Genetic variation in human telomerase is associated with telomere length in Ashkenazi centenarians

Atzmon, Gil; Cho, Miook; Cawthon, Richard M.; Budagov, Temuri; Katz, Micol; Yang, Xiaoman; Siegel, Glenn; Bergman, Aviv; Huffman, Derek M.; Schechter, Clyde B.; Wright, Woodring E.; Barzilai, Nir; Govindaraju, Diddahally R.; Suh, Yousin

doi:10.1073/pnas.0906191106

Cited by 209 publications

(192 citation statements)

References 47 publications

Supporting

Mentioning

176

Contrasting

Unclassified

Order By: Relevance

“…To prevent gene loss, shortened telomeres generally activate damage response pathways that cause cell death or impairment of cellular function (2,3). Evidence that cell replication is limited by shorter TL has been reported in vitro (37)(38)(39)(40) through in vivo experimentation in animal models (41)(42)(43) and in cross-sectional and longitudinal observational studies (7)(8)(9)(10)(11)(12)(13)(44)(45)(46)(47)(48). On the other hand, whether inherited TL alters the risks of developing cancer is unsettled (20,21,(49)(50)(51)(52)(53), so the implications of the association of paternal ages at reproduction with TL for cancer risk are unclear.…”

Section: Discussionmentioning

confidence: 99%

Delayed paternal age of reproduction in humans is associated with longer telomeres across two generations of descendants

Eisenberg

Hayes

Kuzawa

2012

Proc. Natl. Acad. Sci. U.S.A.

180

168

View full text Add to dashboard Cite

Telomeres are repeating DNA sequences at the ends of chromosomes that protect and buffer genes from nucleotide loss as cells divide. Telomere length (TL) shortens with age in most proliferating tissues, limiting cell division and thereby contributing to senescence. However, TL increases with age in sperm, and, correspondingly, offspring of older fathers inherit longer telomeres. Using data and samples from a longitudinal study from the Philippines, we first replicate the finding that paternal age at birth is associated with longer TL in offspring (n = 2,023, P = 1.84 × 10 −6 ). We then show that this association of paternal age with offspring TL is cumulative across multiple generations: in this sample, grandchildren of older paternal grandfathers at the birth of fathers have longer telomeres (n = 234, P = 0.038), independent of, and additive to, the association of their father's age at birth with TL. The lengthening of telomeres predicted by each year that the father's or grandfather's reproduction are delayed is equal to the yearly shortening of TL seen in middle-age to elderly women in this sample, pointing to potentially important impacts on health and the pace of senescent decline in tissues and systems that are cell-replication dependent. This finding suggests a mechanism by which humans could extend late-life function as average age at reproduction is delayed within a lineage.adaptation | epigenetics | evolution | parental effects | transgenerational plasticity T elomeres are repeating DNA sequences at the ends of chromosomes that protect and buffer genes from nucleotide loss as cells divide (1). In many tissues, telomere lengths (TL) are shortened by cellular proliferation, and as a result TL tends to decline with age (2-5). As cell replication generally requires a minimal TL, shortened TL is thought to contribute to senescence (6). Consistent with this, elderly persons with shorter telomeres (in blood) for their age have reduced survival (7-13).Although it is well established that TL shortens with age in most proliferating tissues (e.g., 4, 5), sperm TL is an exceptionolder men have sperm with longer telomeres (4,14,15). This may be explained by the fact that the activity of telomerase (an enzyme that extends TL) is high in testes (16,17). Consistent with the fact that offspring inherit half their chromosomes from sperm, offspring of older fathers tend to have longer telomeres (4,18,19). In contrast, because the pool of ova is established in utero, TL in ova are thought to be stable with age, and there is no evidence for a maternal age effect on TL in offspring (e.g., 4, 20).We recently hypothesized that the age-related TL increase in sperm could lead to cumulative, and thus more biologically significant, multigenerational lengthening or shortening of TL in response to population trends in reproductive scheduling (21). If average reproductive age of recent patrilineal ancestors cumulatively influences TL, this might also lead to changes in TL of sufficient magnitude to influence late-life function and l...

show abstract

Section: Discussionmentioning

confidence: 99%

Delayed paternal age of reproduction in humans is associated with longer telomeres across two generations of descendants

Eisenberg

Hayes

Kuzawa

2012

Proc. Natl. Acad. Sci. U.S.A.

180

168

View full text Add to dashboard Cite

show abstract

“…Although inheritance of telomere length has been reported in human families, the mechanisms underlying telomere-length inheritance remain unclear (19)(20)(21)(22).We have analyzed telomerelength regulation and inheritance in human pedigrees and mouse models, studying telomere shortening in circumstances of telomerase haploinsufficiency and the regulation of telomere length upon restoration of a normal telomerase genotype. In families with TERT haploinsufficiency manifest as aplastic anemia, we observed that some but not all genotypically normal offspring of a haploinsufficient parent or grandparent retained short telomeres.…”

Section: Discussionmentioning

confidence: 99%

Telomere length is inherited with resetting of the telomere set-point

Chiang

Calado

Hathcock

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

We have studied models of telomerase haploinsufficiency in humans and mice to analyze regulation of telomere length and the significance of "set points" in inheritance of telomere length. In three families with clinical syndromes associated with short telomeres resulting from haploinsufficient mutations in TERT, the gene encoding telomerase reverse transcriptase, we asked whether restoration of normal genotypes in offspring of affected individuals would elongate inherited short telomeres. Telomeres were shorter than normal in some but not all genotypically normal offspring of telomerase-mutant parents or grandparents. Analysis of these findings was complicated by heterogeneity of telomere length among individuals, as well as by the admixing of telomeres inherited from affected parents with those inherited from unaffected ("wild-type" TERT) parents. To understand further the inheritance of telomere length, we established a shortened-telomere mouse model. When Tert +/− heterozygous mice were successively cross-bred through 17 generations, telomere length shortened progressively. The late-generation Tert +/− mice were intercrossed to produce genotypically wild-type Tert +/+ mice, for which telomere length was characterized. Strikingly, telomere length in these Tert +/+ mice was not longer than that of their Tert +/− parents. Moreover, when successive crosses were carried out among these short-telomere Tert +/+ offspring mice, telomere length was stable, with no elongation up to six generations. This breeding strategy therefore has established a mouse strain, B6.ST (short telomeres), with C57BL/6 genotype and stable short telomeres. These findings suggest that the set point of telomere lengths of offspring is determined by the telomere lengths of their parents in the presence of normal expression of telomerase.T elomerase is an RNA-dependent DNA polymerase that consists of two essential components, a template RNA (TERC) and a catalytic reverse transcriptase (TERT). The telomerase holoenzyme adds telomeric DNA repeats at the termini of eukaryotic chromosomes, thus maintaining telomere length and function despite telomere attrition that normally occurs during chromosomal replication. Telomeric DNA repeats and specific associated proteins are assembled to form telomere structures that distinguish normal chromosome ends from DNA damage-induced double-strand breaks and thus subserve a critical function in maintaining chromosomal stability (1-3). The functional importance of telomere integrity and telomerase activity has been addressed in a variety of experimental model systems, notably including genetic alterations of telomerase and telomeric proteins in multiple eukaryotic species. Evidence for a physiologically important role of telomerase in humans first emerged from analysis of the genetic syndrome dyskeratosis congenita (DKC), characterized by failure of bone morrow and other rapidly dividing cell lineages. An X-linked form of DKC was the first human disease recognized to be related to telomerase deficiency and is c...

show abstract

“…9,10 Increased TL in leukocytes has been associated with longevity in a comparison of long-lived Ashkenazi Jews and their offspring with younger controls. 11 Genetic association studies have revealed associations between single-nucleotide polymorphisms (SNPs) in the TERC and TERT genes and TL. [11][12][13][14][15][16][17] Other studies reported associations between SNPs in TERC and POT1 with human longevity, 11,17,18 suggesting that genes regulating TL may influence human longevity.…”

Section: Introductionmentioning

confidence: 99%

Meta-analysis of telomere length in 19 713 subjects reveals high heritability, stronger maternal inheritance and a paternal age effect

et al. 2013

View full text Add to dashboard Cite

Telomere length (TL) has been associated with aging and mortality, but individual differences are also influenced by genetic factors, with previous studies reporting heritability estimates ranging from 34 to 82%. Here we investigate the heritability, mode of inheritance and the influence of parental age at birth on TL in six large, independent cohort studies with a total of 19 713 participants. The meta-analysis estimate of TL heritability was 0.70 (95% CI 0.64-0.76) and is based on a pattern of results that is highly similar for twins and other family members. We observed a stronger mother-offspring (r ¼ 0.42; P-value ¼ 3.60 Â 10 À61 ) than father-offspring correlation (r ¼ 0.33; P-value ¼ 7.01 Â 10 À5 ), and a significant positive association with paternal age at offspring birth (b ¼ 0.005; P-value ¼ 7.01 Â 10 À5 ). Interestingly, a significant and quite substantial correlation in TL between spouses (r ¼ 0.25; P-value ¼ 2.82 Â 10 À30 ) was seen, which appeared stronger in older spouse pairs (mean age Z55 years; r ¼ 0.31; P-value ¼ 4.27 Â 10 À23 ) than in younger pairs (mean ageo55 years; r ¼ 0.20; P-value ¼ 3.24 Â 10 À10 ). In summary, we find a high and very consistent heritability estimate for TL, evidence for a maternal inheritance component and a positive association with paternal age. European Journal of Human Genetics (2013) 21, 1163-1168; doi:10.1038/ejhg.2012.303; published online 16 January 2013Keywords: telomere length; heritability; paternal age effect INTRODUCTIONTelomeres are specialized DNA structures located at the terminal ends of chromosomes. 1 Their primary function is to maintain genomic stability. Because of the inability of DNA polymerase to fully replicate the 3 0 end of the DNA strand, that is, the 'end-replication problem' , telomeres naturally shorten with each cell division and, therefore, with age. [2][3][4] In epidemiological studies, both of cross-sectional and prospective design, decreased telomere length (TL) in leukocytes was associated with increased mortality, 5-8 although this finding was not consistent. 9,10 Increased TL in leukocytes has been associated with longevity in a comparison of long-lived Ashkenazi Jews and their offspring with younger controls. 11 Genetic association studies have revealed associations between single-nucleotide polymorphisms (SNPs) in the TERC and TERT genes and TL. [11][12][13][14][15][16][17] Other studies reported associations between SNPs in TERC and POT1 with human longevity, 11,17,18 suggesting that genes regulating TL may influence human longevity.

show abstract

Genetic variation in human telomerase is associated with telomere length in Ashkenazi centenarians

Cited by 209 publications

References 47 publications

Delayed paternal age of reproduction in humans is associated with longer telomeres across two generations of descendants

Delayed paternal age of reproduction in humans is associated with longer telomeres across two generations of descendants

Telomere length is inherited with resetting of the telomere set-point

Meta-analysis of telomere length in 19 713 subjects reveals high heritability, stronger maternal inheritance and a paternal age effect

Contact Info

Product

Resources

About