Analysis of the Association Between TERC and TERT Genetic Variation and Leukocyte Telomere Length and Human Lifespan-A Follow-Up Study.

Daniela Scarabino,Martina Peconi,Rosa Maria Corbo,Franca Pelliccia

doi:10.3390/genes10020082

Abstract

We investigated the possible influence of TERC and TERT genetic variation and leukocyte telomere length (LTL) on human lifespan. Four polymorphisms of TERT and three polymorphisms of TERC were examined in a sample of elderly subjects (70–100 years). After nine years of follow-up, mortality data were collected, and sub-samples of long-lived/not long-lived were defined. TERT VNTR MNS16A L/L genotype and TERT rs2853691 A/G or G/G genotypes were found to be associated with a significantly higher risk to die before the age of 90 years, and with a significantly lower age at death. The association between lifespan and LTL at baseline was analyzed in a subsample of 163 subjects. Age at baseline was inversely associated with LTL (p < 0.0001). Mean LTL was greater in the subjects still living than in those no longer living at follow-up (0.79 T/S ± 0.09 vs. 0.63 T/S ± 0.08, p < 0.0001). Comparison of age classes showed that, among the 70–79-year-olds, the difference in mean LTL between those still living and those no longer living at follow-up was greater than among the 80–90-year-olds. Our data provide evidence that shorter LTL at baseline may predict a shorter lifespan, but the reliability of LTL as a lifespan biomarker seems to be limited to a specific age (70–79 years).

Highlights

The dramatic increase in rates of survival to an advanced old age over the past century has prompted extensive research in the attempt to identify the mechanisms involved in lifespan determination
To evaluate the involvement of the TERT and TERC polymorphisms in lifespan determination, genotype frequencies of TERT and TERC SNPs observed in the long-lived subjects were compared against those observed in the subjects who had died before reaching the age of 90 years
The two TERT polymorphisms were found in strict linkage disequilibrium (p < 0.0001, D = 80% of Dmax), with a trend of the MNS16A L allele to be associated with the rs2853691

Summary

Introduction

The dramatic increase in rates of survival to an advanced old age over the past century has prompted extensive research in the attempt to identify the mechanisms involved in lifespan determination. Among the most extensively studied biological processes associated with longevity are those involved in cell maintenance/senescence. The structures at the ends of eukaryotic chromosomes with a protective action against genome instability, have been widely studied as a possible determinant of lifespan [1]. Human telomeres are composed of repeated TTAGGG nucleotide sequences located at the ends of each chromosome. Because telomere sequences are not fully replicated during DNA replication due to the inability of DNA polymerase to replicate the 30 end of the DNA strand, telomeres shorten as cells divide. In the absence of special telomere maintenance mechanisms, telomeres (and chromosomes) become shorter with each cell division. Once a critically short telomere length is reached, the cell is triggered to enter replicative senescence, leading to cell death

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