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Cited by 161Genetics, Aging, and Longevity in Model OrganismsPI3K/AKT/mTOR signaling in cancerTelomeres, Telomerase, and Senescence

The DOI matches its Crossref record; none of the 107 sources its claims cite is checked for support yet.

Revisiting the antagonistic pleiotropy theory of aging: TOR-driven program and quasi-program

Open access
Blagosklonny, Mikhail V·2010·Cell Cycle
DOI 10.4161/cc.9.16.13120
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Abstract

A half century ago, the antagonistic pleiotropy (AP) theory had solved a mystery of aging, by postulating genes beneficial early in life at the cost of aging. Recently it was argued however that there are very few clear-cut examples of antagonistically pleiotropic (AP) genes other than p53. In contrast, here I discuss that p53 is not a clear-cut example of AP genes but is rather an aging-suppressor (gerosuppressor). In contrast, clear-cut examples of AP genes are genes that encode the TOR (target of rapamycin) pathway. TOR itself is the ultimate example of AP gene because its deletion is lethal in embryogenesis. Early in life the TOR pathway drives developmental program, which persists later in life as an aimless quasi-program of aging and age-related diseases.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that wild-type p53 is not a clear-cut antagonistically pleiotropic gene but rather a gerosuppressor, while the TOR pathway provides the clearest example of antagonistic pleiotropy because it drives early development and later becomes a harmful quasi-program of aging. It proposes that aging is a purposeless continuation of the completed TOR-driven developmental program, with rapamycin and metformin as gerosuppressants.

Key findings

  • p53 is not a clear-cut AP gene: p53-null and p53+/- mice do not live longer; loss of p53 shortens life span by shifting cancer earlier, and p53 inhibits the mTOR pathway, supporting its classification as a gerosuppressor.
  • TOR pathway genes are clear-cut AP genes: complete TOR knockout is lethal in embryogenesis (mouse TOR disruption causes early postimplantation lethality; S6K1/S6K2 double knockout is lethal; yeast deletion of TOR2 or both TOR genes is lethal), while partial TOR deficiency/inactivation extends life span and causes developmental arrest and gonadal degeneration.
  • In C. elegans, inactivation of PI-3K extends medium and maximal life span almost ten-fold, but causes prolonged developmental arrest that is probably fatal in the wild; this is presented as a clear-cut example of antagonistic pleiotropy.
  • The TOR-driven developmental program persists after development as an aimless quasi-program causing aging and age-related diseases; rapamycin and metformin are gerosuppressants, and calorie restriction prolongs life span in budding yeast, worms, flies, mice, rats, monkeys and other species by de-activating nutrient-sensing TOR signaling.

Methods

  • Review/commentary; no primary experimental design, sample, or statistical analysis is reported.
  • Synthesizes published genetic, pharmacological, and life-span studies across yeast, C. elegans, Drosophila, mice, rats, monkeys, and human cells to support a conceptual model.
  • Main analysis is conceptual argument: reclassifies p53 as a gerosuppressor, the TOR pathway as gerogenes/AP program, and proposes a quasi-program framework for aging.

Limitations

  • The paper states no limitations.
  • Evident from the text: it is a narrative review without systematic search or quantitative synthesis, and its conclusions rely on selected cited studies and conceptual interpretation.
  • No new experimental data are presented to directly test the quasi-program model.

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

Integrity signals

Registry

Crossref · 10.4161/cc.9.16.13120

Cites

Statistics

Nothing to recompute.

Verification

Claims the paper makes

0 of 107 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Complete knockout of TOR is lethal in embryogenesis.

    “Thus, a complete knockout of TOR is lethal.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [73]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [74]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [75]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Premisecitation

    Loss of p53 shortens life span by shifting age-related pathology (namely, cancer) earlier in life.

    “In contrast, loss of p53 shortens life span, by shifting age-related pathology (namely, cancer) earlier in life.4”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Interpretationnone given

    TOR itself is the ultimate example of an antagonistically pleiotropic gene because its deletion is lethal in embryogenesis.

    “toR itself is the ultimate example of Ap gene because its deletion is lethal in embryogenesis.”
    Quote in the paperNot a substantial claim
  • Interpretationreasoning

    Clear-cut examples of antagonistically pleiotropic genes are genes that encode the TOR pathway.

    “in contrast, clear-cut examples of Ap genes are genes that encode the toR (target of rapamycin) pathway.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    While causing cell cycle arrest, p53 may actually suppress senescence and convert senescence into quiescence.

    “However, we have recently found that, while causing cell cycle arrest, p53 may actually suppress senescence and convert senescence into quiescence.11”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • Rests on an assumption: p53 causes cell cycle arrest, a prerequisite of cellular senescence.
  • Probably not a substantial claim. 9
  • It may state two separate claims as one. 32

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Aging is associated with a pro-inflammatory state.

    “And aging is also associated with a pro-inflammatory state.[8][9][10]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [8]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [9]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [10]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Interpretationreasoning

    p53 is not a clear-cut example of antagonistically pleiotropic genes but is rather an aging-suppressor (gerosuppressor).

    “in contrast, here i discuss that p53 is not a clear-cut example of Ap genes but is rather an aging-suppressor (gerosuppressor).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    Neither p53-null nor p53 +/- mice live longer.

    “First, neither p53-null nor p53 +/-mice live longer.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Interpretationreasoning

    Early in life the TOR pathway drives a developmental program, which persists later in life as an aimless quasi-program of aging and age-related diseases.

    “early in life the toR pathway drives developmental program, which persists later in life as an aimless quasi-program of aging and age-related diseases.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.

    Interpretationnone given

    Rapamycin suppresses yeast growth; this anti-growth effect hurts yeast, whereas the anti-aging effect of rapamycin is not important in the wild.

    “Rapamycin suppresses yeast growth.This anti-growth effect hurts yeast, whereas the anti-aging effect of rapamycin is not important in the wild.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    Inhibition of the TOR pathway decelerates premature senescence of human cells in vitro, as well as chronological and replicative aging in yeast.

    “Inhibition of the TOR pathway decelerates premature senescence of human cells in vitro, [42][43][44][45][46][47][48] as well as chronological and replicative aging in yeast.[49][50][51][52][53]”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [42]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [43]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [44]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Interpretationreasoning

    A further increase in resistance (a quasi-program) causes over-activation of the ovary, decreasing fertility and finally ovarian failure (menopause).

    “A further increase in the resistance (a quasi-program) causes over-activation of the ovary, decreasing fertility and finally ovarian failure (menopause).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    These dwarf mice age slowly and have an extended lifespan.

    “On the other hand, these mice age slowly and have an extended lifespan.54,55”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [54]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [55]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Based on the fact that FOXO transcription factors extend life span, it was suggested that FOXO must antagonize the TOR pathway.

    “Based on the fact that FOXO transcription factors extend life span, it was suggested that FOXO must antagonize the TOR pathway.92”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [92]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisenone given

    Nutrients including glucose, amino acids and fatty acids activate TOR, which in turn promotes growth early in life and aging late in life.

    “Nutrients including glucose, amino acids and fatty acids activate TOR, which in turn promotes growth (early in life) and aging (late in life).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationnone given

    Damage-repair genes are not antagonistically pleiotropic: they are useful at any age.

    “Second, damage-repair genes are not antagonistically pleiotropic: they are useful at any age.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    Partial TOR deficiency results in developmental arrest, accompanied by marked gonadal degeneration.

    “For example, partial TOR deficiency results in developmental arrest, which is accompanied by marked gonadal degeneration.68”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [68]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisecitation

    Hyperactive mutant p53 and extra copies of p53 shorten life span in mice.

    “Second, hyperactive mutant p53 and extra copies of p53 shorten life span in mice.14,15”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [14]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [15]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim. The paper may give no reason why it holds.

    Interpretationnone given

    Such developmental arrest is probably fatal in the wild.

    “Such developmental arrest is probably fatal in the wild.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. It may be too vague to check against evidence. It may state two separate claims as one.

    Interpretationcitation

    Given that TOR drives aging in mammals, rapamycin can be defined as an anti-aging drug.

    “Given that TOR drives aging in mammals, rapamycin can be definied as an anti-aging drug.[91][92][93]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [91]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [92]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [93]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisecitation

    In Drosophila, overexpression of Tsc1, Tsc2 (upstream inhibitors of TOR) or dominant-negative forms of TOR or S6K all cause lifespan extension.

    “Also, in Drosophila, overexpression of Tsc1, Tsc2 (upstream inhibitors of TOR) or dominant-negative forms of TOR or S6K all cause lifespan extension.[70][71][72]”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [70]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [71]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [72]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Interpretationcitation

    mTOR drives cellular overactivation and hormone resistance, switching reproduction on and then (after 30-40 years) off.

    “As recently proposed, mTOR drives cellular overactivation and hormone resistance, switching reproduction on and then (after 30-40 years) off.122”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [122]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisecitation

    Such mice are resistant to age-related pathologies and live longer.

    “Such mice are resistant to age-related pathologies and live longer.58”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [58]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Interpretationreasoning

    While slowing growth, development and reproduction (harmful early in life), CR inhibits aging (beneficial later in life).

    “While slowing growth, development and reproduction (harmful early in life), CR inhibits aging (beneficial later in life).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it.

    Interpretationreasoning

    This is what could be expected from the ultimately pleiotropic gene.

    “And this is what could be expected from the ultimately pleiotropic gene.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    Dwarf mice (due to decreased IGF-1 levels) have reduced body temperature, delayed puberty and reduced fertility.

    “In fact, to their disadvantage, dwarf mice (due to decreased IGF-1 levels) have reduced body temperature, delayed puberty and reduced fertility.54,55”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [54]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [55]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisecitation

    Metformin, an antidiabetic drug, activates AMPK and thus inhibits mTOR.

    “Metformin, an antidiabetic drug, activates AMPK and thus inhibits mTOR.99”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [99]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisecitation

    TOR is a conserved kinase (from yeast to mammals) that regulates cell growth and metabolism in response to environmental clues.

    “TOR (target of rapamycin) is a conserved kinase (from yeast to mammals), which regulates cell growth and metabolism in response to environmental clues.[30][31][32][33][34][35][36][37][38][39][40]”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [30]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [31]

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    • cites [32]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisecitation

    In C. elegans, inactivations of Daf-2, age-1 and DAF-15 extend life span.

    “In C. elegans, inactivations of Daf-2 (ortholog of insulin/ IGF receptor), age-1 (ortholog of PI3-K) and DAF-15 (ortholog of Raptor) extend life span.[59][60][61][62][63][64][65][66][67]”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [59]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [60]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [61]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisecitation

    Deletion of TOR1 extends lifespan, while deletion of both TOR genes or TOR2 only is lethal.

    “Deletion of TOR1 extends lifespan, deletion of both TOR genes or TOR2 only is lethal.49”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [49]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisecitation

    p53 activity declines with age and is reduced in senescent cells.

    “Intriguingly, p53 activity declines with age 20 and is reduced in senescent cells.21”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [20]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [21]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim. The paper may give no reason why it holds.

    Interpretationnone given

    Inactivation of genes for aging has trade-off early in life.

    “Inactivation of genes for aging has trade-off early in life.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationcitation

    These forms of p53 are indeed antagonistically pleiotropic (AP) genes, but they are not wild-type (natural) p53 genes.

    “Perhaps, these forms of p53 are indeed antagonistically pleiotropic (AP) genes.But these genes are not wild-type (natural) p53 genes.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    In different species, inactivation of PTEN or its orthologs (Daf-18 in C. elegans), NF1, AMPK, Sirt1 (sirtuins, Sir2 in yeast) and FOXO shortens lifespan.

    “In different species, inactivation of PTEN or its orthologs (Daf-18 in C. elegans), NF1, AMP-activated protein kinase AMPK, Sirt1 (sirtuins, Sir2 in yeast) and FOXO shortens lifespan.53,65,104,105”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [53]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [65]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [104]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Interpretationreasoning

    Unlike genetic knockout, pharmacological inhibition of mTOR could be started later in life, when mTOR is harmful, without any trade-off early in life.

    “Unlike genetic knockout, pharmacological inhibition of mTOR could be started later in life, when mTOR is harmful, without any trade-off early in life.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationreasoning

    What all of these genes have in common is that they antagonize the TOR pathway either upstream (PTEN, NF-1, AMPK) or both upstream and downstream (Sirtuins, FOXO).

    “What all of these genes have in common is that they antagonize the TOR pathway either upstream (PTEN, NF-1, AMPK) or both upstream and downstream (Sirtuins, FOXO) (Fig. 2).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Single nucleotide polymorphisms (SNPs) in p53 pathway genes affect human fertility.

    “Further, single nucleotide polymorphisms (SNPs) in p53 pathway genes affect human fertility.28,29”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [28]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [29]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.

    Interpretationnone given

    In laboratory conditions, a decrease in fitness could be insignificant or even unnoticeable, so animals live longer.

    “In laboratory conditions, this could be insignificant or even unnoticeable, so animals live longer.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: In the wild, a decrease in fitness can be lethal.

  • It may state two separate claims as one.

    Interpretationreasoning

    This quasi-program is robust because it can be knocked out genetically only by knocking down essential genes, and this may be lethal early in development.

    “This quasi-program is robust because it can be knocked out genetically only by knocking down essential genes.And this may be lethal early in development.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisenone given

    The mTOR pathway inhibits autophagy, stimulates ribosome biogenesis, protein synthesis (including aggregation-prone proteins), cell growth and secretion of pro-inflammatory and mitogenic factors.

    “In turn, the mTOR pathway inhibits autophagy, stimulates ribosome biogenesis, protein synthesis (including aggregation-prone proteins), cell growth and secretion of pro-inflammatory and mitogenic factors.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    Rapamycin inhibits yeast growth but extends life span of aging yeast.

    “Rapamycin inhibits yeast growth but extends life span of aging yeast.50,90”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [50]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [90]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Premisecitation

    Metformin slows down aging and extends reproduction in mice, and extends C. elegans healthspan.

    “Metformin slows down aging and extends reproduction in mice, 100 and extends C. elegans healthspan.101”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [100]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [101]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Interpretationreasoning

    Aging is not programmed but is a continuation of the completed developmental program.

    “Aging is not programmed but is a continuation of the completed developmental program.”
    Quote in the paperSubstantial claim
38 of 38

  • The paper relies on this without support.

    In the wild, a decrease in fitness can be lethal.

    “In the wild, a decrease in fitness can be lethal.”

  • The paper relies on this without support.

    Most genes are useful.

    “This is not surprising because most genes are useful.”

  • The paper relies on this without support.

    p53 causes cell cycle arrest, a prerequisite of cellular senescence.

    “First, p53 causes cell cycle arrest, a prerequisite of cellular senescence.”

  • The paper relies on this without support.

    The TOR pathway is essential in developmental growth.

    “The TOR pathway is essential in developmental growth.”

  • The paper relies on this without support.

    Food is the most universal gero-promoting factor.

    “Food is the most universal gero-promoting factor.”

  • The paper relies on this without support.

    Genes that drive aging (gerogenes) must be beneficial early in life.

    “Genes that drive aging (gerogenes) must be beneficial early in life.”

  • The paper relies on this without support.

    Inactivation of numerous genes shortens life span in yeast, worms, flies and mice.

    “Inactivation of numerous genes shortens life span in yeast, worms, flies and mice.”
7 of 7

Citations

Cites

Still being checked.

Research works printed but not linked: 97

  1. Williams GC. Pleiotropy, natural selection and the evolution of senescence. Evolution 1957; 11:398-411.
  2. Kirkwood TB. Understanding the odd science of aging. Cell 2005; 120:437-47.
  3. Jacks T, Remington L, Williams BO, Schmitt EM, Halachmi S, Bronson RT, et al. Tumor spectrum analy- sis in p53-mutant mice. Curr Biol 1994; 4:1-7.
  4. Mercer J, Bennett M. The role of p53 in atherosclerosis. Cell Cycle 2006; 5:1907-9.
  5. Guevara NV, Kim HS, Antonova EI, Chan L. The absence of p53 accelerates atherosclerosis by increasing cell proliferation in vivo. Nat Med 1999; 5:335-9.
  6. Komarova EA, Krivokrysenko V, Wang K, Neznanov N, Chernov MV, Komarov PG, et al. p53 is a suppres- sor of inflammatory response in mice. FASEB J 2005; 19:1030-2.
  7. Salvioli S, Capri M, Valensin S, Tieri P, Monti D, Ottaviani E, et al. Inflamm-aging, cytokines and aging: state of the art, new hypotheses on the role of mito- chondria and new perspectives from systems biology. Curr Pharm Des 2006; 12:161-3171.
  8. Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, et al. Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev 2007; 128:92-105.
  9. Altmeyer M, Hottiger MO. Poly(ADP-ribose) poly- merase 1 at the crossroad of metabolic stress and inflammation in aging. Aging 2009; 1:458-69.
  10. Korotchkina LG, Leontieva OV, Bukreeva EI, Demidenko ZN, Gudkov AV, Blagosklonny MV. The choice between p53-induced senescence and quiescence is determined in part by the mTOR pathway. Aging 2010; 2:344-52.
  11. Coppé JP, Patil CK, Rodier F, Sun Y, Muñoz DP, Goldstein J, et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol 2008; 6:2853-68.
  12. Tyner SD, Venkatachalam S, Choi J, Jones S, Ghebranious N, Igelmann H, et al. p53 mutant mice that display early ageing-associated phenotypes. Nature 2002; 415:45-53.
  13. Maier B, Gluba W, Bernier B, Turner T, Mohammad K, Guise T, et al. Modulation of mammalian life span by the short isoform of p53. Genes Dev 2004; 18:306-19.
  14. Mendrysa SM, Perry ME. Tumor suppression by p53 without accelerated aging: Just enough of a good thing? Cell Cycle 2006; 5:714-7.
  15. García-Cao I, García-Cao M, Martín-Caballero J, Criado LM, Klatt P, Flores JM, et al. "Super p53" mice exhibit enhanced DNA damage response, are tumor resistant and age normally. EMBO J 2002; 21:6225-35.
  16. Mendrysa SM, O'Leary KA, McElwee MK, Michalowski J, Eisenman RN, Powell DA, et al. Tumor suppression and normal aging in mice with constitu- tively high p53 activity. Genes Dev 2006; 20:16-21.
  17. Matheu A, Maraver A, Klatt P, Flores I, Garcia-Cao I, Borras C, et al. Delayed ageing through damage protec- tion by the Arf/p53 pathway. Nature 2007; 448:375-9.
  18. Feng Z, Hu W, Teresky AK, Hernando E, Cordon- Cardo C, Levine AJ. Declining p53 function in the aging process: a possible mechanism for the increased tumor incidence in older populations. Proc Natl Acad Sci USA 2007; 104:16633-8.
  19. Huang B, Vassilev LT. Reduced transcriptional activity in the p53 pathway of senescent cells revealed by the MDM2 antagonist nutlin-3. Aging 2009; 1:845-54.
  20. Campisi J. Cellular senescence and apoptosis: how cel- lular responses might influence aging phenotypes. Exp Gerontol 2003; 38:5-11.
  21. Ungewitter E, Scrable H. Antagonistic pleiotropy and p53. Mech Ageing Dev 2009; 130:10-7.
  22. Blagosklonny MV, Campisi J, Sinclair DA, Bartke A, Blasco MA, Bonner WM, et al. Impact papers on aging in 2009. Aging 2010; 2:111-21.
  23. Waskar M, Landis GN, Shen J, Curtis C, Tozer K, Abdueva D, et al. Drosophila melanogaster p53 has developmental stage-specific and sex-specific effects on adult life span indicative of sexual antagonistic pleiot- ropy. Aging 2009; 1:903-36.
  24. Donehower LA. Longevity regulation in flies: a role for p53. Aging 2009; 1:6-8.
  25. Maiuri MC, Malik SA, Morselli E, Kepp O, Criollo A, Mouchel PL, et al. Stimulation of autophagy by the p53 target gene Sestrin2. Cell Cycle 2009; 8:1571-6.
  26. Hu W, Feng Z, Atwal GS, Levine AJ. p53: a new player in reproduction. Cell Cycle 2008; 7:848-52.
  27. Kang HJ, Feng Z, Sun Y, Atwal G, Murphy ME, Rebbeck TR, et al. Single-nucleotide polymorphisms in the p53 pathway regulate fertility in humans. Proc Natl Acad Sci USA 2009; 106:9761-6.
  28. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev 2004; 18:1926-45.
  29. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell 2006; 124:471-84.
  30. Inoki K, Guan KL. Complexity of the TOR signaling network. Trends Cell Biol 2006; 16:206-12.
  31. Manning BD, Cantley LC. AKT/PKB signaling: navi- gating downstream. Cell 2007; 129:1261-74.
  32. Proud CG. Amino acids and mTOR signalling in ana- bolic function. Biochem Soc Trans 2007; 35:1187-90.
  33. Dann SG, Selvaraj A, Thomas G. mTOR Complex1- S6K1 signaling: at the crossroads of obesity, diabetes and cancer. Trends Mol Med 2007; 13:252-9.
  34. Choo AY, Blenis J. Not all substrates are treated equally: implications for mTOR, rapamycin-resistance and cancer therapy. Cell Cycle 2009; 8:567-72.
  35. Kim E, Guan KL. RAG GTPases in nutrient-mediated TOR signaling pathway. Cell Cycle 2009; 8:1014-8.
  36. Glazer HP, Osipov RM, Clements RT, Sellke FW, Bianchi C. Hypercholesterolemia is associated with hyperactive cardiac mTORC1 and mTORC2 signaling. Cell Cycle 2009; 8:1738-46.
  37. Kapahi P, Chen D, Rogers AN, Katewa SD, Li PW, Thomas EL, et al. With TOR, less is more: a key role for the conserved nutrient-sensing TOR pathway in aging. Cell Metab 2010; 11:453-65.
  38. Blagosklonny MV, Hall MN. Growth and aging: a com- mon molecular mechanism. Aging 2009; 1:357-62.
  39. Demidenko ZN, Blagosklonny MV. Growth stimula- tion leads to cellular senescence when the cell cycle is blocked. Cell Cycle 2008; 7:3355-61.
  40. Zhuang D, Mannava S, Grachtchouk V, Tang WH, Patil S, Wawrzyniak JA, et al. C-MYC overexpression is required for continuous suppression of oncogene- induced senescence in melanoma cells. Oncogene 2008; 27:6623-34.
  41. Demidenko ZN, Zubova SG, Bukreeva EI, Pospelov VA, Pospelova TV, Blagosklonny MV. Rapamycin decelerates cellular senescence. Cell Cycle 2009; 8:1888-95.
  42. Colman RJ, Anderson RM, Johnson SC, Kastman EK, Kosmatka KJ, Beasley TM, et al. Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 2009; 325:201-4.
  43. Blagosklonny MV. Calorie restriction: Decelerating mTOR-driven aging from cells to organisms (including humans). Cell Cycle 2010; 9:683-8.
  44. Pan Y, Shadel GS. Extension of chronological life span by reduced TOR signaling requires downregulation of Sch9p and involves increased mitochondrial OXPHOS complex density. Aging 2009; 1:131-45.
  45. Blagosklonny MV. Aging and immortality: quasi-pro- grammed senescence and its pharmacologic inhibition. Cell Cycle 2006; 5:2087-102.
  46. Blagosklonny MV. An anti-aging drug today: from senescence-promoting genes to anti-aging pill. Drug Disc Today 2007; 12:218-24.
  47. Blagosklonny MV. Rapamycin and quasi-programmed aging: four years later. Cell Cycle 2010; 9:1859-62.
  48. Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, et al. Rapamycin fed late in life extends lifespan in genetically heterogenous mice. Nature 2009; 460:392-6.
  49. Anisimov VN, Zabezhinski MA, Popovich IG, Piskunova TS, Semenchenko AV, Tyndyk ML, et al. Rapamycin extends maximal lifespan in cancer-prone mice. Am J Pathol 2010; 176:2092-7.
  50. Bjedov I, Toivonen JM, Kerr F, Slack C, Jacobson J, Foley A, et al. Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab 2010; 11:35-46.
  51. Blagosklonny MV. Inhibition of S6K by resveratrol: In search of the purpose. Aging 2009; 1:511-4.
  52. Shaw RJ, Lamia KA, Vasquez D, Koo SH, Bardeesy N, Depinho RA, et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 2005; 310:1642-6. 100. Anisimov VN, Berstein LM, Egormin PA, Piskunova TS, Popovich IG, Zabezhinski MA, et al. Metformin slows down aging and extends life span of female SHR mice. Cell Cycle 2008; 7:2769-73. 101. Onken B, Driscoll M. Metformin induces a dietary restriction-like state and the oxidative stress response to extend C. elegans Healthspan via AMPK, LKB1 and SKN-1. PLoS One 5:8758. 102. Cheang KI, Sharma ST, Nestler JE. Is metformin a pri- mary ovulatory agent in patients with polycystic ovary syndrome? Gynecol Endocrinol 2006; 22:595-604. 103.
  53. Palomba S, Orio FJ, Falbo A, Russo T, Tolino A, Zullo F. Clomiphene citrate versus metformin as first-line approach for the treatment of anovulation in infer- tile patients with polycystic ovary syndrome. J Clin Endocrinol Metab 2007; 92:3498-503. 104. Guarente L, Picard F. Calorie restriction-the SIR2 connection. Cell 2005; 120:473-82. 105. Guarente L, Kenyon C. Genetic pathways that regulate ageing in model organisms. Nature 2000; 408:255-62. 106.
  54. Southgate RJ, Neill B, Prelovsek O, El-Osta A, Kamei Y, Miura S, et al. FOXO1 regulates the expression of 4E-BP1 and inhibits mTOR signaling in mammalian skeletal muscle. J Biol Chem 2007; 282:21176-86. 107. Chen CC, Jeon SM, Bhaskar PT, Nogueira V, Sundararajan D, Tonic I, et al. FoxOs inhibit mTORC1 and activate Akt by inducing the expression of Sestrin3 and Rictor. Dev Cell 2010; 18:592-604. 108. Harvey KF, Mattila J, Sofer A, Bennett FC, Ramsey MR, Ellisen LW, et al. FOXO-regulated transcription restricts overgrowth of Tsc mutant organs. J Cell Biol 2008; 180:691-6.
  55. Kapahi P, Chen D, Rogers AN, Katewa SD, Li PW, Thomas EL, et al. With TOR, less is more: a key role for the conserved nutrient-sensing TOR pathway in aging. Cell Metab 2010; 11:453-65.
  56. Long X, Spycher C, Han ZS, Rose AM, Muller F, Avruch J. TOR deficiency in C. elegans causes devel- opmental arrest and intestinal atrophy by inhibition of mRNA translation. Curr Biol 2002; 12:1448-61.
  57. Ayyadevara S, Alla R, Thaden JJ, Shmookler Reis RJ. Remarkable longevity and stress resistance of nematode PI3K-null mutants. Aging Cell 2008; 7:13-22.
  58. Kapahi P, Zid BM, Harper T, Koslover D, Sapin V, Benzer S. Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr Biol 2004; 14:885-90.
  59. Tatar M, Kopelman A, Epstein D, Tu MP, Yin CM, Garofalo RS. A mutant Drosophila insulin receptor homolog that extends life-span and impairs neuroen- docrine function. Science 2001; 292:107-10.
  60. Tatar M, Bartke A, Antebi A. The endocrine regula- tion of aging by insulin-like signals. Science 2003; 299:1346-51.
  61. Gangloff YG, Mueller M, Dann SG, Svoboda P, Sticker M, Spetz JF, et al. Disruption of the mouse mTOR gene leads to early postimplantation lethality and pro- hibits embryonic stem cell development. Mol Cell Biol 2004; 24:9508-16.
  62. Murakami M, Ichisaka T, Maeda M, Oshiro N, Hara K, Edenhofer F, et al. mTOR is essential for growth and proliferation in early mouse embryos and embryonic stem cells. Mol Cell Biol 2004; 24:6710-8.
  63. Shiota C, Woo JT, Lindner J, Shelton KD, Magnuson MA. Multiallelic disruption of the rictor gene in mice reveals that mTOR complex 2 is essential for fetal growth and viability. Dev Cell 2006; 11:583-9.
  64. Pende M, Um SH, Mieulet V, Sticker M, Goss VL, Mestan J, et al. S6K1(-/-)/S6K2(-/-) mice exhibit peri- natal lethality and rapamycin-sensitive 5'-terminal oli- gopyrimidine mRNA translation and reveal a mitogen- activated protein kinase-dependent S6 kinase pathway. Mol Cell Biol 2004; 24:3112-24.
  65. Apfeld J, Kenyon C. Regulation of lifespan by sen- sory perception in Caenorhabditis elegans. Nature 1999; 402:804-9.
  66. Alcedo J, Kenyon C. Regulation of C. elegans longevity by specific gustatory and olfactory neurons. Neuron 2004; 41:45-55.
  67. Libert S, Zwiener J, Chu X, Vanvoorhies W, Roman G, Pletcher SD. Regulation of Drosophila life span by olfaction and food-derived odors. Science 2007; 315:1133-7.
  68. Smedal B, Brynem M, Kreibich CD, Amdam GV. Brood pheromone suppresses physiology of extreme longevity in honeybees (Apis mellifera). J Exp Biol Dec 2009; 212:3795-801.
  69. Vinogradova IA, Anisimov VN, Bukalev AV, Semenchenko AV, Zabezhinski MA. Circadian disrup- tion induced by light-at-night accelerates aging and promotes tumorigenesis in rats. Aging 2009; 1:855-65.
  70. Osborne TB, Mendel LB, Ferry EL. The effect of retardation of growth upon the breeding period and duration of life of rats. Science 1917; 45:294-5.
  71. Bordone L, Guarente L. Calorie restriction, SIRT1 and metabolism: understanding longevity. Nat Rev Mol Cell Biol 2005; 6:298-305.
  72. Longo VD, Finch CE. Evolutionary medicine: from dwarf model systems to healthy centenarians? Science 2003; 299:1342-6.
  73. Kennedy BK, Steffen KK, Kaeberlein M. Ruminations on dietary restriction and aging. Cell Mol Life Sci 2007; 64:1323-8.
  74. Holloszy JO, Fontana L. Caloric restriction in humans. Exp Gerontol 2007; 42:709-12.
  75. Grandison RC, Piper MD, Partridge L. Amino-acid imbalance explains extension of lifespan by dietary restriction in Drosophila. Nature 2009; 462:1061-4.
  76. Demidenko ZN, Shtutman M, Blagosklonny MV. Pharmacologic inhibition of MEK and PI-3K con- verges on the mTOR/S6 pathway to decelerate cellular senescence. Cell Cycle 2009; 8:1896-900.
  77. Demidenko ZN, Blagosklonny MV. At concentrations that inhibit mTOR, resveratrol suppresses cellular senescence. Cell Cycle 2009; 8:1901-4.
  78. Demidenko ZN, Blagosklonny MV. Quantifying phar- macologic suppression of cellular senescence: preven- tion of cellular hypertrophy versus preservation of proliferative potential. Aging 2009; 1:1008-16.
  79. Pospelova TV, Demidenko ZN, Bukreeva EI, Pospelov VA, Gudkov AV, Blagosklonny MV. Pseudo-DNA damage response in senescent cells. Cell Cycle 2009; 8:4112-8.
  80. Kaeberlein M, Powers R, Wr KKS, Westman EA, Hu D, Dang N, et al. Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 2005; 310:1193-6.
  81. Powers RWr, Kaeberlein M, Caldwell SD, Kennedy BK, Fields S. Extension of chronological life span in yeast by decreased TOR pathway signaling. Genes Dev 2006; 20:174-84.
  82. Burtner CR, Murakami CJ, Kennedy BK, Kaeberlein M. A molecular mechanism of chronological aging in yeast. Cell Cycle 2009; 8:1256-70.
  83. Pan Y, Shadel GS. Extension of chronological life span by reduced TOR signaling requires downregulation of Sch9p and involves increased mitochondrial OXPHOS complex density. Aging 2009; 1:131-5.
  84. Kaeberlein M. Lessons on longevity from budding yeast. Nature 2010; 464:513-9.
  85. Bartke A, Brown-Borg H. Life extension in the dwarf mouse. Curr Top Dev Biol 2004; 63:189-225.
  86. Bartke A. Long-lived Klotho mice: new insights into the roles of IGF-1 and insulin in aging. Trends Endocrinol Metab 2006; 17:33-5.
  87. Inuzuka Y, Okuda J, Kawashima T, Kato T, Niizuma S, Tamaki Y, et al. Suppression of phosphoinositide 3-kinase prevents cardiac aging in mice. Circulation 2009; 120:1695-703.
  88. Um SH, Frigerio F, Watanabe M, Picard F, Joaquin M, Sticker M, et al. Absence of S6K1 protects against age-and diet-induced obesity while enhancing insulin sensitivity. Nature 2004; 431:200-5.
  89. Selman C, Tullet JM, Wieser D, Irvine E, Lingard SJ, Choudhury AI, et al. Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science 2009; 326:140-4.
  90. Dorman JB, Albinder B, Shroyer T, Kenyon C. The age-1 and daf-2 genes function in a common path- way to control the lifespan of Caenorhabditis elegans. Genetics 1995; 141:1399-406.
  91. Kimura KD, Tissenbaum HA, Liu Y, Ruvkun G. daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 1997; 277:942-6.
  92. Morris JZ, Tissenbaum HA, Ruvkun G. A phospha- tidylinositol-3-OH kinase family member regulat- ing longevity and diapause in Caenorhabditis elegans. Nature 1996; 382:536-9.
  93. Vellai T, Takacs-Vellai K, Zhang Y, Kovacs AL, Orosz L, Muller F. Genetics: influence of TOR kinase on lifespan in C. elegans. Nature 2003; 426:620.
  94. Jia K, Chen D, Riddle DL. The TOR pathway inter- acts with the insulin signaling pathway to regulate C. elegans larval development, metabolism and life span. Development 2004; 131:3897-906.
  95. Apfeld J, O'Connor G, McDonagh T, DiStefano PS, Curtis R. The AMP-activated protein kinase AAK-2 links energy levels and insulin-like signals to lifespan in C. elegans. Genes Dev 2004; 18:3004-9.
  96. Kenyon CJ. The genetics of ageing. Nature 2010; 464:504-12. 121. Tsang CK, Qi H, Liu LF, Zheng XFS. Targeting mam- malian target of rapamycin (mTOR) for health and diseases. Drug Disc Today 2007; 12:112-24. 122. Blagosklonny MV. Why men age faster but reproduce longer than women: mTOR and evolutionary perspec- tives. Aging 2010; 2:265-73. 123. Roa J, Garcia-Galiano D, Varela L, Sanchez-Garrido MA, Pineda R, Castellano JM, et al. The mamma- lian target of rapamycin as novel central regulator of puberty onset via modulation of hypothalamic Kiss1 system. Endocrinology 2009; 150:5016-26. 124. Roa J, Garcia-Galiano D, Castellano JM, Gaytan F, Pinilla L, Tena-Sempere M. Metabolic control of puberty onset: New players, new mechanisms. Mol Cell Endocrinol 2010; 324:87-94. 125. Roa J, Tena-Sempere M. Energy balance and puberty onset: emerging role of central mTOR signaling. Trends Endocrinol Metab Jun 14. 126. Blagosklonny MV. Aging: ROS or TOR. Cell Cycle 2008; 7:3344-54. 115. Medvedik O, Lamming DW, Kim KD, Sinclair DA. MSN2 and MSN4 Link Calorie Restriction and TOR to Sirtuin-Mediated Lifespan Extension in Saccharomyces cerevisiae. PLoS Biol 2007; 5:261. 116. Feng Z, Zhang H, Levine AJ, Jin S. The coordinate regulation of the p53 and mTOR pathways in cells. Proc Natl Acad Sci USA 2005; 102:8204-9. 117. Budanov AV, Karin M. p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling. Cell 2008; 134:451-60. 118. Matthew EM, Hart LS, Astrinidis A, Navaraj A, Dolloff NG, Dicker DT, et al. The p53 target Plk2 interacts with TSC proteins impacting mTOR signal- ing, tumor growth and chemosensitivity under hypoxic conditions. Cell Cycle 2009; 8:4168-75. 119.
  97. Stambolic V, MacPherson D, Sas D, Lin Y, Snow B, Jang Y, et al. Regulation of PTEN transcription by p53. Mol Cell 2001; 8:317-25. 120. Lee JH, Bodmer R, Bier E, Karin M. Sestrins at the crossroad between stress and aging. Aging 2010; 2:369-74. 109. Wu AL, Kim JH, Zhang C, Unterman TG, Chen J. Forkhead box protein O1 negatively regulates skeletal myocyte differentiation through degradation of mam- malian target of rapamycin pathway components. Endocrinology 2008; 149:1407-14. 110. Khatri S, Yepiskoposyan H, Gallo CA, Tandon P, Plas DR. FOXO3a regulates glycolysis via transcriptional control of tumor suppressor TSC1. J Biol Chem 2010; 285:15960-5. 111. Dorman JB, Albinder B, Shroyer T, Kenyon C. The age-1 and daf-2 genes function in a common path- way to control the lifespan of Caenorhabditis elegans. Genetics 1995; 141:1399-406. 112. Mihaylova VT, Borland CZ, Manjarrez L, Stern MJ, Sun H. The PTEN tumor suppressor homolog in Caenorhabditis elegans regulates longevity and dauer formation in an insulin receptor-like signaling pathway. Proc Natl Acad Sci USA 1999; 96:7427-32. 113. Masse I, Molin L, Billaud M, Solari F. Lifespan and dauer regulation by tissue-specific activities of Caenorhabditis elegans DAF-18. Dev Biol 2005; 286:91-101. 114. Solari F, Bourbon-Piffaut A, Masse I, Payrastre B, Chan AM, Billaud M. The human tumour suppres- sor PTEN regulates longevity and dauer formation in Caenorhabditis elegans. Oncogene 2005; 24:20-7.

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Metadata

Authors
Blagosklonny, M. V.
Affiliations
Roswell Park Comprehensive Cancer Center (US)
Corresponding author
Blagosklonny, Mikhail V
Venue
Cell Cycle
Publisher
Informa UK Limited
Published
2010-08-15
Volume
9
Issue
16
Pages
3171-3176
ISSN
  • 1538-4101 (ISSN-L)
  • 1551-4005
DOI
10.4161/cc.9.16.13120
OpenAlex
W2080700230
Semantic Scholar
bfd4a50ff5fe98fd62b93a28b2f45570df2c915e
Cited by
160
References
0
Citations by year
2026: 3 · 2025: 1 · 2024: 2 · 2023: 2 · 2022: 7 · 2021: 12 · 2019: 9 · 2018: 7 · 2017: 11 · 2016: 9 · 2015: 18 · 2014: 12 · 2013: 15 · 2012: 29
FWCI
1.97
Type
journal article
Language
en
Open access
Locations
  • Cell Cycle (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
Keywords
antagonistic pleiotropy, aging, TOR signaling, p53, age-related diseases, developmental programs, embryonic lethality, lifespan
MeSH terms
Aging, Antibiotics, Antineoplastic, Signal Transduction, Tumor Suppressor Protein p53, Sirolimus, Caloric Restriction, TOR Serine-Threonine Kinases, Genetic Pleiotropy

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