Evolution in health and medicine Sackler colloquium: Genetic variation in human telomerase is associated with telomere length in Ashkenazi centenarians

Abstract

Telomere length in humans is emerging as a biomarker of aging because its shortening is associated with aging-related diseases and early mortality. However, genetic mechanisms responsible for these associations are not known. Here, in a cohort of Ashkenazi Jewish centenarians, their offspring, and offspring-matched controls, we studied the inheritance and maintenance of telomere length and variations in two major genes associated with telomerase enzyme activity, hTERT and hTERC. We demonstrated that centenarians and their offspring maintain longer telomeres compared with controls with advancing age and that longer telomeres are associated with protection from age-related diseases, better cognitive function, and lipid profiles of healthy aging. Sequence analysis of hTERT and hTERC showed overrepresentation of synonymous and intronic mutations among centenarians relative to controls. Moreover, we identified a common hTERT haplotype that is associated with both exceptional longevity and longer telomere length. Thus, variations in human telomerase gene that are associated with better maintenance of telomere length may confer healthy aging and exceptional longevity in humans.

Fig. 1.

Comparison of telomere length among Ashkenazi Jewish centenarians (n = 86), their offspring (n = 175), and controls (n = 93). Values are adjusted for age at recruitment and gender in the offspring and control groups and for gender alone in the centenarian group *P < 0.05.

Fig. 2.

Telomere length (adjusted for age, gender, and group) according to the absence (gray bars) or presence (white bars) of various age-related diseases in the study subjects. Number of individuals analyzed in each group: hypertension (n = 125), without hypertension (n = 142), with the metabolic syndrome (n = 59), without the metabolic syndrome (n = 286), diabetes (n = 34), without diabetes (n = 276). The MMSE was performed in centenarians only: MMSE score ≤25 (gray bars, n = 46) or >25 (white bars, n = 32). *P < 0.05.

Fig. 3.

2D gene scanning of human telomerase gene (hTERT and hTERC). The coding regions and exon–intron junctions of the hTERT and hTERC were amplified by 2-step PCR. Eighteen PCR fragments were displayed in a 2D gel according to their size and melting temperature. (A) 2D gene scanning pattern from a centenarian subject with the fragment identification number and a heteroduplex band in exon 14 of the hTERT. (B) Common genetic variation in exon 14 was identified as 3097 C > T (His-1013 His) by nucleotide sequencing.

Fig. 4.

Schematic representation of exons, introns, UTRs, and variants discovered. (A) hTERT. (B) hTERC. Green blocks, coding exons; white blocks, 5′ and 3′ UTRs; *previously unknown variants.