García-Cao, I. et al. Increased p53 activity does not accelerate telomere-driven aging. EMBO Rep. 7, 546-552

Complutense University of Madrid, Madrid, Madrid, Spain
EMBO Reports (Impact Factor: 9.06). 06/2006; 7(5):546-52. DOI: 10.1038/sj.embor.7400667
Source: PubMed


There is a great interest in determining the impact of p53 on ageing and, for this, it is important to discriminate among the known causes of ageing. Telomere loss is a well-established source of age-associated damage, which by itself can recapitulate ageing in mouse models. Here, we have used a genetic approach to interrogate whether p53 contributes to the elimination of telomere-damaged cells and its impact on telomere-driven ageing. We have generated compound mice carrying three functional copies of the p53 gene (super-p53) in a telomerase-deficient background and we have measured the presence of chromosomal abnormalities and DNA damage in several tissues. We have found that the in vivo load of telomere-derived chromosomal damage is significantly decreased in super-p53/telomerase-null mice compared with normal-p53/telomerase-null mice. Interestingly, the presence of extra p53 activity neither accelerates nor delays telomere-driven ageing. From these observations, we conclude that p53 has an active role in eliminating telomere-damaged cells, and we exclude the possibility of an age-promoting effect of p53 on telomere-driven ageing.

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    • "We then used this wild-type mouse metabolomic signature of aging to predict the ages of first-generation (G1) mice deficient in telomerase activity due to deletion of the telomerase RNA component or Terc (G1 Terc À/À mice). These mice show premature aging and decreased median and maximum longevity already at the first generation (Blasco et al., 1997; Lee et al., 1998; Herrera et al., 1999; Garcia-Cao et al., 2006). "
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    ABSTRACT: Our understanding of the mechanisms by which aging is produced is still very limited. Here, we have determined the sera metabolite profile of 117 wild-type mice of different genetic backgrounds ranging from 8-129 weeks of age. This has allowed us to define a robust metabolomic signature and a derived metabolomic score that reliably/accurately predicts the age of wild-type mice. In the case of telomerase-deficient mice, which have a shortened lifespan, their metabolomic score predicts older ages than expected. Conversely, in the case of mice that over-express telomerase, their metabolic score corresponded to younger ages than expected. Importantly, telomerase reactivation late in life by using a TERT based gene therapy recently described by us, significantly reverted the metabolic profile of old mice to that of younger mice, further confirming an anti-aging role for telomerase. Thus, the metabolomic signature associated to natural mouse aging accurately predicts aging produced by telomere shortening, suggesting that natural mouse aging is in part produced by presence of short telomeres. These results indicate that the metabolomic signature is associated to the biological age rather than to the chronological age. This constitutes one of the first aging-associated metabolomic signatures in a mammalian organism. © 2012 The Authors Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.
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    • "Further reinforcing the link between the telomere clock and aging is the observation that mice deficient in telomerase activity have short telomeres and age prematurely [60, 61]. Remarkably, even the first generation of telomerase-deficient mice already has a shortened lifespan, which becomes shorter and shorter in subsequent generations [62]. Moreover, telomeres become measurably shorter in mice, particularly at very old ages [63]. "
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    ABSTRACT: p53 is well known as the "guardian of the genome" for differentiated and neoplastic cells. p53 induces cell-cycle arrest and cell death after DNA damage and thus contributes to the maintenance of genomic stability. In addition to this tumor suppressor function for pro-oncogenic cells, p53 also plays an important role as the central regulator of stress response by maintaining cellular homeostasis at the molecular and biochemical level. p53 regulates aerobic respiration at the glycolytic and oxidative phosphorylation (OXPHOS) steps via transcriptional regulation of its downstream genes TP53-induced glycolysis regulator (TIGAR) and synthesis of cytochrome c oxidase (SCO2). p53 negatively regulates glycolysis through activation of TIGAR (an inhibitor of the fructose-2,6-bisphosphate). On the contrary p53 positively regulates OXPHOS through upregulation of SCO2, a member of the COX-2 assembly involved in the electron-transport chain. It is interesting to notice that p53 antagonistically regulates the inter-dependent glycolytic and OXPHOS cycles. It is important to understand whether the p53-mediated transcriptional regulation of TIGAR and SCO2 is temporally segregated in cancer cells and what is the relation between these paradoxical regulations of glycolytic pathway with the tumor suppressor activity of p53. In this review we will elucidate the importance of p53-mediated regulation of glycolysis and OXPHOS and its relation with the tumor suppressor function of p53. Further since cellular metabolism shares great relation with the process of aging we will also try and establish the role of p53 in regulation of aging via its transcriptional control of cellular metabolism.
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    • "Furthermore, mice with excessive p53 activity maintain cancer protection, but age prematurely including impairment of HSCs [279–282], which is at least in part due to increased sensitivity to senescence-inducing stimuli [280]. Interestingly, concomitant increase of normal p53 and p19Arf leads to increased longevity in mice [283], although elevation of p53 alone is not sufficient to increase longevity [284, 285]. Collectively, these recent studies support an emerging link between senescence regulation and aging, and show the potential importance of senescence regulation in stem cells aging. "
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    ABSTRACT: Senescence is regarded as a physiological response of cells to stress, including telomere dysfunction, aberrant oncogenic activation, DNA damage, and oxidative stress. This stress response has an antagonistically pleiotropic effect to organisms: beneficial as a tumor suppressor, but detrimental by contributing to aging. The emergence of senescence as an effective tumor suppression mechanism is highlighted by recent demonstration that senescence prevents proliferation of cells at risk of neoplastic transformation. Consequently, induction of senescence is recognized as a potential treatment of cancer. Substantial evidence also suggests that senescence plays an important role in aging, particularly in aging of stem cells. In this paper, we will discuss the molecular regulation of senescence its role in cancer and aging. The potential utility of senescence in cancer therapeutics will also be discussed.
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