Telomere length predicts survival independent of genetic influences

Bakaysa, Stephanie; Mucci, Lorelei A.; Slagboom, P. Eline; Boomsma, Dorret I.; McClearn, Gerald E.; Johansson, Boo; Pedersen, Nancy L.

doi:10.1111/j.1474-9726.2007.00340.x

Cited by 277 publications

(217 citation statements)

References 29 publications

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“…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)(8)(9)(10)(11)(12)(13).…”

mentioning

confidence: 71%

“…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%

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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.

185

170

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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...

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confidence: 71%

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.

185

170

View full text Add to dashboard Cite

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“…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][6][7][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.…”

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

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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.

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“…Other recent meta-analyses support the concurrent associations between short telomeres and diabetes (8) and several cancers (9,10). Several studies indicate that short telomeres from varied sources, including leukocytes and saliva, are related to early mortality (11)(12)(13)(14)(15)(16)(17), including a study with >60,000 adults (18), although null studies also exist (19)(20)(21)(22).…”

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confidence: 96%

Lifespan adversity and later adulthood telomere length in the nationally representative US Health and Retirement Study

Puterman

Gemmill

Karasek

et al. 2016

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

146

108

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Stress over the lifespan is thought to promote accelerated aging and early disease. Telomere length is a marker of cell aging that appears to be one mediator of this relationship. Telomere length is associated with early adversity and with chronic stressors in adulthood in many studies. Although cumulative lifespan adversity should have bigger impacts than single events, it is also possible that adversity in childhood has larger effects on later life health than adult stressors, as suggested by models of biological embedding in early life. No studies have examined the individual vs. cumulative effects of childhood and adulthood adversities on adult telomere length. Here, we examined the relationship between cumulative childhood and adulthood adversity, adding up a range of severe financial, traumatic, and social exposures, as well as comparing them to each other, in relation to salivary telomere length. We examined 4,598 men and women from the US Health and Retirement Study. Single adversities tended to have nonsignificant relations with telomere length. In adjusted models, lifetime cumulative adversity predicted 6% greater odds of shorter telomere length. This result was mainly due to childhood adversity. In adjusted models for cumulative childhood adversity, the occurrence of each additional childhood event predicted 11% increased odds of having short telomeres. This result appeared mainly because of social/traumatic exposures rather than financial exposures. This study suggests that the shadow of childhood adversity may reach far into later adulthood in part through cellular aging. cellular aging | telomeres | lifespan adversity | childhood adversity A ging cells play a crucial role in the pathogenesis of noncommunicable diseases, and telomere shortening in cells plays a part of this aging process (1, 2). Telomeres are DNAprotein caps at the ends of chromosomes that protect genetic material from degradation, and their lengths indicate cellular aging (2, 3). Experiments in rodents implicate shortened telomeres and lower activity of telomerase, the enzyme that lengthens telomeres, as causes of mitochondrial and tissue damage associated with disease pathogenesis (4-6).Telomere length is linked cross-sectionally and prospectively with human disease states in many studies. A recent meta-analysis suggests that individuals with observed short leukocyte telomeres are at an ∼80% increased risk of concurrent reports of cardiovascular disease and an ∼40% increased risk of developing cardiovascular disease in the future (7). Other recent meta-analyses support the concurrent associations between short telomeres and diabetes (8) and several cancers (9, 10). Several studies indicate that short telomeres from varied sources, including leukocytes and saliva, are related to early mortality (11-17), including a study with >60,000 adults (18), although null studies also exist (19)(20)(21)(22).Although these studies suggest that telomere length plays a role in disease, they are observational, and studies directly linking genetics...

show abstract

Telomere length predicts survival independent of genetic influences

Cited by 277 publications

References 29 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

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

Lifespan adversity and later adulthood telomere length in the nationally representative US Health and Retirement Study

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