Experimental Gerontology 39 (2004) 1095-1100 www.elsevier.com/locate/expgero 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,* a Department of Geriatric Medicine and Metabolic Diseases, VI Divisione di Medicina Interna, II University of Piazza Miraglia 2, I-80138 Naples, Italy b Department 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). Lifestyle and a genetic background potentially protective against 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 male subjects; long-lived men had an increased frequency of Pro/Ala genotype (20% vs. 8.5%). No differences were found when allele and genotype distribution of Pro/Ala gene polymorphism were analyzed in the two age groups 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 polymorphism 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; Aging body composition 1. Introduction The anthropometric and metabolic derangement found in aged subjects (Paolisso et al., 1995). Lifestyle and a genetic background potentially protective against 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 a determinant of successful aging (Paolisso, 2000) and have demonstrated that, starting from young to very old subjects, aging is associated with 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 transcription 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 adipose tissue (Kersten et al., 2000) where it modulates the expression of target genes involved in adipocyte differentiation (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 thiazolidinedione 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 diabetic nor affected by impaired fasting glucose. No subject used drugs that affect insulin secretion and/or action or plasma lipid levels. In particular, long-lived subjects represented a group of carefully selected individuals free of major age-related diseases. After a, has been extensively studied in relation to BMI and insulin sensitivity. However, previous studies have yielded inconsistent findings on the association between the Ala allele and BMI. Our study found that the Pro/Ala genotype is associated with lower BMI and a trend towards lower insulin resistance degree. Nevertheless, caution in interpreting the data is necessary due to the large standard deviation of BMI in all study groups.

The allele frequency and genotype distribution of the Pro/Ala gene polymorphism did not differ significantly between long-lived and aged subjects, but a higher frequency of Pro/Ala genotype was found in long-lived men. This suggests that individuals genetically predisposed to lower BMI may have an advantage in reaching extreme lifespan limits. Interestingly, gender differences in the association of PPARG gene polymorphism with dyslipidemia, insulin sensitivity, and BMI have been documented previously.

PPAR- gamma is an important regulator of adipose tissue metabolism, insulin sensitivity, and inflammatory response. PPAR-gamma ligands have been shown to reverse the major defect of insulin resistance syndrome and to inhibit atherosclerosis, improve endothelial cell function, and attenuate inflammation. The effect of PPARg locus on survival may be explained by the central role of obesity as a major risk factor for age-related disorders such as hypertension, CAD, dyslipidemias, and type 2 diabetes.