymorphism; Human longevity; Ageing body composition

1. Introduction

the anthropometric and metabolic derangement found in aged subjects (Paolisso et al., 1995).

Life style and a genetic background potentially protec- tive against the age-related metabolic derangement might contribute to the lower body mass index (BMI) and improved insulin sensitivity found among long-lived subjects.

Several recent intriguing studies in Caucasian long-lived subjects have highlighted the role of biological factors as determinant of ‘successful ageing’ (Paolisso, 2000) and have demonstrated that, starting from young to very old subjects, aging is associated with a progressive remodeling (Paolisso, 2000). Such age-remodeling mainly affects anthropometric, endocrine and metabolic factors such as plasma lipid profile and insulin action. So far, long-lived subjects have been shown to have peculiar anthropometric features and metabolic parameters. In particular, it has been shown that long-lived subjects are less prone to

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor subfamily of ligand-dependent transcription factors (Spiegelman, 1998). At the molecular level, PPARs act by binding to the promoter region as a heterodimer with the receptor for 9-cis- retinoic acid, and these heterodimers regulate the transcrip- tion of genes involved in lipid and glucose metabolism (Kersten et al., 2000) There are currently three known subtypes of PPARs: PPARa, PPARd, and PPARg (Kersten et al., 2000). The isoform PPARg2 is mainly expressed in

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M. Barbieri et al. / Experimental Gerontology 39 (2004) 1095–1100

adipose tissue (Kersten et al., 2000) where it modulates the expression of target genes involved in adipocyte differen- tiation (Elbrecht et al., 1996) insulin sensitivity, and inflammatory processes (Lemberger et al., 1996a,b; Blanquart et al., 2003; Ricote et al., 1998, 1999; Plutzky, 2003). This receptor is also the target of the thiazolidine- dione class of insulin-sensitizing drugs that are used to treat insulin resistance (Olefsky, 2000).

within normal range. According to American Diabetes Association criteria (Alberti and Zimmet, 1998), all subjects were neither diabetics nor affected by impaired fasting glucose. No subject used drugs which affects insulin secretion and/or action or plasma lipid level. In particular, long-lived subjects represented a group of carefully selected individuals free of major age-related diseases. After a clear explanation of the potential risk of the study, all subjects (as well as long-lived’s relatives) gave informed consent to participate into the study, which was approved by the Ethical Committee of our Institutions.

3p25 (Beamer et al., 1997) and it contains nine exons (Fajas et al., 1997). Since most of the PPAR target genes in the adipose tissue are implicated in lipogenic pathways, including lipoprotein lipase, acyl-CoA synthase, and fatty acid transport protein, variations in the human PPAR2 gene have received much attention. To date, at least two naturally occurring mutations in this gene have been identified, which impair the function of PPAR2 (Deeb et al., 1998; Ristow et al., 1998). The CG mutation in exon B of the PPAR2 gene leads to the substitution of alanine for proline at codon 12 (Pro12Ala) (Deeb et al., 1998). The PPAR2 Ala allele has reduced ability to activate the transcription of PPAR2 target genes (Deeb et al., 1998).

2.2. Analytical methods