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Cited by 992Telomeres, Telomerase, and SenescenceGenetics, Aging, and Longevity in Model OrganismsCancer-related Molecular Pathways

The common biology of cancer and ageing

Finkel, Toren, Serrano, Manuel, Blasco, Maria A.·2007·Nature
DOI 10.1038/nature05985
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Abstract

At first glance, cancer and ageing would seem to be unlikely bedfellows. Yet the origins for this improbable union can actually be traced back to a sequence of tragic--and some say unethical--events that unfolded more than half a century ago. Here we review the series of key observations that has led to a complex but growing convergence between our understanding of the biology of ageing and the mechanisms that underlie cancer.

AI snapshot

Written from the paper’s full text.

TL;DR

This review traces historical and molecular convergence between cancer and ageing, focusing on cellular senescence, genomic instability, telomeres, autophagy, and metabolism. It argues that cancer and ageing are often—but not always—woven by similar molecular threads, with some protective mechanisms acting antagonistically and others sharing common aetiologies.

Key findings

  • Cellular senescence: Hayflick and Moorhead found normal diploid fibroblasts could not be subcultivated more than about 50 times; p16INK4a increases with ageing and is described as an impressively good biomarker of ageing, while also limiting stem cell renewal and tissue regeneration.
  • Genomic instability: severe DNA damage-sensing/repair defects can accelerate ageing, whereas milder mutations in the same pathways predispose to cancer; “superactive” p53 mice are cancer-resistant but age prematurely, while normally regulated p53 overexpression does not change lifespan.
  • Telomeres and telomerase: telomere shortening predicts replicative capacity and age-associated pathologies; more than 95% of human tumours aberrantly activate telomerase, and Terc-deficient mice show decreased median and maximum lifespan with disease anticipation.
  • Autophagy and metabolism: Becn1 haploinsufficient mice develop tumours; Atg5-null mice die within the first 24 h of life; brain-specific Atg5/Atg7 knockouts show shortened lifespan and age-related neurodegeneration; TOR inhibition and caloric restriction extend lifespan in model organisms.

Methods

  • Narrative review, not primary research; synthesizes historical observations and recent experimental highlights across five areas: cellular senescence and tumour formation, genomic instability, telomere biology, autophagy, and mitochondrial metabolism/energy-dependent signal transduction.
  • Data/sample: published literature and referenced studies, including human inherited syndromes, mouse models, yeast, C. elegans, Drosophila, and cell culture; no new experiments or systematic search strategy are described.
  • Main analysis: conceptual synthesis and model-building, with figures proposing interplay between stem cells, stress, ageing, cancer, telomeres, autophagy, and energy signal transduction.

Limitations

  • Stated in the paper: many fundamental questions remain unanswered; the exact mechanistic link between cancer and autophagy remains obscure; the hierarchy and crosstalk between CDKN2a induction and DNA damage response activation in vivo are not well understood; extension of accelerated ageing models to normal ageing must be done with care; and autophagy’s role in postmitotic C. elegans may be more important than in renewable mammalian systems.
  • Evident from the text: as a narrative review, it lacks a systematic literature search or quantitative synthesis, and its proposed models are speculative rather than validated by primary data.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/nature05985

Cites

101 of 101 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 123 cited sources checked · 0 supported · 0 flagged

  • Premisenone given
    § Cellular senescence as a block to tumour formation

    The critical executioners of senescence in response to the above factors include the tumour suppressor pathways controlled by RB1 and P53.

    “the critical executioners of senescence in response to the above factors seem to include the well known tumour suppressor pathways that are controlled by retinoblastoma 1 (RB1) and P53”
    Quote in the paperSubstantial claim
  • Premisecitation
    § [Figure 1: The potential interplay between stem cells, stress, ageing and cancer.](http://www.nature.com/nature/journal/v448/n7155/fig_tab/nature05985_F1.html)

    Strategies such as caloric restriction, which extend lifespan, also seem to reverse the age-dependent increase in p16INK4a transcription.

    “strategies such as caloric restriction, which extend lifespan, also seem to reverse the age-dependent increase in p16INK4a transcription 16, 18”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [16] Krishnamurthy, J. et al. Ink4a/Arf expression is a biomarker of aging. J. Clin. Invest. 114, 1299–1307 (2004) source

      Not checked in the free run.

    • cites [18] Edwards, M. G. et al. Gene expression profiling of aging reveals activation of a p53-mediated transcriptional program. BMC Genomics 8, 80 (2007) source

      Not checked in the free run.

  • Interpretationnone given
    § [Figure 1: The potential interplay between stem cells, stress, ageing and cancer.](http://www.nature.com/nature/journal/v448/n7155/fig_tab/nature05985_F1.html)

    Tumour progression to full malignancy is favoured when tumour cells acquire mutations that impair the senescence program (for example, mutations in Trp53 or CDKN2a).

    “Tumour progression to full malignancy is favoured when tumour cells acquire mutations that impair the senescence program (for example, mutations in Trp53 or CDKN2a ).”
    Quote in the paperSubstantial claim
  • Premisecitation
    § Cellular senescence as a block to tumour formation

    There are abundant senescent cells within tumours.

    “recent data have shown that there are abundant senescent cells within tumours”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [5] Mooi, W. J. & Peeper, D. S. Oncogene-induced cell senescence—halting on the road to cancer. N. Engl. J. Med. 355, 1037–1046 (2006) source

      Not checked in the free run.

    • cites [6] Collado, M. & Serrano, M. The power and the promise of oncogene-induced senescence markers. Nature Rev. Cancer 6, 472–476 (2006) source

      Not checked in the free run.

  • Interpretationreasoning
    § [Figure 1: The potential interplay between stem cells, stress, ageing and cancer.](http://www.nature.com/nature/journal/v448/n7155/fig_tab/nature05985_F1.html)

    During normal ageing, stem cells accumulate damage and subsequent stress-dependent changes, leading to an increasing abundance of senescent cells within differentiated tissues.

    “During normal ageing, stem cells accumulate damage and subsequent stress-dependent changes (for example, de-repression of the CDKN2a ( INK4a / ARF ) locus or telomere shortening). This leads to the increasing abundance of senescent cells (large blue cells) within differentiated tissues.”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 17
  • May combine two claims. 41

  • Classified as probably not a substantial claim.

    Premisecitation
    § Cellular senescence as a block to tumour formation

    Some intrinsic factor(s) accumulate in cells until they senesce.

    “they concluded that some intrinsic factor/s (later termed 'Hayflick factors') accumulated in these cells until they 'senesced' 1”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Hayflick, L. & Moorhead, P. S. The serial cultivation of human diploid cell strains. Exp. Cell Res. 25, 585–621 (1961) source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § [Figure 1: The potential interplay between stem cells, stress, ageing and cancer.](http://www.nature.com/nature/journal/v448/n7155/fig_tab/nature05985_F1.html)

    Incipient tumours undergo rapid proliferation and pre-malignant tumour cells rapidly accumulate damage, leading to a higher proportion of tumour cells becoming senescent.

    “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).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § [Figure 1: The potential interplay between stem cells, stress, ageing and cancer.](http://www.nature.com/nature/journal/v448/n7155/fig_tab/nature05985_F1.html)

    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.

    “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”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [16] Krishnamurthy, J. et al. Ink4a/Arf expression is a biomarker of aging. J. Clin. Invest. 114, 1299–1307 (2004) source

      Not checked in the free run.

    • cites [17] Kim, W. Y. & Sharpless, N. E. The regulation of INK4/ARF in cancer and aging. Cell 127, 265–275 (2006) source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given
    § Cellular senescence as a block to tumour formation

    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.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Genomic instability links cancer and ageing

    Reducing the level of various mitotic checkpoint genes leads to chromosomal instability, augmented aneuploidy and the phenotypic appearance of progeroid mice.

    “reducing the level of various mitotic checkpoint genes leads to chromosomal instability, augmented aneuploidy and the phenotypic appearance of progeroid mice 36, 37”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [37] Baker, D. J. et al. Early aging-associated phenotypes in Bub3/Rae1 haploinsufficient mice. J. Cell Biol. 172, 529–540 (2006) source

      Not checked in the free run.

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    Premisecitation
    § Genomic instability links cancer and ageing

    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.

    “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”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [45] Vaquero, A. et al. Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin. Mol. Cell 16, 93–105 (2004) source

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    • cites [46] Pruitt, K. et al. Inhibition of SIRT1 reactivates silenced cancer genes without loss of promoter DNA hypermethylation. PLoS Genet. 2, e40 (2006) source

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    Premisecitation
    § Genomic instability links cancer and ageing

    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.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [47] Mostoslavsky, R. et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell 124, 315–329 (2006) source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premiseown data
    § Telomeres and telomerase

    Telomeres are highly conserved in most eukaryotic organisms, with the exception of some flies.

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

  • May combine two claims.

    Interpretationcitation
    § Genomic instability links cancer and ageing

    Sirt6-deficient mice 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 and mice lacking the NER enzyme ERCC4.

    “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”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [39] Niedernhofer, L. J. et al. A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis. Nature 444, 1038–1043 (2006) source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation
    § Genomic instability links cancer and ageing

    WRN is essential for proper telomere maintenance through its interaction with the telomeric binding proteins TERF1 and TERF2.

    “One attractive explanation is that WRN is essential for proper telomere maintenance through its interaction with the telomeric binding proteins TERF1 and TERF2 41”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given
    § [Figure 1: The potential interplay between stem cells, stress, ageing and cancer.](http://www.nature.com/nature/journal/v448/n7155/fig_tab/nature05985_F1.html)

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

    “not every strategy that could protect us from cancer comes at the expense of accelerating ageing.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation
    § Genomic instability links cancer and ageing

    The accelerated ageing phenotype in mice expressing altered isoforms of p53 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.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisereasoning
    § Telomeres and telomerase

    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.

    “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 .”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Telomeres and telomerase

    Telomeres consist of tandem G-rich repeats that expanded until the chromosome end.

    “Telomeres were found to consist of tandem G-rich repeats that expanded until the chromosome end.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given
    § Genomic instability links cancer and ageing

    Insulin-IGF signalling is known to regulate lifespan in lower organisms.

    “insulin-IGF signalling is known to regulate lifespan in lower organisms.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given
    § Genomic instability links cancer and ageing

    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 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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning
    § Genomic instability links cancer and ageing

    In 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 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).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given
    § Genomic instability links cancer and ageing

    The RecQ helicase family is conserved from Escherichia coli to man, and humans have five RecQ homologues that have important roles in recombination, the replication stress response and maintaining genomic stability.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Telomeres and telomerase

    Some cells could elongate preexisting telomeres, implying the existence of telomere elongation mechanisms.

    “The identification of telomeres rapidly led to the realization that some cells could elongate preexisting telomeres, implying the existence of telomere elongation mechanisms 49”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Shampay, J., Szostak, J. W. & Blackburn, E. H. DNA sequences of telomeres maintained in yeast. Nature 310, 154–157 (1984) source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Genomic instability links cancer and ageing

    Mice lacking Atm show rapid ageing and depletion of their haematopoietic stem cell compartment.

    “mice lacking Atm show rapid ageing and depletion of their haematopoietic stem cell compartment 34”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

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    Premisenone given
    § Genomic instability links cancer and ageing

    Human inherited cancer syndromes such as Li-Fraumeni syndrome, ataxia-telangiectasia (AT) and common forms of familial breast and ovarian cancer can be caused by germline mutations in the genes for P53, the ATM kinase and BRCA1, respectively-three proteins that are essential in the surveillance of DNA damage.

    “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.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Telomeres and telomerase

    Telomerase was discovered by Carol Greider and Elizabeth Blackburn.

    “Such an enzymatic activity was soon discovered by Carol Greider and Elizabeth Blackburn and was named telomerase 50”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [50] Greider, C. W. & Blackburn, E. H. Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell 43, 405–413 (1985) source

      Not checked in the free run.

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    Premisecitation
    § Genomic instability links cancer and ageing

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

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [43] Liu, B. et al. Genomic instability in laminopathy-based premature aging. Nature Med. 11, 780–785 (2005) source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § Genomic instability links cancer and ageing

    Severe deficiencies in proteins involved in DNA damage sensing and DNA repair might accelerate ageing, while milder mutations in these same pathways might predispose individuals to cancer.

    “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.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given
    § Genomic instability links cancer and ageing

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

    “Alternatively, the absence of DNA repair might cause enough direct damage to fully differentiated cells to impair overall homeostasis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Genomic instability links cancer and ageing

    Mice genetically engineered to express altered isoforms of p53 with increased activity seem to be resistant to cancer but age prematurely.

    “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”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [29] Tyner, S. D. et al. p53 mutant mice that display early ageing-associated phenotypes. Nature 415, 45–53 (2002) source

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    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation
    § Genomic instability links cancer and ageing

    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.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] Haigis, M. C. & Guarente, L. P. Mammalian sirtuins—emerging roles in physiology, aging, and calorie restriction. Genes Dev. 20, 2913–2921 (2006) source

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    Premisenone given
    § Genomic instability links cancer and ageing

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

    “Seven mammalian sirtuins have been identified, with the closest mammalian homologue to yeast Sir2 being Sirt1.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning
    § [Figure 1: The potential interplay between stem cells, stress, ageing and cancer.](http://www.nature.com/nature/journal/v448/n7155/fig_tab/nature05985_F1.html)

    p16INK4a serves as a break for the proliferation of cancer cells and also limits the long-term renewal of stem cells.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning
    § [Figure 3: The potential role of autophagy in cancer and ageing.](http://www.nature.com/nature/journal/v448/n7155/fig_tab/nature05985_F3.html)

    Removal of damaged cellular components, especially damaged mitochondria, might decrease ROS, which might reduce genomic instability or forestall cellular senescence.

    “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.”
    Quote in the paperSubstantial claim

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    Premisecitation
    § Autophagy and the cell biology of waste management

    In human malignancies, the BECN1 locus is commonly deleted, and tumour suppressors including Pten and p53 stimulate autophagy.

    “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 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [78] Kondo, Y. & Kondo, S. Autophagy and cancer therapy. Autophagy 2, 85–90 (2006) source

      Not checked in the free run.

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    Premisecitation
    § Autophagy and the cell biology of waste management

    Oncogenes can inhibit autophagy and tumour suppressors can stimulate it.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [78] Kondo, Y. & Kondo, S. Autophagy and cancer therapy. Autophagy 2, 85–90 (2006) source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation
    § [High resolution image and legend (157K)](http://www.nature.com/nature/journal/v448/n7155/fig_tab/nature05985_F2.html)

    Mice with short telomeres are resistant to tumours, with a few exceptions, arguing that telomere shortening is a potent in vivo tumour suppressor mechanism.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

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    Premisecitation
    § [Figure 3: The potential role of autophagy in cancer and ageing.](http://www.nature.com/nature/journal/v448/n7155/fig_tab/nature05985_F3.html)

    Mice lacking Atg5 are born normally but die within first 24 h due to inability to activate macroautophagy required for energy homeostasis after birth.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [79] Kuma, A. et al. The role of autophagy during the early neonatal starvation period. Nature 432, 1032–1036 (2004) source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § [Figure 3: The potential role of autophagy in cancer and ageing.](http://www.nature.com/nature/journal/v448/n7155/fig_tab/nature05985_F3.html)

    Moderate increases in autophagy might reduce cancer incidence and prolong lifespan.

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

  • Classified as probably not a substantial claim.

    Interpretationreasoning
    § [High resolution image and legend (157K)](http://www.nature.com/nature/journal/v448/n7155/fig_tab/nature05985_F2.html)

    Manipulation of telomerase activity might increase the lifespan of mammals.

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

  • May combine two claims.

    Premisecitation
    § [Figure 3: The potential role of autophagy in cancer and ageing.](http://www.nature.com/nature/journal/v448/n7155/fig_tab/nature05985_F3.html)

    Dauer formation and lifespan extension by daf-2 require the worm orthologue of beclin.

    “Interestingly, both dauer formation and lifespan extension by daf-2 have been shown to require the worm orthologue of beclin 82 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] Melendez, A. et al. Autophagy genes are essential for dauer development and lifespan extension in C. elegans. Science 301, 1387–1391 (2003) source

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    Premisecitation
    § Metabolism links cancer and ageing

    TOR is activated in presence of abundant nutrients and inactivated under starvation.

    “For our purpose, suffice it to say that TOR is activated in the presence of abundant nutrients, and inactivated under starvation.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [85] Sabatini, D. M. mTOR and cancer: insights into a complex relationship. Nature Rev. Cancer 6, 729–734 (2006) source

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

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    Premisecitation
    § Telomeres and telomerase

    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.

    “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”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [56] Bodnar, A. G. et al. Extension of life-span by introduction of telomerase into normal human cells. Science 279, 349–352 (1998) source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation
    § Autophagy and the cell biology of waste management

    Becn1 haploinsufficient mice develop tumours, indicating autophagy might act as an important in vivo tumour suppressor.

    “In this case, the haploinsufficient mice developed tumours, indicating that autophagy might act as an important in vivo tumour suppressor 76, 77 .”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § [High resolution image and legend (157K)](http://www.nature.com/nature/journal/v448/n7155/fig_tab/nature05985_F2.html)

    Disease anticipation is 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.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § [High resolution image and legend (157K)](http://www.nature.com/nature/journal/v448/n7155/fig_tab/nature05985_F2.html)

    First generation mice lacking the telomerase RNA component Terc show decreased median and maximum lifespan, and these effects become more pronounced with each subsequent generation.

    “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 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [65] García-Cao, I. et al. Increased p53 activity does not accelerate telomere-driven aging. EMBO Rep. 7, 546–552 (2006) source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Telomeres and telomerase

    Progressive telomere loss was proposed to be at the basis of cellular senescence and ageing in the 'telomere hypothesis'.

    “this progressive telomere loss was proposed to be at the basis of cellular senescence and ageing in the 'telomere hypothesis' 53”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] Harley, C. B., Futcher, A. B. & Greider, C. W. Telomeres shorten during ageing of human fibroblasts. Nature 345, 458–460 (1990) source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Metabolism links cancer and ageing

    Rapamycin is being actively pursued as a treatment for human malignancies.

    “Similarly, the use of the TOR inhibitor rapamycin is currently being actively pursued as a treatment for human malignancies 85 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [85] Sabatini, D. M. mTOR and cancer: insights into a complex relationship. Nature Rev. Cancer 6, 729–734 (2006) source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § [High resolution image and legend (157K)](http://www.nature.com/nature/journal/v448/n7155/fig_tab/nature05985_F2.html)

    Most human cancers activate telomerase at some point during tumorigenesis, while telomerase activity is largely absent in most normal tissues.

    “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 .”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § [High resolution image and legend (157K)](http://www.nature.com/nature/journal/v448/n7155/fig_tab/nature05985_F2.html)

    Tert transgenic mice with increased telomerase showed improved tissue regeneration and a slight increase in maximum lifespan despite increased cancer mortality.

    “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 .”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Telomeres and telomerase

    Telomere length has been shown to predict the replicative capacity of human cells and the appearance of certain age-associated pathologies in humans.

    “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”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given
    § Autophagy and the cell biology of waste management

    Interfering with normal degradation of organelles leads to retention of older, damaged mitochondria that serve as a source of damaging reactive oxygen species.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § [Figure 3: The potential role of autophagy in cancer and ageing.](http://www.nature.com/nature/journal/v448/n7155/fig_tab/nature05985_F3.html)

    Brain-specific conditional knockouts of Atg5 and Atg7 show shortened lifespan and accelerated age-related neuronal degeneration.

    “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 .”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [81] Hara, T. et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885–889 (2006) source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationreasoning
    § Autophagy and the cell biology of waste management

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

    “Such a mechanism would provide a strong connection between common insults that could both contribute to cancer and accelerate ageing.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning
    § Henrietta's gift

    Decrease in stem/progenitor cell number/function predisposes organism to impaired tissue homeostasis and regenerative capacity and could contribute to ageing and age-related pathologies.

    “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.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Long-lived cells such as stem cells accumulate DNA damage over the lifespan from stresses including intracellular oxidants generated from normal metabolism.
    • Rests on an assumption: The default pathway for damaged stem cells is to undergo growth arrest, apoptosis or senescence.

  • May combine two claims.

    Interpretationreasoning
    § Metabolism links cancer and ageing

    Tumours in SDH and FH mutation syndromes arise secondary to increase in succinate and fumarate, respectively.

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

  • May combine two claims.

    Premisecitation
    § Metabolism links cancer and ageing

    Mammalian forkhead family members act as tumour suppressors and regulators of mammalian stem cell lifespan.

    “There is also growing evidence that mammalian forkhead family members act as tumour suppressors and regulators of mammalian stem cell lifespan 92, 93, 94 .”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [92] Hu, M. C. et al. IκB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a. Cell 117, 225–237 (2004) source

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [94] Tothova, Z. et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128, 325–339 (2007) source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Metabolism links cancer and ageing

    Nutrient and energy sensing is an integrated system biology endeavour.

    “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 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation
    § [Figure 4: Energy signal transduction.](http://www.nature.com/nature/journal/v448/n7155/fig_tab/nature05985_F4.html)

    Overall lifespan is influenced by many sensors and effectors, indicating an intimate connection between energy sensing and longevity.

    “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 .”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

55 of 55

  • The paper relies on this without support.

    Most human malignancies develop in the presence of a functional immune system.

    “as it is clear that most human malignancies develop in the presence of a functional immune system.”

  • The paper relies on this without support.

    Genomic instability is a hallmark of most cancers.

    “Given that genomic instability is a hallmark of most cancers”

  • The paper relies on this without support.

    Telomeres are essential for chromosomal stability.

    “Telomeres protect natural chromosome ends from fusion events and are therefore essential for chromosomal stability.”

  • The paper relies on this without support.

    Long-lived cells such as stem cells accumulate DNA damage over the lifespan from stresses including intracellular oxidants generated from normal metabolism.

    “Over the lifespan of an organism, longlived cells (such as stem cells) accumulate DNA damage from a number of stresses including intracellular oxidants generated from normal metabolism.”

  • The paper relies on this without support.

    The default pathway for damaged stem cells is to undergo growth arrest, apoptosis or senescence.

    “The default pathway for such damaged stem cells is to undergo growth arrest, apoptosis or senescence.”

  • The authors state this as an assumption.

    Some rare cells can escape this normal default pathway by acquiring additional mutations that allow them to continue to proliferate even in the setting of damaged DNA.

    “Presumably, some rare cells can escape from this normal default pathway by acquiring additional mutations that allow them to continue to proliferate even in the setting of damaged DNA.”
6 of 6

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • High cellular ROS levels are associated with cancer, diabetes, inflammatory diseases, ischemia-related diseases, and neurodegeneration.

    “Second, high cellular ROS levels are associated with cancer, diabetes, inflammatory diseases, ischemia-related diseases, and neurodegeneration, and are thus commonly thought to contribute to human pathologies and aging 80–83.”

    From Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes (2010) · cites this paper as [80]

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Related

Authors
Finkel, T., Serrano, M., & Blasco, M. A.
Affiliations
  • National Institutes of Health (US)
  • Spanish National Cancer Research Centre (ES)
Corresponding author
Finkel, Toren
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2007-08-16
Volume
448
Issue
7155
Pages
767-774
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature05985
OpenAlex
W2134390575
Cited by
988
References
102
Citations by year
2026: 13 · 2025: 31 · 2024: 33 · 2023: 41 · 2022: 53 · 2021: 62 · 2020: 59 · 2019: 52 · 2018: 69 · 2017: 56 · 2016: 73 · 2015: 67 · 2014: 52 · 2013: 52 · 2012: 43
FWCI
6.17
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • Ellison Medical Foundation
  • National Institutes of Health
Topics
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Keywords
cancer, aging, genomic instability, telomeres, autophagy, cellular senescence, carcinogenesis, mitochondrial metabolism, HeLa cells, history of cancer research, systems biology
MeSH terms
Animals, Autophagy, Humans, Neoplasms, Telomere, Cellular Senescence, Telomerase, Genomic Instability

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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