Effects of initial telomere length distribution on senescence onset and heterogeneity

Bourgeron, Thibault; Xu, Zhou

doi:10.1016/j.jtbi.2016.11.010

Cited by 10 publications

(18 citation statements)

References 42 publications

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“…Senescence heterogeneity, induced by telomere shortening, depends on the initial variance in TL [32]. Hence, TL is a promising predictor of the propofol dose combined with the physiological status of the body.…”

Section: Discussionmentioning

confidence: 99%

Association between telomere length in the DNA of peripheral blood leukocytes and the propofol dose in anesthesia induction

Zhang¹,

Xu²,

Xie³

et al. 2020

Preprint

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Background Propofol is a widely used anesthetic and its dose is closely related to aging. Telomere length (TL) is a unique heritable trait, and emerging as a biomarker of aging, health and disease. We proposed a hypothesis that propofol dose can be determined by telomere length, which greatly reduced the risk of anesthesia, especially the elderly.Methods/design To evaluate the association between the propofol dose in anesthesia induction and: TL in the DNA of peripheral blood leukocytes; body weight;sex;difference of the Bispectral Index (BIS) before and after anesthesia induction in patients. To detect deletion at the 5′end or 3′end of telomerase RNA component (TERC). 100 patients scheduled for elective surgery. Multivariable linear regression analyses were undertaken.Results We found that propofol dose in anesthesia induction was clearly correlated significantly with TL (r = 0.78, p <0.001), sex (r = 0.83, p <0.001), body weight (r = 0.84, p = 0.004), and difference of BIS before and after anesthesia induction (r = 0.85, p = 0.029). By comparing the absolute values of standardized regression coefficients (0.58, 0.19, 0.21, and 0.12) of the four variables, it can be seen that TL contributes the most to the propofol dose in anesthesia induction. However, detection of deletion at the 5′ end or 3′ end of TERC was not found, which showed that telomerase in these patients was relatively stable.Discussion These findings provide preliminary evidence that the propofol dose in anesthesia induction was clearly correlated with genetically determined TL. TL may be a promising predictor of the propofol dose, which is beneficial to improve the safety of anesthesia and reduce perioperative complications.

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Section: Discussionmentioning

confidence: 99%

Association between telomere length in the DNA of peripheral blood leukocytes and the propofol dose in anesthesia induction

Zhang¹,

Xu²,

Xie³

et al. 2020

Preprint

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“…Telomeres at eukaryotic chromosome ends protect the chromosome ends from end-to-end fusion, degradation, and prevent misrecognition of the ends as double-stranded DNA breaks (DSBs) ( Tham and Zakian, 2002 ; Dieckmann et al, 2016 ). Telomeres have terminal single-stranded (ss) DNA overhangs with 3′ repetitive guanine-rich sequences (termed G tail or G-overhang) ( Giraud-Panis et al, 2010 ; Eugène et al, 2017 ). Telomeres are marked by tandem repeats such as G 3 T 2 A in vertebrates and TG 1 – 3 in budding yeast Saccharomyces cerevisiae ( Tran et al, 2011 ; Wellinger and Zakian, 2012 ).…”

Section: Maintenance Of Telomre Length Homeostasis Prevents Cellular mentioning

confidence: 99%

Genomic Instability and Cellular Senescence: Lessons From the Budding Yeast

Lee

Ong

2021

Front. Cell Dev. Biol.

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Aging is a complex biological process that occurs in all living organisms. Aging is initiated by the gradual accumulation of biomolecular damage in cells leading to the loss of cellular function and ultimately death. Cellular senescence is one such pathway that leads to aging. The accumulation of nucleic acid damage and genetic alterations that activate permanent cell-cycle arrest triggers the process of senescence. Cellular senescence can result from telomere erosion and ribosomal DNA instability. In this review, we summarize the molecular mechanisms of telomere length homeostasis and ribosomal DNA stability, and describe how these mechanisms are linked to cellular senescence and longevity through lessons learned from budding yeast.

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“…We used the same approach as in (16,17) and tested how the shortening dynamics of a linear combination of the lengths of the two shortest telomeres, that is L1 + a L2 (where L1 and L2 represent the length of the shortest and second shortest telomeres, respectively, and a is a positive scalar) reaching a threshold Lmin could fit the data. To do so, we simulated the senescence onsets of individual lineages according to (16,17) and compared them to the experiments by minimizing the following error value, describing the distance between the simulation and the experimental data of the onset of the first arrest: where N is the number of simulations, n is the number of experimental lineages (here n = 115) and for the j th simulation, G(i,j;a) represents the i th lineage out of n lineages, ordered from shortest to longest and simulated with the law of telomeric signalling L1 + a L2 = Lmin, and ( ) is the i th shortest lineage in the ordered set of the n experimental lineages. Interestingly, as in ( 16) for the onset of senescence, the parameter a that minimized e was always 0, indicating that taking only the length of the shortest telomere into account, and not the second, led to the best fit.…”

Section: A Telomere-shortening-dependent Model Fits the Timing Of The First Non-terminal Arrestmentioning

confidence: 99%

“…Because of the apparent stochastic nature of the early arrests, mathematical analysis and modelling are powerful approaches to describe them, test hypotheses on their nature and propose underlying laws governing their appearance. We previously built a telomere-shortening model that incorporated the asymmetric molecular mechanism of telomere replication (16,17).…”

Section: Introductionmentioning

confidence: 99%

Telomere shortening causes distinct cell division regimes during replicative senescence inSaccharomyces cerevisiae

Martin¹,

Doumic

Teixeira

et al. 2021

Preprint

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Background: Telomerase-negative cells have limited proliferation potential. In these cells, telomeres shorten until they reach a critical length and induce a permanently arrested state. This process called replicative senescence is associated with genomic instability and participates in tissue and organismal ageing. Experimental data using single-cell approaches in the budding yeast model organism show that telomerase-negative cells often experience abnormally long cell cycles, which can be followed by cell cycles of normal duration, before reaching the terminal senescent state. These series of non-terminal cell cycle arrests contribute to the heterogeneity of senescence and likely magnify its genomic instability. Due to their apparent stochastic nature, investigating the dynamics and the molecular origins of these arrests has been difficult. In particular, whether the non-terminal arrests series stem from a mechanism similar to the one that triggers terminal senescence is not known. Results: Here, we provide a mathematical description of sequences of non-terminal arrests to understand how they appear. We take advantage of an experimental data set of cell cycle duration measurements performed in individual telomerase-negative yeast cells that keep track of the number of generations since telomerase inactivation. Using numerical simulations, we show that the occurrence of non-terminal arrests is a generation-dependent process that can be explained by the shortest telomere reaching a probabilistic threshold length. While the onset of senescence is also triggered by telomere shortening, we highlight differences in the laws that describe the number of consecutive arrests in non-terminal arrests compared to senescence arrests, suggesting distinct underlying mechanisms and cellular states. Conclusions: Replicative senescence is a complex process that affects cell divisions earlier than anticipated, as exemplified by the frequent occurrence of non-terminal arrests early after telomerase inactivation. The present work unravels two kinetically and mechanistically distinct generation-dependent processes underlying non-terminal and terminal senescence arrests. We suggest that these two processes are responsible for two consequences of senescence at the population level, the increase of genome instability on the one hand, and the limitation of proliferation capacity on the other hand.

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Effects of initial telomere length distribution on senescence onset and heterogeneity

Cited by 10 publications

References 42 publications

Association between telomere length in the DNA of peripheral blood leukocytes and the propofol dose in anesthesia induction

Association between telomere length in the DNA of peripheral blood leukocytes and the propofol dose in anesthesia induction

Genomic Instability and Cellular Senescence: Lessons From the Budding Yeast

Telomere shortening causes distinct cell division regimes during replicative senescence inSaccharomyces cerevisiae

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