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Telomere biology in metazoa
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Resumo(s)
Telomerase, the enzyme that maintains telomeres, is absent from most adult human somatic cells, producing a progressive telomere shortening that limits the proliferative potential of primary human cell cultures (Shay and Wright 2007). This programmed telomere shortening, replicative aging, functions as a tumor suppressor program that generates a barrier for the outgrowth of tumors. Remarkably, this telomere tumor suppressor program is not conserved in laboratory rats and mice, which have long telomeres and constitutive telomerase (Sherr and DePinho 2000; Wright and Shay 2000). The present study examines over 60 mammalian species to determine the phylogenetic distribution of the telomere tumor suppressor pathway. Phylogeny based statistical analysis demonstrates that telomere length inversely correlates with lifespan but not body size, while telomerase expression inversely correlates with body size but not lifespan. The ancestral mammalian phenotype was determined to have short telomeres and repressed telomerase. At least 5-7 independent times in different orders smaller, shorter lived species changed to having long telomeres and expressing telomerase, suggesting tradeoffs between the advantages and drawbacks of using replicative aging as a tumor suppression mechanism. We show that one advantage is consistent with reducing the energetic/cellular costs of specific oxidative protection mechanism needed to maintain short telomeres. We propose that the telomere tumor suppressor pathway represents an initial adaptation to the increased mutational load of homeothermy by ancestral mammals, has adaptive advantage in large and long-lived animals, but has been abandoned by many species. These observations resolve a longstanding confusion about the use of telomeres in humans and mice, support a role for telomere length in limiting lifespan, provide a critical framework for interpreting studies of the role 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.
Descrição
Tese de doutoramento, Engenharia Biomédica e Biofísica, Universidade de Lisboa, Faculdade de Ciências, 2011
Palavras-chave
Evolução (Biologia) Telómeros Senescência Mamíferos Teses de doutoramento - 2011