The common biology of cancer and ageing

In the paper

“For our purpose, suffice it to say that TOR is activated in the presence of abundant nutrients, and inactivated under starvation.”

What the sources say

• Not checked yetcites [85] Sabatini, D. M. mTOR and cancer: insights into a complex relationship. Nature Rev. Cancer 6, 729–734 (2006) source
• Supported

  The Nutrients section (p. 6) reports that amino acid starvation rapidly reduces phosphorylation of mTORC1 effectors, while reintroducing amino acids restores it. The Physiological Roles section (p. 3) likewise says TOR is active when growth conditions are favorable and describes reduced growth-related activity during nitrogen starvation. Together, these support the sentence’s broad summary of nutrient-dependent TOR signaling. (LLM, conf=0.91)

  cites [86] Wullschleger, S., Loewith, R. & Hall, M. N. TOR signaling in growth and metabolism. Cell 124, 471–484 (2006) source

In the paper

“they concluded that some intrinsic factor/s (later termed 'Hayflick factors') accumulated in these cells until they 'senesced' 1”

What the sources say

• Not checked yetcites [1] Hayflick, L. & Moorhead, P. S. The serial cultivation of human diploid cell strains. Exp. Cell Res. 25, 585–621 (1961) source

In the paper

“Incipient tumours, arising directly from stem cells or from more committed cells, undergo rapid proliferation (small red cells). These pre-malignant tumour cells rapidly accumulate damage, in part owing to the presence of oncogenes, leading to a higher proportion of tumour cells becoming senescent (small blue cells).”

In the paper

“It is well established that the CDKN2a locus is activated during organismal ageing in both rodents and humans, and the levels of p16INK4a constitute an impressively good overall biomarker of ageing 16, 17”

What the sources say

• Not checked yetcites [16] Krishnamurthy, J. et al. Ink4a/Arf expression is a biomarker of aging. J. Clin. Invest. 114, 1299–1307 (2004) source
• Not checked yetcites [17] Kim, W. Y. & Sharpless, N. E. The regulation of INK4/ARF in cancer and aging. Cell 127, 265–275 (2006) source

In the paper

“The CDKN2a locus encodes two separate proteins including p16INK4a, which regulates RB1 activity by directly inhibiting the cyclin-dependent kinases, and p19ARF, which regulates the function of P53.”

In the paper

“reducing the level of various mitotic checkpoint genes leads to chromosomal instability, augmented aneuploidy and the phenotypic appearance of progeroid mice 36, 37”

What the sources say

• Not checked yetcites [36] Baker, D. J. et al. BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice. Nature Genet. 36, 744–749 (2004) source
• Not checked yetcites [37] Baker, D. J. et al. Early aging-associated phenotypes in Bub3/Rae1 haploinsufficient mice. J. Cell Biol. 172, 529–540 (2006) source

In the paper

“evidence from cell culture models indicates that Sirt1 is involved in heterochromatin formation and might be particularly important in the silencing of certain tumour suppressors 45, 46”

What the sources say

• Not checked yetcites [45] Vaquero, A. et al. Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin. Mol. Cell 16, 93–105 (2004) source
• Not checked yetcites [46] Pruitt, K. et al. Inhibition of SIRT1 reactivates silenced cancer genes without loss of promoter DNA hypermethylation. PLoS Genet. 2, e40 (2006) source

In the paper

“mice with a targeted deletion in Sirt6 manifest an accelerated ageing phenotype that on a cellular level is accompanied by genomic instability and defects in DNA repair 47”

What the sources say

• Not checked yetcites [47] Mostoslavsky, R. et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell 124, 315–329 (2006) source

In the paper

“Cloning of additional telomeres revealed that they are highly conserved in most eukaryotic organisms, with the exception of some flies.”

In the paper

“The Sirt6 -deficient mice therefore add to a growing but poorly understood connection between genomic instability and altered IGF-1 signalling, as insulin-IGF signalling is also perturbed in other mouse models of accelerated ageing, including animals with increased p53 activity 30 and mice lacking the NER enzyme ERCC4 39”

What the sources say

• Not checked yetcites [30] Maier, B. et al. Modulation of mammalian life span by the short isoform of p53. Genes Dev. 18, 306–319 (2004) source
• Not checked yetcites [39] Niedernhofer, L. J. et al. A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis. Nature 444, 1038–1043 (2006) source

In the paper

“One attractive explanation is that WRN is essential for proper telomere maintenance through its interaction with the telomeric binding proteins TERF1 and TERF2 41”

What the sources say

• Not checked yetcites [41] Opresko, P. L. et al. The Werner syndrome helicase and exonuclease cooperate to resolve telomeric D loops in a manner regulated by TRF1 and TRF2. Mol. Cell 14, 763–774 (2004) source

In the paper

“not every strategy that could protect us from cancer comes at the expense of accelerating ageing.”

In the paper

“this accelerated ageing phenotype might be unique to expression of these altered forms of 'superactive' p53, as simple transgenic overexpression of full-length p53 using its endogenous promoter to regulate expression does not result in a change in lifespan 31”

What the sources say

• Not checked yetcites [31] Garcia-Cao, I. et al. “Super p53” mice exhibit enhanced DNA damage response, are tumor resistant and age normally. EMBO J. 21, 6225–6235 (2002) source

In the paper

“This telomere elongation was proposed to rely either on recombination events between telomeres or on the existence of a novel enzymatic activity that could synthesize telomere repeats de novo .”

In the paper

“Telomeres were found to consist of tandem G-rich repeats that expanded until the chromosome end.”

What the sources say

• Not checked yetcites [48] Blackburn, E. H. & Gall, J. G. A tandemly repeated sequence at the termini of the extrachromosomal ribosomal RNA genes in Tetrahymena. J. Mol. Biol. 120, 33–53 (1978) source

In the paper

“insulin-IGF signalling is known to regulate lifespan in lower organisms.”

In the paper

“In yeast, Sir2 has been implicated in the increase in lifespan that is seen after caloric restriction and in both yeast and worms, overexpression of Sir2 is sufficient to extend lifespan.”

In the paper

“In each of these cases, ageing is the apparent result of either a chronic increase in the level of DNA damage (ATM and BRCA1 deficiency) or the presumed chronic engagement of DNA damage signalling ('superactive' p53).”

In the paper

“This family of enzymes is conserved from Eschericia coli to man, and humans have five RecQ homologues that have important roles in recombination, the replication stress response and maintaining genomic stability.”

In the paper

“The identification of telomeres rapidly led to the realization that some cells could elongate preexisting telomeres, implying the existence of telomere elongation mechanisms 49”

What the sources say

• Not checked yetcites [49] Shampay, J., Szostak, J. W. & Blackburn, E. H. DNA sequences of telomeres maintained in yeast. Nature 310, 154–157 (1984) source

In the paper

“mice lacking Atm show rapid ageing and depletion of their haematopoietic stem cell compartment 34”

What the sources say

• Not checked yetcites [34] Ito, K. et al. Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature 431, 997–1002 (2004) source

In the paper

“These conditions can be caused by germline mutations in the genes for P53, the ataxia-telangiectasia mutated (ATM) kinase and breast cancer 1 (BRCA1), respectively-three proteins that are essential in the surveillance of DNA damage.”

In the paper

“Such an enzymatic activity was soon discovered by Carol Greider and Elizabeth Blackburn and was named telomerase 50”

What the sources say

• Not checked yetcites [50] Greider, C. W. & Blackburn, E. H. Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell 43, 405–413 (1985) source

In the paper

“the gene responsible for the progeroid Hutchinson-Gilford syndrome has also been identified, and there is evidence that its product helps to maintain nuclear architecture and to regulate genomic stability 43”

What the sources say

• Not checked yetcites [43] Liu, B. et al. Genomic instability in laminopathy-based premature aging. Nature Med. 11, 780–785 (2005) source

In the paper

“Together these observations indicate that severe deficiencies in proteins that are involved in DNA damage sensing and DNA repair might accelerate ageing, while milder mutations in these same pathways might predispose individuals to cancer.”

In the paper

“Alternatively, the absence of DNA repair might cause enough direct damage to fully differentiated cells to impair overall homeostasis.”

In the paper

“mice that are genetically engineered to express altered isoforms of p53 with increased activity seem to be resistant to cancer but age prematurely 29, 30”

What the sources say

• Not checked yetcites [29] Tyner, S. D. et al. p53 mutant mice that display early ageing-associated phenotypes. Nature 415, 45–53 (2002) source
• Not checked yetcites [30] Maier, B. et al. Modulation of mammalian life span by the short isoform of p53. Genes Dev. 18, 306–319 (2004) source

In the paper

“One common feature of the sirtuins is their enzymatic function as NAD-dependent deacetylases and for yeast Sir2, this biochemical activity is required for the proteins' ability to regulate silencing, recombination and genomic stability 44”

What the sources say

• Not checked yetcites [44] Haigis, M. C. & Guarente, L. P. Mammalian sirtuins—emerging roles in physiology, aging, and calorie restriction. Genes Dev. 20, 2913–2921 (2006) source

In the paper

“Seven mammalian sirtuins have been identified, with the closest mammalian homologue to yeast Sir2 being Sirt1.”

In the paper

“These observations point to p16INK4a both serving as a break for the proliferation of cancer cells, and also limiting the long-term renewal of stem cells.”

In the paper

“The removal of damaged cellular components, especially damaged mitochondria, might decrease the level of reactive oxygen species (ROS), which in turn might reduce genomic instability or forestall cellular senescence.”

In the paper

“This notion is also supported by observations that in human malignancies the BECN1 locus is commonly deleted and by experimental evidence that several tumour suppressors, including the phosphatase and tensin homologue Pten and p53, stimulate autophagy 78 .”

What the sources say

• Not checked yetcites [78] Kondo, Y. & Kondo, S. Autophagy and cancer therapy. Autophagy 2, 85–90 (2006) source

In the paper

“Indeed, although the available evidence indicates that oncogenes can inhibit autophagy and tumour suppressors can stimulate it, the exact mechanistic link between cancer and autophagy remains obscure (Fig. 3).”

What the sources say

• Not checked yetcites [78] Kondo, Y. & Kondo, S. Autophagy and cancer therapy. Autophagy 2, 85–90 (2006) source

In the paper

“Conversely, mice with short telomeres are resistant-with a few exceptions-to tumours 73 , arguing that telomere shortening represents a potent in vivo tumour suppressor mechanism.”

What the sources say

• Not checked yetcites [73] Blanco, R., Muñoz, P., Klatt, P., Flores, J. M. & Blasco, M. A. Telomerase abrogation dramatically accelerates TRF2-induced epithelial carcinogenesis. Genes Dev. 21, 206–220 (2007) source

In the paper

“Mice lacking autophagy-related gene 5 ( Atg5 ) are born normally but subsequently die within the first 24 h of life 79 . This death is a result of the inability of these mice to activate the macroautophagy program that is required for energy homeostasis immediately after birth.”

What the sources say

• Not checked yetcites [79] Kuma, A. et al. The role of autophagy during the early neonatal starvation period. Nature 432, 1032–1036 (2004) source

In the paper

“Such mechanisms might allow moderate increases in autophagy to reduce the incidence of cancer and prolong lifespan.”

In the paper

“Conversely, these findings also support the fascinating idea that the manipulation of telomerase activity might increase the life span of mammals.”

In the paper

“Interestingly, both dauer formation and lifespan extension by daf-2 have been shown to require the worm orthologue of beclin 82 .”

What the sources say

• Not checked yetcites [82] Melendez, A. et al. Autophagy genes are essential for dauer development and lifespan extension in C. elegans. Science 301, 1387–1391 (2003) source

In the paper

“re-introduction of the TERT telomerase gene was sufficient to bypass replicative senescence and to confer immortal growth on a number of human primary cell lines 56”

What the sources say

• Not checked yetcites [56] Bodnar, A. G. et al. Extension of life-span by introduction of telomerase into normal human cells. Science 279, 349–352 (1998) source

In the paper

“In this case, the haploinsufficient mice developed tumours, indicating that autophagy might act as an important in vivo tumour suppressor 76, 77 .”

What the sources say

• Not checked yetcites [76] Yue, Z., Jin, S., Yang, C., Levine, A. J. & Heintz, N. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc. Natl Acad. Sci. USA 100, 15077–15082 (2003) source
• Not checked yetcites [77] Qu, X. et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J. Clin. Invest. 112, 1809–1820 (2003) source

In the paper

“This phenomenon is also observed in some patients with dyskeratosis congenita, and is likely to be seen in patients with aplastic anaemia or pulmonary fibrosis due to telomerase deficiencies.”

In the paper

“First generation mice lacking the telomerase RNA component Terc show a decrease in both their median and maximum lifespan, and these effects become more pronounced with each subsequent generation 65 .”

What the sources say

• Not checked yetcites [65] García-Cao, I. et al. Increased p53 activity does not accelerate telomere-driven aging. EMBO Rep. 7, 546–552 (2006) source

In the paper

“this progressive telomere loss was proposed to be at the basis of cellular senescence and ageing in the 'telomere hypothesis' 53”

What the sources say

• Not checked yetcites [53] Harley, C. B., Futcher, A. B. & Greider, C. W. Telomeres shorten during ageing of human fibroblasts. Nature 345, 458–460 (1990) source

In the paper

“Similarly, the use of the TOR inhibitor rapamycin is currently being actively pursued as a treatment for human malignancies 85 .”

What the sources say

• Not checked yetcites [85] Sabatini, D. M. mTOR and cancer: insights into a complex relationship. Nature Rev. Cancer 6, 729–734 (2006) source

In the paper

“Over the last decade it has become clear that most human cancers activate telomerase at some point during tumorigenesis, while this activity is largely absent in most normal tissues 70, 71 .”

What the sources say

• Not checked yetcites [70] Kim, N. W. et al. Specific association of human telomerase activity with immortal cells and cancer. Science 266, 2011–2015 (1994) source
• Not checked yetcites [71] Counter, C. M., Hirte, H. W., Bacchetti, S. & Harley, C. B. Telomerase activity in human ovarian carcinoma. Proc. Natl Acad. Sci. USA 91, 2900–2904 (1994) source

In the paper

“In spite of their increased mortality due to cancer, these transgenic mice did show evidence of improved tissue regeneration as well as a slight increase in maximum life span 68 .”

What the sources say

• Not checked yetcites [68] Gonzalez-Suarez, E., Geserick, C., Flores, J. M. & Blasco, M. A. Antagonistic effects of telomerase on cancer and aging in K5-mTert transgenic mice. Oncogene 24, 2256–2270 (2005) source

In the paper

“telomere length has been shown to predict the replicative capacity of human cells and the appearance of certain age-associated pathologies in humans 54, 55”

What the sources say

• Not checked yetcites [54] Allsopp, R. C. et al. Telomere length predicts replicative capacity of human fibroblasts. Proc. Natl Acad. Sci. USA 89, 10114–10118 (1992) source
• Not checked yetcites [55] Cawthon, R. M. et al. Association between telomere length in blood and mortality in people aged 60 years or older. Lancet 361, 393–395 (2003) source

In the paper

“One possibility is that interfering with the normal degradation of organelles leads to the retention of older, damaged mitochondria that serve as a source for damaging reactive oxygen species.”

In the paper

“Nonetheless, two subsequent studies that used brain-specific conditional knockouts of Atg5 and Atg7 revealed that, in these animals, the absence of autophagy leads to a shortened lifespan and an accelerated form of age-related neuronal degeneration 80, 81 .”

What the sources say

• Not checked yetcites [80] Komatsu, M. et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880–884 (2006) source
• Not checked yetcites [81] Hara, T. et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885–889 (2006) source

In the paper

“Such a mechanism would provide a strong connection between common insults that could both contribute to cancer and accelerate ageing.”

In the paper

“As more and more stem cells withdraw from the proliferative pool, there is a decrease in the overall number and/or functionality of both stem and progenitor cells. This decrease predisposes the organism to impaired tissue homeostasis and regenerative capacity and could contribute to ageing and age-related pathologies.”

In the paper

“In both of these cases, tumours seem to arise secondary to an increase in metabolic intermediates (succinate and fumarate, respectively).”

In the paper

“There is also growing evidence that mammalian forkhead family members act as tumour suppressors and regulators of mammalian stem cell lifespan 92, 93, 94 .”

What the sources say

• Not checked yetcites [92] Hu, M. C. et al. IκB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell 117, 225–237 (2004) source
• Not checked yetcites [93] Paik, J. H. et al. FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis. Cell 128, 309–323 (2007) source
• Not checked yetcites [94] Tothova, Z. et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128, 325–339 (2007) source

In the paper

“There is a growing awareness that, as far as the cell is concerned, sensing nutrient availability and energetic status is an integrated and 'system biology' endeavour 101 .”

What the sources say

• Not checked yetcites [101] Levine, A. J., Feng, Z., Mak, T. W., You, H. & Jin, S. Coordination and communication between the p53 and IGF-1-AKT-TOR signal transduction pathways. Genes Dev. 20, 267–275 (2006) source

In the paper

“Overall lifespan seems to be influenced by many of these sensors and effectors, indicating that there is an intimate connection between energy sensing and longevity 101 .”

What the sources say

• Not checked yetcites [101] Levine, A. J., Feng, Z., Mak, T. W., You, H. & Jin, S. Coordination and communication between the p53 and IGF-1-AKT-TOR signal transduction pathways. Genes Dev. 20, 267–275 (2006) source