Owing to its ability to confer with unlimited proliferative poten- tial, TERT over-expression is a common feature of human cancers and can increase cancer incidence in the context of classical mouse TERT transgenesis (Bernardes de Jesus et al., 2012). However, at the same time, telomerase-transfected normal human cell types exhibit elongated telomeres, vigorous cell divisions, reduced senescence bio- markers and elongated life-span by at least 20 doublings (Bodnar et al., 1998). Thus, it is highly conceivable that strong telomerase activ- ity may promote both cancer and longevity.

further supported by the significant LTL attrition that we found along the three age classes, for L*/L* genotype carriers only.

et al., 2012) which employed SNPs to assess the association of TERT locus with longevity, we used a functional VNTR located downstream of the TERT gene. VNTRs constitute a relatively under-examined class of genomic variants in the context of complex disease because of their sequence complexity and the challenges in assaying them (El-Sayed Moustafa et al., 2012). It has been suggested that complex multiallelic loci such as VNTRs are among the most likely structural variants to be enrichedfor functionalimpact (Conrad et al.,2010;El-Sayed Moustafaet al., 2012). The involvement of VNTRs in complex traits has been previ- ously demonstrated by the association of VNTR in the INS gene with type-1 diabetes (Julier et al., 1991), the VNTRs located in the SLC6A3 and SLC6A4 genes with several psychiatric conditions (Ueno, 2003) and the VNTRs in SIRT3andAPOB genes with human longevity (Bellizzi et al., 2005; De Benedictis et al., 1998).

Although we found a LTL attrition along the three age classes (p = 0.0001), that remains significant only in L*/L* genotype carriers (p = 0.002) when the analysis was conducted according to MNS16A genotype, this result should be taken with caution due to limited sample size. Moreover, it should be noted that the difference between the average LTL among the two elderly groups (Age Class 2 and Age Class 3) (Table 2 and Fig. 2) seems to be insignificant, indeed appearing unchanged. This fact is supported by several studies that reported the leveling off of telomere length in advanced age groups (Ishikawa et al., 2012), the dependence of LTL on the health status of centenarians (Terry et al., 2008), and the lack of association of LTL with the overall survival or life span in elderly persons (Njajou et al., 2009), respectively.

It has been reported that VNTR MNS16A affects the putative pro- moter region of the antisense transcript of TERT giving rise to a poten- tial allele-dependent regulation of telomerase expression (Wang et al., 2003). Indeed, longer alleles at MNS16A exhibit stronger promot- er activity compared to the shorter alleles (Wang et al., 2003). In turn, this lead to an increased expression of antisense TERT mRNA with a conceivable, at least partial, silencing of sense telomerase transcript (Wang et al., 2003). Accordingly, carriers of the MNS16A*S allele

It is noteworthy that some TERT polymorphisms correlated to telo- mere length but did not affect longevity or the parameters of healthy aging (Soerensen et al., 2012). This is probably due to the great environ- mental component affecting telomere length; oxidative stress, depres- sion and uncertainty for the future have been found to significantly correlate with shorter telomeres (Cherkas et al., 2006; Epel et al., 2004; Lung et al., 2007; Yen and Lung, 2013). Thus, environmental factors

Table 2

Mean LTL expressed as T/S ratio among the MNS16A genotypes divided by age classes. Values are expressed as mean ± S.D. Values showing significant differences are shown bold. p-Values were obtained by ANOVA.

⁎ Genotype Age Class 1 (N = 24) Age Class 2 (N = 24) Age Class 3 (N = 24) p-Value L*/L* (N = 8 for each Age Class) 1.455 ± 0.274 1.019 ± 0.198 1.003 ± 0.257 0.002 S*/L* (N = 8 for each Age Class) 1.285 ± 0.331 1.035 ± 0.262 1.073 ± 0.280 0.207 S*/S* (N = 8 for each Age Class) 1.140 ± 0.205 1.033 ± 0.328 0.966 ± 0.129 0.345 ⁎⁎ p-Value 0.097 0.992 0.649

⁎ p-Value obtained by comparing the mean T/S ratio along the three age classes. ⁎⁎ p-Value obtained by comparing the mean T/S ratio along the three MNS16A genotypes.

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