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      The role of telomeres in the mechanisms and evolution of life-history trade-offs and ageing

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          Abstract

          Evolutionary biology and biomedicine have seen a surge of recent interest in the possibility that telomeres play a role in life-history trade-offs and ageing. Here, I evaluate alternative hypotheses for the role of telomeres in the mechanisms and evolution of life-history trade-offs and ageing, and highlight outstanding challenges. First, while recent findings underscore the possibility of a proximate causal role for telomeres in current–future trade-offs and ageing, it is currently unclear (i) whether telomeres ever play a causal role in either and (ii) whether any causal role for telomeres arises via shortening or length-independent mechanisms. Second, I consider why, if telomeres do play a proximate causal role, selection has not decoupled such a telomere-mediated trade-off between current and future performance. Evidence suggests that evolutionary constraints have not rendered such decoupling impossible. Instead, a causal role for telomeres would more plausibly reflect an adaptive strategy, born of telomere maintenance costs and/or a function for telomere attrition (e.g. in countering cancer), the relative importance of which is currently unclear. Finally, I consider the potential for telomere biology to clarify the constraints at play in life-history evolution, and to explain the form of the current–future trade-offs and ageing trajectories that we observe today.

          This article is part of the theme issue ‘Understanding diversity in telomere dynamics’.

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          Most cited references81

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          Aging, Cellular Senescence, and Cancer

          For most species, aging promotes a host of degenerative pathologies that are characterized by debilitating losses of tissue or cellular function. However, especially among vertebrates, aging also promotes hyperplastic pathologies, the most deadly of which is cancer. In contrast to the loss of function that characterizes degenerating cells and tissues, malignant (cancerous) cells must acquire new (albeit aberrant) functions that allow them to develop into a lethal tumor. This review discusses the idea that, despite seemingly opposite characteristics, the degenerative and hyperplastic pathologies of aging are at least partly linked by a common biological phenomenon: a cellular stress response known as cellular senescence. The senescence response is widely recognized as a potent tumor suppressive mechanism. However, recent evidence strengthens the idea that it also drives both degenerative and hyperplastic pathologies, most likely by promoting chronic inflammation. Thus, the senescence response may be the result of antagonistically pleiotropic gene action.
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            Oxidative stress shortens telomeres.

            Telomeres in most human cells shorten with each round of DNA replication, because they lack the enzyme telomerase. This is not, however, the only determinant of the rate of loss of telomeric DNA. Oxidative damage is repaired less well in telomeric DNA than elsewhere in the chromosome, and oxidative stress accelerates telomere loss, whereas antioxidants decelerate it. I suggest here that oxidative stress is an important modulator of telomere loss and that telomere-driven replicative senescence is primarily a stress response. This might have evolved to block the growth of cells that have been exposed to a high risk of mutation.
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              Extension of life-span by introduction of telomerase into normal human cells.

              Normal human cells undergo a finite number of cell divisions and ultimately enter a nondividing state called replicative senescence. It has been proposed that telomere shortening is the molecular clock that triggers senescence. To test this hypothesis, two telomerase-negative normal human cell types, retinal pigment epithelial cells and foreskin fibroblasts, were transfected with vectors encoding the human telomerase catalytic subunit. In contrast to telomerase-negative control clones, which exhibited telomere shortening and senescence, telomerase-expressing clones had elongated telomeres, divided vigorously, and showed reduced straining for beta-galactosidase, a biomarker for senescence. Notably, the telomerase-expressing clones have a normal karyotype and have already exceeded their normal life-span by at least 20 doublings, thus establishing a causal relationship between telomere shortening and in vitro cellular senescence. The ability to maintain normal human cells in a phenotypically youthful state could have important applications in research and medicine.
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                Author and article information

                Journal
                Philos Trans R Soc Lond B Biol Sci
                Philos. Trans. R. Soc. Lond., B, Biol. Sci
                RSTB
                royptb
                Philosophical Transactions of the Royal Society B: Biological Sciences
                The Royal Society
                0962-8436
                1471-2970
                5 March 2018
                15 January 2018
                15 January 2018
                : 373
                : 1741 , Theme issue ‘Understanding diversity in telomere dynamics’ compiled and edited by Pat Monaghan, Dan Eisenberg, Lea Harrington and Dan Nussey
                : 20160452
                Affiliations
                School of Biosciences, University of Exeter Penryn Campus , Penryn TR10 9FE, UK
                Author notes

                One contribution of 19 to a theme issue ‘ Understanding diversity in telomere dynamics’.

                Author information
                http://orcid.org/0000-0003-0560-6549
                Article
                rstb20160452
                10.1098/rstb.2016.0452
                5784072
                29335379
                fe5b6739-e394-405a-9e1f-20f47034cd38
                © 2018 The Authors.

                Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited.

                History
                : 19 October 2017
                Funding
                Funded by: Biotechnology and Biological Sciences Research Council, http://dx.doi.org/10.13039/501100000268;
                Award ID: BB/H022716/1
                Categories
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                Custom metadata
                March 5, 2018

                Philosophy of science
                telomere,senescence,oxidative stress,cancer,constraint,adaptation
                Philosophy of science
                telomere, senescence, oxidative stress, cancer, constraint, adaptation

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