Interestingly, the increased proportion of Pro/Ala genotype found in long-lived men suggest that those individuals who are genetically predisposed to have lower BMI are advantageous in reaching the extreme limits of lifespan. Our results are strengthened by the evidence of an higher prevalence of Pro/Ala genotype among long-lived subjects even after a more refined age categorization (long lived, bottom 50% of aged, top 50% of aged) with no significant difference among the two subgroups of aged subjects (data not shown).

Peroxisome proliferator-activated receptor (PPAR)g-2 is an important regulator of adipose tissue metabolism, insulin sensitivity and inflammatory response (Elbrecht et al., 1996; Lemberger et al., 1996a,b; Blanquart et al., 2003; Ricote et al., 1998, 1999; Plutzky, 2003). Interestingly, PPAR- gamma ligands reverse the major defect of the insulin resistance syndrome and have important effects that, inhibit atherosclerosis, improve endothelial cell function and attenuate inflammation (Hsueh and Law, 2003).

The central role of obesity as a major risk factor for a number of age-related disorders including hypertension, coronary artery disease (CAD), dyslipidemias, and type 2 diabetes may explain the effect of PPARg locus on survival.

The common Pro/Ala polymorphism occurring in the PPARG-2 exon B, which causes a reduction in the transcriptional activity of PPARg-2 (Deeb et al., 1998), has been extensively investigated for association with obesity and type 2 diabetes in different populations (Deeb et al., 1998; Ristow et al., 1998; Rosmond et al., 2003a; Koch et al., 1999; Valve et al., 1999; Meirhaeghe et al., 2000; Evans et al., 2000; Altshuler et al., 2000; Clement

Our results suggest that survival selection through Pro/Ala locus is differentially affected in male and female. Indeed, the sex specific association of longevity with alleles or genotypes of several gene related to risk factors for a variety of age-related diseases, including PPARG genotype is not unexpected on the basis of previous studies on the genetics of longevity in centenarians

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

et al., 2001a; Ivanova et al., 1998). In fact, despite the fact that several genes have been found associated with long- evity in both genders (Puca et al., 2001; Schachter et al., 1994), different finding in male and female have been also observed in previous gene/longevity association studies (regarding tyrosine hydroxilase, mithocondrial DNA hap- logroups and IL-6 gene), pointing out that gender is a major variable in the genetics of longevity and suggesting that men and women follow different strategies to reach longevity. To this regard, it has been hypothesized that female centenar- ians are more likely to reach 100 years of age because of a more favorable environmental condition and a healthier life style (Bonafe` et al., 2001a).

Ala variant in the peroxisome proliferator activated receptor g

with obesity in two Caucasian population. Diabetes

,

–

Blanquart, C., Barbier, O., Fruchart, J.C., Staels, B., Glineur, C., Peroxisome proliferator-activated receptors: regulation of tional activities and roles in inflammation. J. Steroid Biochem. Biol.

(

–

),

–

Bonafe`, M., Olivieri, F., Cavallone, L., Giovagnetti, S., Marchegiani, Cardelli, M., Pieri, C., Marra, M., Antonicelli, R., Rosmarie, L., M.R., Paolisso, G., Monti, D., Franceschi, C.,

a. A dependent genetic predisposition to produce high levels of IL-

detrimental for longevity. Eur. J. Immunol.

,

–

Bonafe`, M., Cardelli, M., Marchegiani, F., Cavallone, L., Giovagnetti, Olivieri, F., Lisa, R., Pieri, C., Franceschi, C.,

b. Increase homozygosity in centenarians revealed by a new inter-Alu technique. Exp. Gerontol.

(

),

–

Bonora, E., Targher, G., Alberiche, M., Bonadonna, R.C., Saggiani, Zenere, M.B., Monauni, T., Muggeo, M.,

Homeostasis assessment closely mirrors the glucose clamp technique in assessment of insulin sensitivity. Studies in subjects with degrees of glucose tolerance and insulin sensitivity. Diabetes Care

–

Caruso, C., Candore, G., Colonna Romano, G., Lio, D., Bonafe, Valensin, S., Franceschi, C.,

HLA, aging, and longevity: a reappraisal. Hum. Immunol.

(

),

–

Chen, Y.J., Vortmeyer, A., Zhuang, Z., Huang, S., Jensen, R.T.,

of heterozygosity of chromosome

q in gastrinomas: occurrence prognostic significance. Cancer Res.

(

),

–

Clement, K., Hercberg, S., Passinge, B., Galan, P., Varroud-Vial, Shuldiner, A.R., Beamer, B.A., Charpentier, G., Guy-Grand, Froguel, P., Vaisse, C.,

The Pro

Gln and Pro

Ala gene mutations in obesity and type

diabetes. Int. J. Obes. Metab. Disord.

,

–

De Benedictis, G., Rose, G., carrieri, G., De Luca, M., Falcone, Passarino, G., Bonafe`, M., Monti, D., Baggio, G., Bertolini, S., D., Mattace, R., Franceschi, C.,

Mithocondrial DNA variants are associated with succesful ageing and longevity in FASEB J.

,

–

Deeb, S.S., Fajas, L., Nemoto, M., Pihlajamaki, J., Mykkanen, L., J., Laakso, M., Fujimoto, W., Auwerx, J.,

A substitution in PPARgamma

associated with decreased activity, lower body mass index and improved insulin Nat. Genet.

(

),

–

Ek, J., Urhammer, S.A., Sorensen, T.I., Andersen, T., Auwerx, J., O.,

Homozygosity of the Pro

Ala variant of the proliferation-activated receptor-gamma

(PPAR-gamma

): modulating effects on body mass index in obese and lean men. Diabetologia

(

),

–

Elbrecht, A., Chen, Y., Cullinan, C.A., Hayes, N., Leibowitz, M., D.E., Berger, J.,

Molecular cloning, expression and ation of human peroxisome proliferator activated receptors gamma and gamma

Biochem. Biophys. Res. Commun.

,

–

Ellerhorst, J.A., Hildebrand, W.H., Cavett, J.W., Fernandez-Vina, Hodges, S., Poindexter, N., Fischer, H., Grimm, E.A.,

zygosity or homozygosity for

HLA class II haplotypes favorable outcomes for renal cell carcinoma treated with therapy. J. Urol.

(

),

–