BTlackwell Phublishing, Lted. G/C polymorphism of transforming growth factor 915 ββββ 1 is associated with human longevity: a study in Italian centenarians

Giuseppina Carrieri,

* Erika Marzi,

* Fabiola Olivieri,

Francesca Marchegiani, Luca Cavallone, Maurizio Cardelli,

Simona Giovagnetti,

Rosalia Stecconi,

Cinzia Molendini, Chiara Trapassi, Giovanna De Benedictis,

Dimitri Kletsas

and Claudio Franceschi

,

,

I.N.R.C.A., Italian National Research Center on Aging, Ancona, Italy

C.I.G., Interdepartmental Center ‘L. Galvani’ for Integrated Studies on Bioinformatics, Biophysics, and Biocomplexity, University of Bologna, Bologna, Italy

Department of Experimental Pathology, University of Bologna, Bologna, Italy

Department of Cell Biology, University of Calabria, Rende, Italy

Institute of Biology, N.C.S.R. Demokritos, Athens, Greece

younger individuals (P = 0.007). Finally, active TGF-ββββ 1 plasma levels were significantly increased in the elderly group, but no relationship with TGF-ββββ 1 genotypes was observed. These results suggest that, at least in this popu- lation, the variability of the TGF-ββββ 1 gene influences lon- gevity and that the age-related increase in plasma levels of active TGF-ββββ 1 seems not to be genetically regulated. Key words: aging; centenarians; inflammation; longevity; polymorphism; TGF-ββββ 1.

Introduction

A growing amount of data suggest that aging is associated with an up-regulation of the inflammatory response, probably due to the chronic antigenic stress which impinges lifelong upon innate immunity and leads to a pro-inflammatory status that we proposed to call inflamm-aging (Franceschi et al., 2000a). Indeed, a series of studies demonstrated that inflammation is involved in the pathogenesis of several age-related disorders (e.g. atherosclerosis, Alzheimer’s disease and osteoporosis) and in the increase of the mortality risk (Franceschi et al., 2000a; Bruunsgaard et al., 2001; Lio et al., 2003). Cytokines play an important role in inflamm-aging and many of them may be involved in the pathogenesis of those age-related disorders having an important inflammatory component. Interestingly, a number of studies suggest that common sequence variations of the cytokine genes may have an effect on the amount of the cytokine secreted (Bidwell et al., 1999, 2001) and may con- sequently affect the interindividual differences in the inflam- matory response, thus modulating susceptibility and severity of several pathologies (Keen et al., 1998; Francis et al., 1999; Licastro et al., 2000). Moreover, sequence variations in several cytokines, such as interleukin-6, interleukin-10 and interferon-γ have been shown to be associated with successful aging and longevity (Bonafè et al., 2001; Lio et al., 2002a,b).

Summary

Sequence variations in a variety of pro- or anti-inflammatory cytokine genes have been found to influence successful aging and longevity. Because of the role played by the transforming growth factor ββββ 1 (TGF-ββββ 1) cytokine in inflammation and regulation of immune responses, the variability of the TGF-ββββ 1 gene may affect longevity by playing a role in inflamm-aging. Two polymorphisms, G/ A and C/T , located in the 5′′′′ region, and two mis- −−−−800 −−−−509 sense polymorphisms, T/C and G/C which change 869 915 (Leu > Pro) and (Arg > Pro) , respectively, located in the 10 25 signal peptide, were analysed in 419 subjects from North- ern and Central Italy, including 172 centenarians and 247 younger controls. In addition, the effects of the TGF-ββββ 1 genetic variability on plasma levels of the biologically active form (naturally processed) of this cytokine were studied in 143 randomly selected subjects, including 73 centenarians. Significant differences were found at the +915 site as far as the C allele and GC genotype were con- cerned, both of them being lower in centenarians than in young controls (P = 0.034 and 0.028, respectively), but none of the other tested genetic variants was signifi- cantly different between centenarians and controls. Moreover, a particular haplotype combination (G /C −−−−800 −−−− /C /C ) was notably lower in centenarians than in 509 869 915

In line with these findings, it is conceivable that transforming growth factor-β1 (TGF-β1) could play a role in longevity. TGF- β1, the prototypic member of the TGF-β superfamily, is secreted in a latent form and activated by proteolysis during processes such as immune modulation, differentiation and cell growth (Saharinen et al., 1999). This cytokine has been shown to have an essential role in inflammation and in maintenance of immune response homeostasis (Letterio & Roberts, 1998; Cottrez & Groux, 2001; Gorelik & Flavell, 2002). TGF-β1 belongs to the group of cytokines with anti-inflammatory effects, being a deac- tivating factor of macrophages having potent anti-inflammatory properties (Vodovotz et al., 1993; Smith et al., 1996; Weiss

Correspondence

et al., 1999). TGF-β1-deficient mice showed a severe and multifocal inflammatory response with the production of mul- tiple effector cytokines (Shull et al., 1992; McCartney-Francis & Wahl, 2002). Moreover, recent studies in mice have indicated that TGF-β1 is probably necessary to develop overt organ- specific age-related diseases with an inflammatory pathogenesis (Wyss-Coray et al., 2000; Mallat et al., 2001).

Table 1 Absolute allelic and genotypic frequencies of G/A and C/T −800 −509 polymorphisms of the promoter region of the TGF-β1 gene in centenarians (n = 172) and younger controls (n = 247). Relative frequencies (×100) with standard errors are given in parentheses

G/A Centenarians Younger controls −800 Alleles G 330 (95.9 ± 1.0) 477 (96.6 ± 1.0) A 14 (4.1 ± 1.0) 17 (3.4 ± 1.0) Genotypes GG 158 (91.9 ± 2.1) 231 (93.5 ± 1.6) GA 14 (8.1 ± 2.1) 15 (6.1 ± 1.5) AA 0 (0.0) 1 (0.4 ± 0.4)