www.elsevier.com/locate/neuaging - VEGF Gene Variability in the Italian Population: Lessons Learned
Del Bo, Serena Ghezzi, Marina Scarlato, Diego Albani, Daniela Galimberti, Ugo Lucca, Mauro Tettamanti, Elio Scarpini, Gianluigi Forloni, Nereo Bresolin, Giacomo Pietro Comi

Dino Ferrari Centre, Department of Neurological Sciences, University of Milan, IRCCS Foundation Ospedale Maggiore Mangiagalli and Regina Elena, Padiglione Ponti, Via F. Sforza 35, 20122 Milano, Italy
Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy

Abstract:
Vascular endothelial growth factor (VEGF) gene polymorphisms have been associated with an increased risk of developing a wide variety of disorders from diabetes to neurodegenerative diseases. This suggests functions for VEGF not confined to its originally described vascular effects. Based on the protective roles of VEGF undisclosed in pathological conditions, we evaluated whether VEGF variability might also be a determinant for longevity. We analyzed four polymorphisms (2578C/A, 1190G/A, 1154G/A and 634G/C) within the VEGF gene promoter region in 490 unrelated healthy Italian subjects. Significant changes of allele frequencies were observed between young/elderly and long-lived subjects suggesting that VEGF gene variability can be inserted among the genetic factors influencing lifespan.

Keywords: Aging; Vascular endothelial growth factor; Genetic risk factor; Longevity

Introduction:
Vascular endothelial growth factor (VEGF) is an important angiogenesis cytokine that undergoes transcriptional and post-transcriptional induction by hypoxia. It has been implicated in several pathological conditions, from tumour proliferation to inflammatory and ischemic processes (Carmeliet, 2003; Ferrara et al., 2003). VEGF has been originally identified on the basis of its vascular effects, but recently has been recognized as an important signaling molecule in the nervous system, as well as in neurodegenerative disorders and in peripheral neuropathies (Rosenstein and Krum, 2004; Storkebaum and Carmeliet, 2004). An age-dependent decline in VEGF expression has been reported in different tissues; however, the molecular alterations responsible for this reduction have not been elucidated. Longevity represents a very complex phenomenon due to the interaction among genetic, environmental and lifestyle factors. Identification of genetic and non-genetic factors involved in aging has progressed extensively in recent years because of increased interest in defining the determinants of human life expectancy. It has been suggested that genes and biochemical factors likely to be implicated in aging-related disorders may have an important role also in human longevity. Among genetic markers, several variants in pro- or anti-inflammatory cytokines and in vascular factors have been shown to affect successful aging.

Materials and methods:
A total of 490 unrelated Italian individuals (40.2% males) born and resident in Northern Italy, ranging from 25 to 99 years of age, were enrolled for this study. We screened for four well-known polymorphisms localized in the promoter and 5'UTR region of VEGF gene. To carry out a comparative analysis of the genotypes, the whole cohort was divided into three age groups: (i) 166 young subjects (ranging from 25 to 65 years of age; mean standard deviation (S.D.) = 47.4 ± 11.2 years; 45.5% males); (ii) 158 elderly subjects (ranging from 66 to 84 years of age, mean S.D. = 75.7 ± 5.7 years; MMSE: available only in 35 subjects aged more than 80 years: 25.6 ± 1.8 points; 50.4% males); (iii) 166 long-lived subjects (ranging from 85 to 99 years of age; mean S.D. = 90.1 ± 3.3 years; MMSE: available only in six subjects aged more than 80 years: 28 ± 1.2 points; 48.8% males).