p38MAPK in the Senescence of Human and Murine Fibroblasts
Florence Debacq‐ChainiauxEmmanuelle BoilanJérémie Dedessus Le MoutierGeoffroy WeemaelsOlivier Toussaint
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Senescence
Primary human cells in culture invariably stop dividing and enter a state of growth arrest called replicative senescence. This transition is induced by programmed telomere shortening, but the underlying mechanisms are unclear. Here, we report that overexpression of TRF2, a telomeric DNA binding protein, increased the rate of telomere shortening in primary cells without accelerating senescence. TRF2 reduced the senescence setpoint, defined as telomere length at senescence, from 7 to 4 kilobases. TRF2 protected critically short telomeres from fusion and repressed chromosome-end fusions in presenescent cultures, which explains the ability of TRF2 to delay senescence. Thus, replicative senescence is induced by a change in the protected status of shortened telomeres rather than by a complete loss of telomeric DNA.
Senescence
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Critical telomere shortening induces senescence in many normal human cell types grown in culture. Recent data have revealed that dysfunctional telomeres can resemble certain forms of DNA damage, and point to a role for DNA damage signaling in the establishment and maintenance of telomere-initiated senescence. Here, we review these new observations and highlight potential avenues of future research. We consider the identities of the key DNA damage response factors involved in senescence and discuss a model for the molecular events occurring in pre-senescent cells that ultimately lead to a permanent cell cycle arrest phenotype.
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Cellular senescence
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Replicative senescence is accompanied by a telomere‐specific DNA damage response (DDR). We found that DDR+ telomeres occur spontaneously in early‐passage normal human cells and increase in number with increasing cumulative cell divisions. DDR+ telomeres at replicative senescence retain TRF2 and RAP1 proteins, are not associated with end‐to‐end fusions and mostly result from strand‐independent, postreplicative dysfunction. On the basis of the calculated number of DDR+ telomeres in G1‐phase cells just before senescence and after bypassing senescence by inactivation of wild‐type p53 function, we conclude that the accrual of five telomeres in G1 that are DDR+ but nonfusogenic is associated with p53‐dependent senescence.
Senescence
Cellular Aging
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Objective: Observe changes of telomere length and telomerase activity during the process of retarding the cellular senescence by Epithalon polypeptide(Ala-Gly-Asp-Glu).Method: Effects of retarding the cellular senescence by Epithalon were evaluated through cell cycle analysis,detection of telomerase activity and telomere length by the means of in vitro inducing L-02 cell senescence using tert-butyl hydroperoxide(t-BHP).Results: The aging model by t-BHP induction was established.Telomere length was shortened obviously.Epithalon significantly retarded cellular senescence,reduced telomere shortening caused by t-BHP and increased telomerase activity.Conclusion: Epithalon has some anti-aging effects,could retard the shortening of telomere and prolong cell lifespan.
Senescence
Cellular senescence
Cellular Aging
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Senescence
Cellular senescence
Cellular Aging
Asynchrony (computer programming)
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Cellular senescence can be activated by various types of stressful stimuli, including telomere shortening, oncogenic or tumor suppressor signals, and DNA damage. Progressive telomere shortening in successive cell divisions induces senescence due to the loss of terminal sequences during DNA replication. Maintenance of the telomere sequences at human chromosome ends is essential for immortalized cells to escape from the normal limitations of the proliferation capacity. In this article, the molecular and functional details of telomere maintenance and cellular senescence are reviewed, including the signals that trigger senescence, telomere capping, and the telomere length maintenance mechanisms.
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Replicative senescence, induced by telomere shortening, exhibits considerable asynchrony and heterogeneity, the origins of which remain unclear. Here, we formally study how telomere shortening mechanisms impact on senescence kinetics and define two regimes of senescence, depending on the initial telomere length variance. We provide analytical solutions to the model, highlighting a non-linear relationship between senescence onset and initial telomere length distribution. This study reveals the complexity of the collective behavior of telomeres as they shorten, leading to senescence heterogeneity.
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Asynchrony (computer programming)
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Senescence
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Senescence is a genetically regulated process that involves decomposition of cellular structures and distribution of the products of this degradation to other plant parts. Reactions involving reactive oxygen species are the intrinsic features of these processes and their role in senescence is suggested. The malfunction of protection against destruction induced by reactive oxygen species could be the starting point of senescence. This article reviews biochemical changes during senescence in relation to reactive oxygen species and changes in antioxidant protection.
Senescence
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