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Cited by 466Telomeres, Telomerase, and SenescenceGenetics, Aging, and Longevity in Model OrganismsSirtuins and Resveratrol in Medicine

Markers of cellular senescence. Telomere shortening as a marker of cellular senescence

Open access
Bernadotte, Alexandra, Mikhelson, Victor M., Spivak, Irina M.·2016·Aging
DOI 10.18632/aging.100871PMC PMC4761709
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Abstract

The cellular senescence definition comes to the fact of cells irreversible proliferation disability. Besides the cell cycle arrest, senescent cells go through some morphological, biochemical, and functional changes which are the signs of cellular senescence. The senescent cells (including replicative senescence and stress-induced premature senescence) of all the tissues look alike. They are metabolically active and possess the set of characteristics in vitro and in vivo, which are known as biomarkers of aging and cellular senescence. Among biomarkers of cellular senescence telomere shortening is a rather elegant frequently used biomarker. Validity of telomere shortening as a marker for cellular senescence is based on theoretical and experimental data.

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Written from the paper’s full text.

TL;DR

This review argues that telomere shortening is a valid, elegant, and frequently used biomarker of cellular senescence, supported by telomere theory and experimental links to aging, age-related diseases, progerias, and other senescence markers. It concludes that telomere shortening is the senescence biomarker of choice, but recommends assessing the amount of critically shortened telomeres in tissues rather than average telomere length.

Key findings

  • Telomere shortening is proposed as the cellular senescence biomarker of choice because it reflects replicative cellular and tissue potential and is supported by theoretical and experimental data.
  • Structurally, vertebrate telomeres consist of TTAGGG repeats; telomere length is species-specific and varies between 4000 and 15000 nucleotides, with human 3′ single-strand tails of approximately 100–280 nucleotides. Critical shortening is reported as 12.8 repeats, and the shortest telomere among 256 telomeres (4 per chromosome) is said to turn a cell senescent, not average telomere length.
  • Age-related and disease data include hematopoietic stem cells replicating approximately 42 times per year in newborns with 1.2 kb telomere loss until age 3, then 0.7 times per year and 0.5 kb per year until age 13; inverse correlations are reported with cardiovascular disease, renal failure, various cancers, Alzheimer’s disease, and Parkinson’s disease.
  • Telomere shortening correlates or overlaps with other senescence markers including SA-β-galactosidase, SAHF, γ-H2AX, epigenetic modifications, 53BP1, and PML-NBs; γ-H2AX is described as not suitable as a stand-alone marker because it lacks specificity and can be reversible.

Methods

  • Narrative review synthesizing theoretical and experimental literature on telomere biology, aging theories, cellular senescence biomarkers, age-related diseases, and short telomere syndromes; no new primary data are presented.
  • The main analysis is conceptual and comparative: it evaluates telomere shortening against criteria for a good senescence marker, contrasts telomere theory with oxidative stress theory, and cites specific studies and numerical examples as evidence.
  • No systematic search strategy, meta-analysis, or primary experimental protocol is described.

Limitations

  • Stated: all markers of cellular senescence, including telomere shortening, have limitations; telomere length varies between tissues and among individuals of the same age, and average telomere length alone may not be informative. The paper recommends considering the amount of shortened telomeres in tissues instead of average telomere length.
  • Stated: literature on telomere length and mortality or life expectancy is inconsistent, with some studies finding no significant correlation between average telomere length and mortality risk in the elderly.
  • Evident: as a narrative review, the paper does not use a systematic review protocol, quantitative synthesis, or independent primary validation, so its conclusions rely on selected cited studies.

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

Integrity signals

Registry

Crossref · 10.18632/aging.100871

Cites

103 of 103 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 145 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Telomere theory depends on the principle that aging is programmed.

    “Telomere theory depends on three specific principles, the three pillars the Telomere theory stands on: first, that aging is programmed; the second being that irreversible cell cycle arrest happens in response to the telomere shortening; and lastly, that the total number of cell divisions in the absence of telomerase activity cannot exceed a particular limit termed the Hayflick limit [6, 7, 10, 11]”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [6] Olovnikov, 1973, A theory of marginotomy. The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon, J Theor Biol source

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    • cites [7] Blackburn, 1987, The telomere terminal transferase of tetrahymena is a ribonucleoprotein enzyme with two kinds of primer specificity, Cell source

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    • cites [10] Olovnikov, 1971, Principle of marginotomy in template synthesis of polynucleotides, Dokl Akad Nauk SSSR

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    • cites [11] Moorhead, 1961, The serial cultivation of human diploid cell strains, Exp Cell Res

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  • Premisecitation

    Telomeres shorten with every cell division due to the mechanism of replication.

    “Due to the mechanism of replication, telomeres shorten with every cell division, ticking as a cellular “molecular clock” [2-8].”
    Quote in the paperSubstantial claim0 of 7 sources checked
    • cites [2] Moyzis, 1989, Conservation of the human telomere sequence (TTAGGG). among vertebrates, Proc Natl Acad Sci U S A

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    • cites [3] Varmus, 1990, Structure and Variability of Human Chromosome Ends, Mol Cell Biol

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    • cites [4] Shay, 1997, Normal human chromosomes have long G-rich telomeric overhangs at one end, Genes Dev

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    • cites [5] de Lange, 2005, POT1 protects telomeres from a transient DNA damage response and determines how human chromosomes end, EMBO J source

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    • cites [6] Olovnikov, 1973, A theory of marginotomy. The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon, J Theor Biol source

      Not checked in the free run.

    • cites [7] Blackburn, 1987, The telomere terminal transferase of tetrahymena is a ribonucleoprotein enzyme with two kinds of primer specificity, Cell source

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    • cites [8] Blackburn, 2004, Telomeres and telomerase, Philos Trans R Soc B Biol Sci source

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  • Premisecitation

    Telomere theory depends on the principle that irreversible cell cycle arrest happens in response to telomere shortening.

    “Telomere theory depends on three specific principles, the three pillars the Telomere theory stands on: first, that aging is programmed; the second being that irreversible cell cycle arrest happens in response to the telomere shortening; and lastly, that the total number of cell divisions in the absence of telomerase activity cannot exceed a particular limit termed the Hayflick limit [6, 7, 10, 11]”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [6] Olovnikov, 1973, A theory of marginotomy. The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon, J Theor Biol source

      Not checked in the free run.

    • cites [7] Blackburn, 1987, The telomere terminal transferase of tetrahymena is a ribonucleoprotein enzyme with two kinds of primer specificity, Cell source

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    • cites [10] Olovnikov, 1971, Principle of marginotomy in template synthesis of polynucleotides, Dokl Akad Nauk SSSR

      Not checked in the free run.

    • cites [11] Moorhead, 1961, The serial cultivation of human diploid cell strains, Exp Cell Res

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  • Premisecitation

    The cellular response to telomere shortening is similar to the common cellular response to DNA double-strand breaks; both go through ATR-dependent H2AX phosphorylation.

    “The cellular response mechanism to telomere shortening is similar to that common cellular response to DNA double- strand breaks; both mechanisms go through the ATR-dependent H2AX phosphorylation [28].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Herrmann, 2006, Senescence of Human Fibroblasts after Psoralen Photoactivation Is Mediated by ATR Kinase and Persistent DNA Damage Foci at Telomeres, Mol Biol Cell

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  • Premisecitation

    A strong correlation was found between mean telomere length and paternal lifespan if inherited by female offspring in humans.

    “Nevertheless, a strong correlation was found between mean telomere length in early life and lifespan [16], and even between mean telomere length and paternal lifespan if inherited by female offspring in humans [39].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Garant, 2007, Telomere length is paternally inherited and is associated with parental lifespan, Proc Natl Acad Sci U S A source

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  • Classified as probably not a substantial claim. 8
  • May combine two claims. 33

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

    Premisecitation

    Cellular senescence is an irreversible proliferation disability resistant to growth or proliferation factors.

    “Cellular senescence describes how cells can induce an irreversible proliferation disability, which is resistant to growth or proliferation factors [1].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Smith, 1991, Senescent cells fail to express cdc2, cycA, and cycB in response to mitogen stimulation, Proc Natl Acad Sci U S A

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  • May combine two claims.

    Premisecitation

    Telomere theory is based on the telomere shortening mechanism and indicates telomeres as a promising marker of cellular senescence.

    “Telomere theory, a major aging theory, is based on this telomeres shortening mechanism [6, 7, 9] and indicates telomeres as a promising marker of cellular senescence.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [6] Olovnikov, 1973, A theory of marginotomy. The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon, J Theor Biol source

      Not checked in the free run.

    • cites [7] Blackburn, 1987, The telomere terminal transferase of tetrahymena is a ribonucleoprotein enzyme with two kinds of primer specificity, Cell source

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    • cites [9] Olovnikov, 1996, Telomeres, telomerase, and aging: origin of the theory, Exp Gerontol source

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    • Rests on an assumption: Telomere theory considers telomere shortening to be the main trigger of aging.

  • May combine two claims.

    Premisecitation

    When a telomere reaches the critical point of shortening, it leads to cell cycle arrest, cellular senescence, and apoptosis.

    “However, when telomere reached critical point of shortening it leads to cell cycle arrest, cellular senescence, and apoptosis – conditions, which can be considered as protection from to telomere dysfunction consequences [23, 24].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [23] Wright, 2004, Does a Sentinel or a Subset of Short Telomeres Determine Replicative Senescence⍰?, Mol Biol Cell

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    • cites [24] Szostak, 1989, A mutant with a defect in telomere elongation leads to senescence in yeast, Cell

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  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Interpretationreasoning

    This unites the majority of aging theories with mutual pathogenesis.

    “This unites the majority of aging theories with mutual pathogenesis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Telomere length reflects cells' proliferative ability, which changes over time.

    “Telomere length reflects cells' proliferative ability, which changes over time. It was shown that telomeres in highly proliferative somatic tissues, such as: human fibroblasts, leukocytes, and adipocytes were shorter than in cells of non- or low rate proliferative tissues [29].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [29] Kimura, 2013, Telomeres shorten at equivalent rates in somatic tissues of adults, Nat Commun source

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

    Interpretationreasoning

    After a sufficient amount of cells undergoes senescent conditions, tissues cannot function at the same level and the vicious cycle of aging begins.

    “After a sufficient amount of cells undergoes senescent conditions, tissues cannot function at the same level and the vicious cycle of aging begins.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Hematopoietic stem cells replicate approximately 42 times per year in newborns with a telomere loss of 1.2 kb until reaching age three and 0.7 times and 0.5 kb per year respectively until age 13.

    “Indeed, hematopoietic stem cells were shown to replicate approximately 42 times per year in newborns with a telomere loss of 1.2 kb until reaching the age of three and 0.7 times and 0.5 kb per year respectively until age 13 [30].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Aviv, 2009, Leukocyte telomere dynamics and human hematopoietic stem cell kinetics during somatic growth, Exp Hematol source

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

    Premisecitation

    The telomere single strand forms a T-loop, accompanied by proteins, which caps DNA and prevents fusion or damage of chromosome ends.

    “This single strand forms a telomere hairpin loop structure, termed a T-loop, and is often accompanied by numerous proteins, which together works to cap DNA and aid in preventing fusion or damage of the chromosome ends [18-20].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [18] Moyzis, 1999, Reduced telomere DNA content is correlated with genomic instability and metastasis in invasive human breast carcinoma, Breast Cancer Res Treat

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    • cites [19] Moss, 1999, Mammalian Telomeres End in a Large Duplex Loop, Cell

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    • cites [20] Kranaster, 2011, Rudimentary G-quadruplex-based telomere capping in Saccharomyces cerevisiae, Nat Struct Mol Biol source

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  • May combine two claims.

    Premisecitation

    Many studies have shown a dependence of telomere length on age: average telomere lengths are shorter in senescent cells than in cells of younger age groups and are also shorter for male than for female.

    “Conversely, many studies have shown a dependence of telomere length on age: average telomere lengths are shorter in senescent cells than in cells of younger age groups and are also shorter for male than for female [12-17].”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [12] Greider, 1990, Telomeres shorten during ageing of human fibroblasts, Nature

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    • cites [13] Futcher, 1992, Telomere length predicts replicative capacity of human fibroblasts, Proc Natl Acad Sci USA

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    • cites [14] Huso, 2005, Short telomeres, even in the presence of telomerase, limit tissue renewal capacity, Cell source

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    • cites [15] Massemin, 2013, Telomere length correlations among somatic tissues in adult zebra finches, PLoS One source

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    • cites [16] Monaghan, 2012, Telomere length in early life predicts lifespan, Proc Natl Acad Sci U S A source

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    • cites [17] Reddel, 2012, Five dysfunctional telomeres predict onset of senescence in human cells, EMBO Rep source

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  • May combine two claims.

    Interpretationreasoning

    Cell cycle arrest is a universal process and starts each time there is a risk of malignization or comes to the final point of cell development - aging.

    “Thus, the cell cycle arrest is a universal process and starts each time there is a risk of malignization or comes to the final point of cell development – aging.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The single strand tail length at the 3′ end of telomeres varies between approximately 100 and 280 nucleotides in humans.

    “The single strand tail length varies between approximately 100 and 280 nucleotides in humans [12-17].”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [12] Greider, 1990, Telomeres shorten during ageing of human fibroblasts, Nature

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    • cites [13] Futcher, 1992, Telomere length predicts replicative capacity of human fibroblasts, Proc Natl Acad Sci USA

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    • cites [14] Huso, 2005, Short telomeres, even in the presence of telomerase, limit tissue renewal capacity, Cell source

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    • cites [15] Massemin, 2013, Telomere length correlations among somatic tissues in adult zebra finches, PLoS One source

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    • cites [16] Monaghan, 2012, Telomere length in early life predicts lifespan, Proc Natl Acad Sci U S A source

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    • cites [17] Reddel, 2012, Five dysfunctional telomeres predict onset of senescence in human cells, EMBO Rep source

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  • May combine two claims.

    Premisecitation

    Critical telomere shortening (12.8 repeats) or loss of telomere-capping proteins results in telomere dysfunction with consequent chromosome fusion and genome instability.

    “Critical telomere shortening (12.8 repeats of repetitive clusters) either as a loss of telomere-capping proteins results to telomere dysfunction with consequent chromosomes fusion and genome instability [22].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] Man, 2007, The nature of telomere fusion and a definition of the critical telomere length in human cells, Genes Dev source

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  • May combine two claims.

    Interpretationreasoning

    It is reasonable to consider the amount of cells with crucially shortened telomeres in certain tissues or organs as a whole system instead of merely considering average telomere length overall; cells in the tissue do not exhaust their proliferative potential in a simultaneous manner.

    “It is reasonable to consider the amount of cells with crucially shortened telomeres in certain tissues or organs as a whole system instead of merely considering average telomere length overall; cells in the tissue do not exhaust their proliferative potential in a simultaneous manner.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Telomere length is an individual characteristic.

    “It has been suggested that telomere length is an individual characteristic [34].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Oshimura, 2002, Telomere lengths are characteristic in each human individual, Exp Gerontol

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    Premisecitation

    The telomere capping structure can form a G-quadruplex structure from two or four parallel or antiparallel single strands.

    “Moreover, this capping structure can form a G-quadruplex structure from two or four parallel or antiparallel single strands [21].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Caruana, 2014, The Presence of Telomere Fusion in Sporadic Colon Cancer Independently of Disease Stage, TP53/KRAS Mutation Status, Mean Telomere Length, and Telomerase Activity, Neoplasia source

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  • May combine two claims.

    Premisecitation

    Telomere shortening correlates with senescence-associated heterochromatin foci (SAHF), which are facultative heterochromatin domains associated with irreversible cell cycle arrest and accumulate in senescent cells.

    “Telomere shortening correlates with senescence-associated heterochromatin foci (SAHF), which are facultative heterochromatin domains associated with irreversible cell cycle arrest and accumulate in senescent cells [74, 75].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [74] Spector, 2003, Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence, Cell

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    • cites [75] Hearn, 2006, A novel role for high-mobility group a proteins in cellular senescence and heterochromatin formation, Cell source

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    Premisecitation

    The number of β-galactosidase stained cells was found as a function of population doubling level (PDL) on human retinal pigment epithelial cells; telomere length shrank from 10 kb to 4 kb between 12 PDL and 57 PDL.

    “The number of β-galactosidase stained cells was found as a function of population doubling level (PDL) on human retinal pigment epithelial cells; while simultaneously telomere length, which was observed in a stage of 12 PDL and in old culture of 57 PDL, shrank from 10 kb to 4kb respectively [73].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [73] Hjelmeland, 1999, Beta-Galactosidase Histochemistry and Telomere Loss in Senescent Retinal Pigment Epithelial Cells, Invest Ophthalmol Vis Sci

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  • May combine two claims.

    Premisecitation

    Studies of cells with defective lysosomal β-galactosidase have shown that β-galactosidase does not trigger cellular senescence and only accompanies senescent alterations.

    “Studies of cells with defective lysosomal β-galactosidase have shown that β–galactosidase does not trigger cellular senescence [71, 72] and only accompanies senescent alterations.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [71] Goodwin, 2006, Senescence-associated beta-galactosidase is lysosomal beta-galactosidase, Aging Cell source

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    • cites [72] Cristofalo, 2000, Is beta-galactosidase staining a marker of senescence in vitro and in vivo?, Exp Cell Res

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    Premisecitation

    Both type 2 diabetes and cancer were significantly more likely to occur in patients with shorter initial telomere lengths.

    “Both diseases were shown to be significantly more likely to occur in patients with shorter initial telomere lengths.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [55] Mayr, 2014, Leucocyte telomere length and risk of type 2 diabetes mellitus: new prospective cohort study and literature-based meta-analysis, PLoS One source

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    • cites [54] Su, 2011, Leukocyte Telomere Length in Major Depression: Correlations with Chronicity, Inflammation and Oxidative Stress - Preliminary Findings, PLoS One source

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    • cites [56] Kiechl, 2011, Fifteen-Year Follow-up of Association Between Telomere Length and Incident Cancer and Cancer Mortality, JAMA

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    Premisecitation

    Telomeres and telomere-associated proteins play an important role in the aging process and accelerated telomere erosion is associated with metabolic and inflammatory diseases associated with aging.

    “Studies investigating telomere biology have demonstrated that telomeres and telomere-associated proteins play an important role in the aging process and that accelerated telomere erosion is associated with metabolic and inflammatory diseases associated with aging [42]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Wang, 2013, Telomere shortening in human diseases, FEBS J source

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  • May combine two claims.

    Premisecitation

    SAHF is not a universal marker of aging cells, but it is a tissue and species dependent senescent marker.

    “SAHF is not a universal marker of aging cells, but it is tissue and species dependent senescent marker [74, 78].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [74] Spector, 2003, Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence, Cell

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    • cites [78] Adams, 2010, Senescent mouse cells fail to overtly regulate the HIRA histone chaperone and do not form robust Senescence Associated Heterochromatin Foci, Cell Div source

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  • May combine two claims.

    Interpretationcitation

    This shortening is most likely associated not only with accelerated replicative aging, but also with the failure of telomere repair processes.

    “It is most likely that this shortening is associated not only with accelerated replicative aging, but also with the failure of telomere repair processes [58].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58] Peters, 2007, Mitochondrial dysfunction accounts for the stochastic heterogeneity in telomere-dependent senescence, PLoS Biol source

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  • May combine two claims.

    Premisecitation

    An inverse correlation with the length of telomeres was shown for the development of cardiovascular disease, renal failure, various cancers, Alzheimer's disease, and Parkinson's disease.

    “Additionally, an inverse correlation with the length of telomeres was shown for the development of cardiovascular disease [44-47], renal failure [48, 49], various cancers [50, 51], Alzheimer's disease [52], and Parkinson's disease [53].”
    Quote in the paperSubstantial claim0 of 8 sources checked
    • cites [44] Herbert, 2006, Insulin resistance, oxidative stress, hypertension, and leukocyte telomere length in men from the Framingham Heart Study, Aging Cell source

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    • cites [45] Andrés, 2005, Aging, telomeres, and atherosclerosis, Cardiovasc Res source

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    • cites [46] Adler, 2006, Cell aging in relation to stress arousal and cardiovascular disease risk factors, Psychoneuroendocrinology source

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    • cites [47] Jenny, 2011, Leukocyte telomere length and mortality in the Cardiovascular Health Study, J Gerontol A Biol Sci Med Sci source

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    • cites [48] Rodríguez, 2005, Stress-induced premature senescence in mononuclear cells from patients on long-term hemodialysis, Am J Kidney Dis source

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    • cites [49] von Zglinicki, 2006, Telomere shortening and haemodialysis, Blood Purif source

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    • cites [50] Albin, 2005, Constitutional short telomeres are strong genetic susceptibility markers for bladder cancer, Carcinogenesis source

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    • cites [51] Rangel, 2006, Genes and pathways downstream of telomerase in melanoma metastasis, Proc Natl Acad Sci U S A source

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  • May combine two claims.

    Interpretationcitation

    Telomere length may be an effective marker of cellular pathology in neurological diseases; specifically, it has been demonstrated in dementia, Huntington's disease, and ataxia telangiectasia.

    “As telo-mere shortening is related to premature cellular senescence, telomere length may be an effective marker of cellular pathology in neurological diseases; specifically, it has been demonstrated in dementia, Huntington's disease, and ataxia telangiectasia.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [43] Varghese, 2015, Reduced telomere length in neurodegenerative disorders may suggest shared biology, J Neuropsychiatry Clin Neurosci source

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  • May combine two claims.

    Premisecitation

    Formation of SAHF may be spontaneously stochastic and programmed; it can be induced in senescent cells by oncogenes, toxic agents, or telomere shortening.

    “Formation of SAHF may be spontaneously stochastic and program-med; it can be induced in senescent cells by oncogenes, toxic agents, or telomere shortening [74, 76, 79-81].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [74] Spector, 2003, Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence, Cell

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    • cites [76] Daganzo, 2005, Formation of MacroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA, Dev Cell source

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    • cites [79] Bartek, 2011, Senescence-associated heterochromatin foci are dispensable for cellular senescence, occur in a cell type- and insult-dependent manner and follow expression of p16(ink4a), Cell Cycle

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    • cites [80] Adams, 2007, Molecular Dissection of Formation of Senescence-Associated Heterochromatin Foci, Mol Cell Biol source

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    • cites [81] Gargiulo, 2011, Interplay between oncogene-induced DNA damage response and heterochromatin in senescence and cancer, Nat Cell Biol source

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  • May combine two claims.

    Interpretationreasoning

    Telomere shortening observed in these syndromes is not only a symptom of the disease, but also the cause.

    “Furthermore, telomere shortening observed in these syndromes is not only a symptom of the disease, but also the cause.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    These syndromes are all characterized by dramatically shortened telomeres as well as premature replicative senescence with a decreased Hayflick limit in cell cultures of patients and aging phenotypes, which develops much earlier in such patients than in healthy individuals.

    “These syndromes are all characterized by dramatically shortened telomeres as well as premature replicative senescence with a decreased Hayflick limit in cell cultures of patients and aging phenotypes, which develops much earlier in such patients than in the healthy individuals [60-62].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [60] Collins, 1999, A telomerase component is defective in the human disease dyskeratosis congenita, Nature

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    • cites [61] Mason, 1998, X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions, Nat Genet

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    • cites [62] Faragher, 2000, Telomerase prevents the accelerated cell ageing of Werner syndrome fibroblasts, Nat Genet

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  • May combine two claims.

    Interpretationreasoning

    Telomere shortening meets the requirements of the best marker and shares similar trends with a majority of various other senescence-associated cellular markers.

    “Telomere shortening meets these requirements and shares similar trends with a majority of various other senescence-associated cellular markers.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The best marker should address both in vivo and in vitro conditions, apply to various tissues and species, and show consistency and overlapping with other reliable markers.

  • May combine two claims.

    Premisecitation

    β-galactosidase activity in normal young cells can be detected at pH 4; activity in senescent cells is observed at pH 6 and is termed senescence-associated β-galactosidase (SA-βgal).

    “Enzyme activity of β-galactosidase in normal (young) cells can be detected using 5-bromo-4-chloro-3-indolyl β-D-galacto-pyranoside (X-Gal) at pH 4; activity of the enzyme (or its isoform) in senescent cells, however, is observed at pH 6 and is termed senescence-associated β-galactosidase (SA-βgal) [64, 67, 68].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [64] Roskelley, 1995, A biomarker that identifies senescent human cells in culture and in aging skin in vivo, Proc Natl Acad Sci U S A

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    • cites [67] Erusalimsky, 2000, Senescence-associated β-galactosidase reflects an increase in lysosomal mass during replicative ageing of human endothelial cells, J Cell Sci

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    • cites [68] Senapati, 2014, X-gal staining of canine skin tissues: A technique with multiple possible applications, J Nat Sci Biol Med source

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  • May combine two claims.

    Premisecitation

    All previously mentioned syndromes are characterized by an age-progressive persistent decline in organ and tissue function, reproductive function, increased mortality risk, and predisposition to malignancies - all of which are phenotypic symptoms of human aging.

    “Indeed, all previously mentioned syndromes are characterized by an age-progressive persistent decline in organ and tissue function, reproductive function, increased mortality risk, and predisposition to malignancies – all of which are phenotypic symptoms of human aging [63].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [63] Reddel, 2015, The wide-ranging clinical implications of the Short Telomere Syndromes, Intern Med J source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    γ-H2AX foci reflect not only age-dependent irreversible DSBs (including telomere shortening) but also temporal accumulation of DSBs, which may be a result of massive ionizing radiation.

    “Thus, γ-H2AX foci reflect – not only age-dependent irreversible DSBs (including telomere shortening) – but also temporal accumulation of DSBs, which may be a result of massive ionizing radiation (1 Gy of ionizing radiation, about 2 × 106 bp of DDBs, triggers phosphorylation of about 1% of the H2AX) [90].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [90] Bonner, 1998, DNA Double-stranded Breaks Induce Histone H2AX Phosphorylation on Serine 139, J Biol Chem source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Formation of telomere dysfunction-induced foci accompanied by γ-H2AX is reversible and the number of telomere dysfunction-induced foci can be reduced during the early G1 phase of the cell cycle.

    “Indeed, it was reported that the formation of telomere dysfunction-induced foci accompanied by γ-H2AX is reversible and the number of telomere dysfunction-induced foci can be reduced during the early G1 phase of the cell cycle [17].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Reddel, 2012, Five dysfunctional telomeres predict onset of senescence in human cells, EMBO Rep source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Methylation of DNA and histones is a marker of cellular senescence and contributes to gene silencing theory.

    “Methylation of DNA and histones is a marker of cellular senescence and contributes to another major theory of aging: gene silencing theory [92].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [92] Burzynski, 2003, Gene silencing - a new theory of aging, Med Hypotheses source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    γ-H2AX can accompany telomere shortening but should not be considered as a stand-alone marker of cellular senescence.

    “This marker can be accompany telomere shortening but should not be considered as a stand-alone marker of cellular senescence.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Expression of p53-binding protein 1 (53BP1) is a traditional marker of DNA repair processes.

    “Another traditional marker of the DNA repair processes is expression of p53-binding protein 1 (53BP1) [98].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [98] Stern, 2014, NFBD1/MDC1, 53BP1 and BRCA1 have both redundant and unique roles in the ATM pathway, Cell Cycle source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The appearance of 53BP1 in the presence of telomere shortening is another reliable marker of senescent cells, which again vindicates validity of telomere shortening as a marker for cellular senescence.

    “The appearance of 53BP1 in the presence of telomere shortening is another reliable marker of senescent cells, which again vindicates validity of telomere shortening as a marker for cellular senescence.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    γ-H2AX can be misleading in cases where there is high risk of ionizing radiation and some cases may show discordance with other senescent markers.

    “Hence, γ-H2AX can be misleading in cases where there is high risk of ionizing radiation and some cases may show discordance with other senescent markers.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Histone γ-H2AX is the most sensitive marker of double-stranded DNA breaks (DSBs) and telomere shortening.

    “Histone γ-H2AX is the most sensitive marker of double-stranded DNA breaks (DSBs) and telomere shortening [28, 82].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [28] Herrmann, 2006, Senescence of Human Fibroblasts after Psoralen Photoactivation Is Mediated by ATR Kinase and Persistent DNA Damage Foci at Telomeres, Mol Biol Cell

      Not checked in the free run.

    • cites [82] Barrett, 2004, Senescing human cells and ageing mice accumulate DNA lesions with unrepairable double-strand breaks, Nat Cell Biol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Experimental results have indicated that γ-H2AX foci colocalize with DSB repair factors (such as Rad51, BRCA1, Mre11, Rad50, and Nbs1) and participate in the repair of DSBs.

    “Experimental results have indicated that γ-H2AX foci colocalize with DSB repair factors (such as Rad51, BRCA1, Mre11, Rad50, and Nbs1) [86, 91] and participate the repair of DSBs [85, 89, 90].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [86] Bonner, 2000, A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage, Curr Biol source

      Not checked in the free run.

    • cites [91] Sedelnikova, 2003, Phosphorylation of histone H2AX and activation of Mre11, Rad50, and Nbs1 in response to replication-dependent DNA double-strand breaks induced by mammalian DNA topoisomerase I cleavage complexes, J Biol Chem source

      Not checked in the free run.

    • cites [85] Geard, 2004, Replication protein A and gamma-H2AX foci assembly is triggered by cellular response to DNA double-strand breaks, Exp Cell Res

      Not checked in the free run.

    • cites [89] Goodarzi, 2010, GammaH2AX foci analysis for monitoring DNA double-strand break repair: strengths, limitations and optimization, Cell Cycle source

      Not checked in the free run.

    • cites [90] Bonner, 1998, DNA Double-stranded Breaks Induce Histone H2AX Phosphorylation on Serine 139, J Biol Chem source

      Not checked in the free run.

39 of 39

  • The paper relies on this without support.

    Senescent cells undergo morphological, biochemical, and functional changes in addition to cell cycle arrest, and these changes are signs of cellular senescence.

    “Aside from cell cycle arrest, senescent cells undergo morphological, biochemical, and functional changes, which are signs of cellular senescence.”

  • The paper relies on this without support.

    Senescent cells of all tissue types, including those undergoing replicative and stress-induced premature senescence, look alike and show similar characteristics.

    “Senescent cells of all tissue types (including those undergoing replicative and stress-induced premature senescence) look alike and show similar characteristics.”

  • The paper relies on this without support.

    Senescent cells are metabolically active and possess the set of characteristics in vitro and in vivo known as biomarkers of cellular senescence.

    “Specifically, senescent cells are metabolically active and possess the set of characteristics in vitro and in vivo, which are known as biomarkers of cellular senescence.”

  • The paper relies on this without support.

    The best marker of cellular senescence should provide insight into the root causes of aging.

    “The best marker of cellular senescence should provide insight into the root causes of aging.”

  • The paper relies on this without support.

    The best marker should address both in vivo and in vitro conditions, apply to various tissues and species, and show consistency and overlapping with other reliable markers.

    “The best marker, however, should address both in vivo and in vitro conditions, apply to various tissues and species, and show consistency and overlapping with other reliable markers.”

  • The paper relies on this without support.

    Telomere theory considers telomere shortening to be the main trigger of aging.

    “Telomere theory considers telomere shortening to be the main trigger of aging.”

  • The paper relies on this without support.

    Telomere theory provided the theoretical base of the telomere marker.

    “Telomere theory provided theoretical base of telomere marker”
7 of 7

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?

  • Telomere shortening is another hallmark of senescent T cells.

    “Another hallmark of senescent T cells is telomere shortening [21, 44] (Fig. 2), which is caused by the continuous replication of T cells and the decrease in expression of the human telomerase RNA component.”

    From Immunosenescence: a key player in cancer development (2020) · cites this paper as [44]

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Authors
Bernadotte, A., Mikhelson, V. M., & Spivak, I. M.
Affiliations
  • Russian Academy of Sciences (RU)
  • Institute of Cytology, Russian Academy of Sciences, Saint-Petersburg, 194064, Russia
Corresponding author
Bernadotte, Alexandra
ORCID
Bernadotte, Alexandra
Venue
Aging
Publisher
Impact Journals, LLC
Published
2016-01-23
Volume
8
Issue
1
Pages
3-11
ISSN
1945-4589 (ISSN-L)
DOI
10.18632/aging.100871
PMC
PMC4761709
OpenAlex
W2265820610
Cited by
466
References
103
Citations by year
2026: 33 · 2025: 56 · 2024: 53 · 2023: 62 · 2022: 52 · 2021: 56 · 2020: 54 · 2019: 38 · 2018: 27 · 2017: 27 · 2016: 8
FWCI
3.92
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Aging (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
Russian Foundation for Basic Research
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 › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
Keywords
cellular senescence, telomere shortening, aging biomarkers, replicative senescence, stress-induced premature senescence, cell cycle arrest, senescence markers
MeSH terms
Age Factors, Aging, Animals, Genetic Markers, Heterochromatin, Histones, Humans, Phenotype, Reproducibility of Results, Telomere, Cellular Senescence, Genetic Predisposition to Disease, Chromatin Assembly and Disassembly, Cell Proliferation, Cell Cycle Checkpoints, Telomere Shortening

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