Telomeres and the natural lifespan limit in humans

Steenstrup, Troels; Kark, Jeremy D.; Verhulst, Simon; Thinggaard, Mikael; Hjelmborg, Jacob; Dalgård, Christine; Kyvik, Kirsten Ohm; Christiansen, Lene; Mangino, Massimo; Spector, Timothy D.; Petersen, Inge; Kimura, Masayuki; Bénétos, Athanase; Labat, Carlos; Sinnreich, Ronit; Hwang, Shih Jen; Levy, Daniel; Hunt, Steven C.; Fitzpatrick, Annette L.; Chen, Wei; Berenson, Gerald S.; Barbieri, Michelangela; Paolisso, Giuseppe; Gadalla, Shahinaz M.; Savage, Sharon A.; Christensen, Kaare; Yashin, Anatoliy I.; Arbeev, Konstantin G.; Aviv, Abraham

doi:10.18632/aging.101216

Cited by 88 publications

(97 citation statements)

References 48 publications

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“…12,13,25 Incremental telomere shortening, while, quintessential to aging, the process is also crucial in cancer development. 12,13,25 Incremental telomere shortening, while, quintessential to aging, the process is also crucial in cancer development.…”

Section: Discussionmentioning

confidence: 99%

“…5,6 Constitutive telomere length, a polygenic trait with high estimated heritability, has hitherto been demonstrated to be associated with nine different genetic loci, with 6 harboring genes related to telomere homeostasis. 11,12 Telomere shortening is further influenced by oxidative damage and replicative stress caused by genetic, epigenetic, and environmental factors. 11,12 Telomere shortening is further influenced by oxidative damage and replicative stress caused by genetic, epigenetic, and environmental factors.…”

Section: Introductionmentioning

confidence: 99%

“…[7][8][9][10] Telomeres, due to inherent limitations of DNA replication and telomerase suppression in most somatic cells through epigenetic reprogramming of the telomerase reverse transcriptase (TERT) gene, undergo incremental attrition. 11,12 Telomere shortening is further influenced by oxidative damage and replicative stress caused by genetic, epigenetic, and environmental factors. 13,14 In most cancers, enhanced TERT transcription, due to various mechanisms and consequent telomerase rejuvenation, imparts tumor cells an infinite capability to surmount proliferative barrier through telomere stabilization.…”

Section: Introductionmentioning

confidence: 99%

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Telomere length, telomerase reverse transcriptase promoter mutations, and melanoma risk

Rachakonda

Kong

Srinivas

et al. 2018

Genes Chromosomes & Cancer

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Telomere repeats at chromosomal ends, critical for genomic integrity, undergo age-dependent attrition and telomere length has been associated with different disorders including cancers. In this study, based on 1469 patients and 1158 healthy controls, we show a statistically significant (P = 6 × 10 ) association between increased telomere length and melanoma risk. Mendelian randomization, using 5 telomere length-associated polymorphisms, ruled out confounding factors or reverse causality and showed association between increased telomere length and melanoma risk with odds ratio of 2.66 (95% confidence interval: 2.07-3.25). Age-dependent telomere attrition was faster in melanoma cases than controls (P = .01). The carriers of a highly penetrant germline -57A>C TERT promoter mutation, in a previously reported melanoma family, had longer telomeres than the noncarriers. The mutation causes increased TERT and telomerase levels through creation of a binding motif for E-twenty six (ETS) transcription factors and the carriers develop melanoma with an early age of onset and rapid progression to metastasis. In analogy, we hypothesize that increased telomere length in melanoma patients reflects stochastic increased telomerase levels due to common genetic variation. Paradoxically, we observed shorter telomeres (P = 1 × 10 ) in primary tumors from unrelated melanoma patients with (121) than without (170) somatic TERT promoter mutations that similar to the germline mutation, also create binding motifs for ETS transcription factors. However, the age-dependent telomere attrition was faster in tumors with the TERT promoter mutations than in those without such mutations. Besides a robust association between increased telomere length and risk, our data show a perturbed telomere homeostasis in melanoma.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Telomere length, telomerase reverse transcriptase promoter mutations, and melanoma risk

Rachakonda

Kong

Srinivas

et al. 2018

Genes Chromosomes & Cancer

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“…Based on their length, two types of telomeres at the end of chromosomes have been described (Delany et al, ): shorter or Class II telomeres (8–40 kb) and ultralong or Class III telomeres (up to 2.0 Mb). Class II telomeres are found to shorten with age in several species, such as humans, jackdaws and common terns (Bauch et al, ; Salomons et al, ; Steenstrup et al, ). Delany et al () found no evidence for shortening of Class III telomeres in chickens, but their analyses were cross‐sectional and data sets were small.…”

Section: Introductionmentioning

confidence: 99%

Ultralong telomeres shorten with age in nestling great tits but are static in adults and mask attrition of short telomeres

Atema

Mulder

Noordwijk

et al. 2019

Molecular Ecology Resources

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Telomere length (TL) is increasingly being used as a biomarker of senescence, but measuring telomeres remains a challenge. Within tissue samples, TL varies between cells and chromosomes. Class I telomeres are (presumably static) interstitial telomeric sequences, while terminal telomeres have been divided in shorter (Class II) telomeres and ultralong (Class III) telomeres, and the presence of the latter varies strongly between species. Class II telomeres typically shorten with age, but little is known of Class III telomere dynamics. Using multiple experimental approaches, we show great tits to have ultralong telomeres, and we investigated age effects on Class II and III telomeres using a longitudinal approach (our method excludes Class I telomeres). In adults, TL averaged over the whole distribution did not significantly change with age. However, more detailed analyses showed that Class II TL did shorten with age, and, as in other species, the longest Class II telomeres within individuals shortened more quickly with age. In contrast, Class III TL did not shorten with age within individual adults. Surprisingly, we found the opposite pattern in nestlings: Class III TL shortened significantly with age, while the age effect on Class II TL was close to zero. Thus, Class III TL may provide information on developmental history, while Class II TL provides information on telomere dynamics in adulthood. These findings have practical implications for telomere studies and raise the interesting question of what causes variation in TL dynamics between chromosomes within individuals and how this is related to development.

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“…Importantly, the Wiener process first passage time to a boundary naturally captures the onset of HSC senescence when telomere length reaches the Hayflick limit (Hayflick and Moorhead 1961) as proposed by Dingli et al (2008). Furthermore, Steenstrup et al (2017) proposed telomere length plausibly establishes a biological limit to longevity. Accumulation of DNA mutations and epigenetic alterations should have similar properties in that once sufficient damage has accumulated DNA replication becomes unstable.…”

Section: Methodsmentioning

confidence: 96%

The relationship of mammal survivorship and body mass modeled by metabolic and vitality theories

Anderson¹

2018

Population Ecology

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A model describes the relationship between mammal body mass and survivorship by combining replicative senescence theory postulating a cellular basis of aging, metabolic theory relating metabolism to body mass, and vitality theory relating survival to vitality loss and extrinsic mortality. In the combined framework, intrinsic mortality results from replicative senescence of the hematopoietic stem cells and extrinsic mortality results from environmental challenges. Because the model expresses the intrinsic and extrinsic rates with different powers of body mass, across the spectrum of mammals, survivorship changes from Type I to Type II curve shapes with decreasing body mass. Fitting the model to body mass and maximum lifespan data of 494 nonvolant mammals yields allometric relationships of body mass to the vitality parameters, from which full survivorship profiles were generated from body mass alone. Because maximum lifespan data is predominantly derived from captive populations, the generated survivorship curves were dominated by intrinsic mortality. Comparison of the mass-derived and observed survivorship curves provides insights into how specific populations deviate from the aggregate of populations observed under captivity.

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Telomeres and the natural lifespan limit in humans

Cited by 88 publications

References 48 publications

Telomere length, telomerase reverse transcriptase promoter mutations, and melanoma risk

Telomere length, telomerase reverse transcriptase promoter mutations, and melanoma risk

Ultralong telomeres shorten with age in nestling great tits but are static in adults and mask attrition of short telomeres

The relationship of mammal survivorship and body mass modeled by metabolic and vitality theories

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