Comparative biology of mammalian telomeres: hypotheses on ancestral states and the roles of telomeres in longevity determination
Nuno M.V. Gomes,Nuno M.V. Gomes,Oliver A. Ryder,Marlys L. Houck,Suellen J. Charter,William Walker,Nicholas R. Forsyth,Steven N. Austad,Chris Venditti,Chris Venditti,Mark Pagel,Mark Pagel,Jerry W. Shay,Woodring E. Wright +13 more
TLDR
Observations support a role for human‐like telomeres in allowing longer lifespans to evolve, demonstrate the need to include telomere length in the analysis of comparative studies of oxidative protection in the biology of aging, and identify which mammals can be used as appropriate model organisms for the study of the role of telomees in human cancer and aging.Abstract:
Progressive telomere shortening from cell division (replicative aging) provides a barrier for human tumor progression. This program is not conserved in laboratory mice, which have longer telomeres and constitutive telomerase. Wild species that do / do not use replicative aging have been reported, but the evolution of different phenotypes and a conceptual framework for understanding their uses of telomeres is lacking. We examined telomeres / telomerase in cultured cells from > 60 mammalian species to place different uses of telomeres in a broad mammalian context. Phylogeny-based statistical analysis reconstructed ancestral states. Our analysis suggested that the ancestral mammalian phenotype included short telomeres (< 20 kb, as we now see in humans) and repressed telomerase. We argue that the repressed telomerase was a response to a higher mutation load brought on by the evolution of homeothermy. With telomerase repressed, we then see the evolution of replicative aging. Telomere length inversely correlated with lifespan, while telomerase expression co-evolved with body size. Multiple independent times smaller, shorter-lived species changed to having longer telomeres and expressing telomerase. Trade-offs involving reducing the energetic / cellular costs of specific oxidative protection mechanisms (needed to protect < 20 kb telomeres in the absence of telomerase) could explain this abandonment of replicative aging. These observations provide a conceptual framework for understanding different uses of telomeres in mammals, support a role for human-like telomeres in allowing longer lifespans to evolve, demonstrate the need to include telomere length in the analysis of comparative studies of oxidative protection in the biology of aging, and identify which mammals can be used as appropriate model organisms for the study of the role of telomeres in human cancer and aging.read more
Citations
More filters
Journal ArticleDOI
Ageing as a Risk Factor for Disease
Teresa Niccoli,Linda Partridge +1 more
TL;DR: Lowered activity of the nutrient-sensing insulin/insulin-like growth factor/Target of Rapamycin signalling network can extend healthy lifespan in yeast, multicellular invertebrates, mice and, possibly, humans.
Journal ArticleDOI
Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation
Marzia Fumagalli,Francesca Rossiello,Michela Clerici,Sara Barozzi,Davide Cittaro,Davide Cittaro,Jessica Kaplunov,Gabriele Bucci,Miryana Dobreva,Valentina Matti,Christian Beauséjour,Utz Herbig,Maria Pia Longhese,Fabrizio d'Adda di Fagagna +13 more
TL;DR: It is proposed that linear genomes are not uniformly reparable and that telomeric DNA tracts, if damaged, are irreparable and trigger persistent DDR and cellular senescence.
Journal ArticleDOI
Telomere length in early life predicts lifespan
Britt J. Heidinger,Jonathan D. Blount,Winnie Boner,Kate Griffiths,Neil B. Metcalfe,Pat Monaghan +5 more
TL;DR: In this article, the authors measured telomere length in zebra finches from the nestling stage and at various points thereafter, and recorded their natural lifespan (which varied from less than 1 to almost 9 y).
Journal ArticleDOI
Telomeres in cancer: tumour suppression and genome instability
John Maciejowski,Titia de Lange +1 more
TL;DR: Current data, reviewed here, provide new evidence for the telomere tumour suppressor pathway and has revealed that telomeres crisis can induce numerous cancer-relevant changes, including chromothripsis, kataegis and tetraploidization.
Journal ArticleDOI
Role of telomeres and telomerase in cancer.
Jerry W. Shay,Woodring E. Wright +1 more
TL;DR: There is mounting evidence for the existence of an important relationship between telomeres and telomerase and cellular aging and cancer and this has led to the development of targeted telomersase cancer therapeutic approaches that are presently in advanced clinical trials.
References
More filters
Journal ArticleDOI
Aging: A Theory Based on Free Radical and Radiation Chemistry
TL;DR: It seems possible that one factor in aging may be related to deleterious side attacks of free radicals (which are normally produced in the course of cellular metabolism) on cell constituents.
Book
DNA Repair and Mutagenesis
TL;DR: Nucleotide excision repair in mammalian cells: genes and proteins Mismatch repair The SOS response and recombinational repair in prokaryotes Mutagenesis in proKaryote Mutagenisation in eukaryotes Other DNA damage tolerance responses in eUKaryotes.
Journal ArticleDOI
Inferring the historical patterns of biological evolution
TL;DR: The combination of these phylogenies with powerful new statistical approaches for the analysis of biological evolution is challenging widely held beliefs about the history and evolution of life on Earth.
Journal ArticleDOI
A survey of telomerase activity in human cancer
Jerry W. Shay,Silvia Bacchetti +1 more
TL;DR: All major types of cancer have been screened and the presence of telomerase activity has been detected in the vast majority of cases, and a summary, in table form, of the current data is provided.
Journal ArticleDOI
Phylogenetic analysis and comparative data: a test and review of evidence
TL;DR: Simulations show λ to be a statistically powerful index for measuring whether data exhibit phylogenetic dependence or not and whether it has low rates of Type I error, which demonstrates that even partial information on phylogeny will improve the accuracy of phylogenetic analyses.