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journal homepage: www.elsevier.com/locate/expgero

The functional VNTR MNS16A of the TERT gene is associated with human longevity in a population of Central Italy

Fabio Concetti a,b, Nazzareno Lucarini a, Francesco M. Carpi a, Fabio Di Pietro c, Serena Dato d, Melania Capitani a, Massimo Nabissi e, Giorgio Santoni e, Fiorenzo Mignini e, ⁎ Giuseppe Passarino d, Valerio Napolioni a,

a School of Biosciences and Biotechnologies, University of Camerino, b I.R.C.C.S. Neuromed, Pozzilli, Italy c UO of Molecular biology, BIOLAB Srl, Comunanza, Italy d Department of Cell Biology, University of Calabria, Rende, Italy e School of Pharmacy, University of Camerino, Camerino, Italy



Background: Telomerase, encoded by TERT, is the ribonucleoprotein polymerase that maintains telomere ends and it plays a crucial role in cellular senescence. TERT single nucleotide polymorphisms (SNPs) have been as- sociated both with various malignancies and telomere length (TL). The association of TERT SNPs with longev- ity remains uncertain and varies with ethnicity. The aim of this study was to investigate whether the functional variable number of tandem repeat (VNTR) MNS16A of TERT is associated with longevity. Methods: MNS16A genotypes have been determined for 1072 unrelated healthy individuals from Central Italy (18–106 yearsold)dividedintothreegender-specificageclassesdefinedaccordingtodemographicinformation andaccountingforthedifferentsurvivalsbetweensexes:formen(women),thefirstclassconsistsofindividuals b66 years old (b73 years old), the second class of individuals 66–88 years old (73–91 years old), and the third class of individuals >88 years old (>91 years old). TL was assessed using genomic DNA from wholeblood of 72 selected individuals by a multiplex real-time PCR assay. Results: MNS16A appears associated to longevity, showing significant associations in Comparison 2 (Age Class 3 vs. Age Class 2) under both additive (odds ratio [O.R.] 0.749; p = 0.019) and dominant (O.R. 0.579; p = 0.011) models. The MNS16A*Lalleleissignificantlyunderrepresented inAgeClass 3 (O.R. 0.759;p = 0.020)compared toAgeClass 2.A significanttelomereattrition isreportedalong thethree age classes (p = 0.0001), thatremains significant only in L*/L* genotype carriers (p = 0.002) when the analysis was conducted according to MNS16A genotype. Conclusions:TheTERTMNS16A*Lalleleappearsnegativelyassociatedwithlongevity.Theconcomitantsignificant telomere cross sectional attrition rate observed for L*/L* genotype suggests that this polymorphism could influ- ence human longevity by affecting TL.

Methods: MNS16A genotypes have been determined for 1072 unrelated healthy individuals from Central Italy (18–106 yearsold)dividedintothreegender-specificageclassesdefinedaccordingtodemographicinformation andaccountingforthedifferentsurvivalsbetweensexes:formen(women),thefirstclassconsistsofindividuals b66 years old (b73 years old), the second class of individuals 66–88 years old (73–91 years old), and the third class of individuals >88 years old (>91 years old). TL was assessed using genomic DNA from wholeblood of 72 selected individuals by a multiplex real-time PCR assay. Results: MNS16A appears associated to longevity, showing significant associations in Comparison 2 (Age Class 3

Results: MNS16A appears associated to longevity, showing significant associations in Comparison 2 (Age Class 3 vs. Age Class 2) under both additive (odds ratio [O.R.] 0.749; p = 0.019) and dominant (O.R. 0.579; p = 0.011) models. The MNS16A*Lalleleissignificantlyunderrepresented inAgeClass 3 (O.R. 0.759;p = 0.020)compared toAgeClass 2.A significanttelomereattrition isreportedalong thethree age classes (p = 0.0001), thatremains significant only in L*/L* genotype carriers (p = 0.002) when the analysis was conducted according to MNS16A genotype.

cross sectional attrition rate observed for L*/L* genotype suggests that this polymorphism could influ- human longevity by affecting TL.

© 2013 Elsevier Inc. All rights reserved.

1. Introduction

accumulation of molecular damage and an attenuation of the cellular defense mechanisms.

Telomeres are specialized DNA structures, consisting of TTAGGG re- peats, located at the terminal ends of chromosomes that progressively shorten every mitotic division, playing a critical role in maintaining the genome integrity (Blackburn, 2010; Chan and Blackburn, 2004). Human telomerase is the ribonucleoprotein polymerase that main- tains telomere ends and consists of two molecules each of human telo- merase reversetranscriptase (TERT), telomerase RNA (TR or TERC), and dyskerin (DKC1) (Cohen et al., 2007). Cells lacking telomerase inevita- bly undergo senescence. Telomere shortening is associated with organ- ismal aging, and leukocyte telomere length (LTL) is inversely related to age (Lindsey et al., 1991; Slagboom et al., 1994). Indeed, increased telomere length (TL) shortening has been associated to several clinical conditions and to multiple aging-associated diseases (Armanios and

Human longevity is a complex phenotype where environmental, genetic, epigenetic and stochastic factors are involved. Twin studies suggest that approximately 25% of the variation in adult life-span is at- tributable to inter-individual genetic differences (Herskind et al., 1996; Ljungquist et al., 1998). Many common gene variants have been associ- ated with longevity, but only few of them have been consistently repli- cated (Novelli et al., 2008). Genes involved in cellular maintenance pathways and repair mechanisms have been widely studied in human longevity since aging (among other things) is due to a progressive

⁎ Corresponding author at: School of Biosciences and Biotechnologies, Via Gentile III da Varano, University of Camerino, 62032 Camerino, Italy. Fax: +39 0737 402727. E-mail address: napvale@gmail.com (V. Napolioni).