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Cited by 823Epigenetics and DNA MethylationPluripotent Stem Cells ResearchRetinal Development and Disorders

Reprogramming to recover youthful epigenetic information and restore vision

Open access
Lu, Yuancheng, Brommer, Benedikt, Tian, Xiao, Krishnan, Anitha, Meer, Margarita, Wang, Chen, Vera, Daniel L., Zeng, Qiurui +21 more·2020·Nature
DOI 10.1038/s41586-020-2975-4PMC PMC7752134
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Abstract

Ageing is a degenerative process that leads to tissue dysfunction and death. A proposed cause of ageing is the accumulation of epigenetic noise that disrupts gene expression patterns, leading to decreases in tissue function and regenerative capacity 1-3. Changes to DNA methylation patterns over time form the basis of ageing clocks 4, but whether older individuals retain the information needed to restore these patterns-and, if so, whether this could improve tissue function-is not known. Over time, the central nervous system (CNS) loses function and regenerative capacity 5-7. Using the eye as a model CNS tissue, here we show that ectopic expression of Oct4 (also known as Pou5f1), Sox2 and Klf4 genes (OSK) in mouse retinal ganglion cells restores youthful DNA methylation patterns and transcriptomes, promotes axon regeneration after injury, and reverses vision loss in a mouse model of glaucoma and in aged mice. The beneficial effects of OSK-induced reprogramming in axon regeneration and vision require the DNA demethylases TET1 and TET2. These data indicate that mammalian tissues retain a record of youthful epigenetic information-encoded in part by DNA methylation-that can be accessed to improve tissue function and promote regeneration in vivo.

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Crossref · 10.1038/s41586-020-2975-4

Cites

71 of 71 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

38 of 59 cited sources checked · 17 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    DNA methylation changes over time are the basis of ageing clocks.

    “Changes to DNA methylation patterns over time form the basis of ageing clocks4, but whether older individuals retain the information needed to restore these patterns—and, if so, whether this could improve tissue function—is not known.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [4] Horvath, S. DNA methylation age of human tissues and cell types. Genome Biol. 14, 3156 (2013). source
  • Premisecitation

    In mammals, the CNS is one of the first systems to lose regenerative potential.

    “In mammals, one of the first systems to lose regenerative potential is the CNS5–7.”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites [5] Kennard, M. A. Relation of age to motor impairment in man and in subhuman primates. Arch. Neurol. Psychiatry 44, 377–397 (1940). source
    • cites [6] Goldberg, J. L., Klassen, M. P., Hua, Y. & Barres, B. A. Amacrine-signaled loss of intrinsic axon growth ability by retinal ganglion cells. Science 296, 1860–1864 (2002). source
    • cites [7] Yun, M. H. Changes in regenerative capacity through lifespan. Int. J. Mol. Sci. 16, 25392–25432 (2015). source

      Section 2.1 (page unavailable) says mammals can regenerate their spinal cords only partially and only during early development, supporting early loss of regenerative potential in part of the CNS. It does not establish that the CNS as a whole is one of the first systems to lose that potential; Section 2.2 also describes adult neurogenesis that declines with age. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
  • Findingcitation

    Tet1 and Tet2, but not Tet3, were upregulated by OSK.

    “Because Tet1 and Tet2, but not Tet3, were upregulated by OSK35,36 (Extended Data Fig. 6a), we tested the effect of knocking down Tet1 or Tet2 (sh-Tet1 or sh-Tet2) using AAV37 in the context of damaged, OSK-treated RGCs (Extended Data Fig. 6b–d).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [35] Koh, K. P. et al. Tet1 and Tet2 regulate 5-hydroxymethylcytosine production and cell lineage specification in mouse embryonic stem cells. Cell Stem Cell 8, 200–213 (2011). source

      The Results section reports that Tet1 and Tet2 expression increased, while Tet3 expression decreased, when mouse fibroblasts were reprogrammed to iPS cells. However, the paper used Oct4, Sox2, Klf4 and c-Myc (OSKM), not OSK alone, so it does not establish the claimed response to OSK. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [36] Gao, Y. et al. Replacement of Oct4 by Tet1 during iPSC induction reveals an important role of DNA methylation and hydroxymethylation in reprogramming. Cell Stem Cell 12, 453–469 (2013). source

      In “Tet1 Can Facilitate Traditional iPSC Induction in a Hydroxylase-Dependent Manner” (page unavailable), the paper reports that Tet1 progressively increased in both OSK and OSKM reprogramming and that Tet3 was repressed in iPSCs. It reports early Tet2 upregulation for OSKM, but does not establish Tet2 upregulation by OSK alone. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
  • Premisecitation

    c-Myc is not required for initiation of cellular reprogramming.

    “Among the Yamanaka factors, c-Myc is an oncogene that reduces mouse lifespan20 and is not required for the initiation of cellular reprogramming21.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [21] Rand, T. A. et al. MYC releases early reprogrammed human cells from proliferation pause via retinoblastoma protein inhibition. Cell Rep. 23, 361–375 (2018). source
  • Premisecitation

    Injection of polystyrene microbeads into the anterior chamber elevates intraocular pressure.

    “Elevation of IOP was induced unilaterally by injection of polystyrene microbeads (FluoSpheres; Invitrogen, Carlsbad, CA; 15-μm diameter) to the anterior chamber of the right eye of each animal under a surgical microscope, as previously reported40.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [40] Krishnan, A. et al. Overexpression of soluble Fas ligand following adeno-associated virus gene therapy prevents retinal ganglion cell death in chronic and acute murine models of glaucoma. J. Immunol. 197, 4626–4638 (2016). source
  • May combine two claims. 31
  • Classified as probably not a substantial claim. 35

  • May combine two claims.

    Premisecitation

    The central nervous system loses function and regenerative capacity with age.

    “Over time, the central nervous system (CNS) loses function and regenerative capacity5–7.”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [5] Kennard, M. A. Relation of age to motor impairment in man and in subhuman primates. Arch. Neurol. Psychiatry 44, 377–397 (1940). source
    • cites [6] Goldberg, J. L., Klassen, M. P., Hua, Y. & Barres, B. A. Amacrine-signaled loss of intrinsic axon growth ability by retinal ganglion cells. Science 296, 1860–1864 (2002). source
    • cites [7] Yun, M. H. Changes in regenerative capacity through lifespan. Int. J. Mol. Sci. 16, 25392–25432 (2015). source

  • May combine two claims.

    Premisecitation

    During ageing, DNA methylation patterns change in ways that can be used to calculate DNA methylation age, a representation of biological age that predicts future health and lifespan.

    “During ageing, for reasons that are unclear, these patterns change in ways that can be used to calculate DNA methylation (DNAm) age, a representation of biological age that can predict future health and lifespan4.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [4] Horvath, S. DNA methylation age of human tissues and cell types. Genome Biol. 14, 3156 (2013). source

      The Background and Conclusions (pages not provided) describe age-related methylation changes and a DNAm-age biomarker derived from them. The paper demonstrates prediction of age, but the passages do not establish that DNAm age predicts future health or lifespan; the Conclusions say its role as a marker of aging needs further research. (LLM, conf=0.89)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    Klf4 can repress rather than promote axonal growth.

    “Because Klf4 can repress rather than promote axonal growth24, we tested a dual-cistron of only Oct4 and Sox2 and observed no regenerative effect.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [24] Moore, D. L. et al. KLF family members regulate intrinsic axon regeneration ability. Science 326, 298–301 (2009). source

  • May combine two claims.

    Premisecitation

    Embryonic and neonatal RGCs can regenerate axons after damage, but this capacity is lost within days after birth, likely due to a molecular program intrinsic to RGCs.

    “If damaged, RGCs of embryos and neonates can regenerate axons, but this capacity is lost within days after birth, likely due to a molecular program intrinsic to the RGCs6,22.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [6] Goldberg, J. L., Klassen, M. P., Hua, Y. & Barres, B. A. Amacrine-signaled loss of intrinsic axon growth ability by retinal ganglion cells. Science 296, 1860–1864 (2002). source
    • cites [22] Laha, B., Stafford, B. K. & Huberman, A. D. Regenerating optic pathways from the eye to the brain. Science 356, 1031–1034 (2017). source

      The “Intrinsic factors that limit RGC regeneration” section (page not supplied) says RGC axon growth speed falls sharply from embryonic to postnatal ages, likely because of molecular programs intrinsic to RGCs. It does not say that embryonic and neonatal RGCs regenerate after damage or that this capacity is lost within days after birth. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In cell culture, ectopic expression of OSKM can reprogram somatic cells to pluripotent stem cells, erasing cellular identity and resetting DNAm age.

    “In cell culture, the ectopic expression of the four Yamanaka transcription factors Oct4, Sox2, Klf4, and c-Myc (OSKM) can reprogram cultured somatic cells to become pluripotent stem cells14, a process that erases cellular identity and resets DNAm age4,15.”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [14] Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006). source
    • cites [4] Horvath, S. DNA methylation age of human tissues and cell types. Genome Biol. 14, 3156 (2013). source
    • cites [15] Petkovich, D. A. et al. Using DNA methylation profiling to evaluate biological age and longevity interventions. Cell Metab. 25, 954–960.e6 (2017). source

  • Classified as probably not a substantial claim.

    Premisecitation

    Many regenerative approaches that work well in young individuals often fail in older ones.

    “Many regenerative approaches that work well in young individuals often fail in older ones25,26.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [25] Geoffroy, C. G., Hilton, B. J., Tetzlaff, W. & Zheng, B. Evidence for an age-dependent decline in axon regeneration in the adult mammalian central nervous system. Cell Rep. 15, 238–246 (2016). source

      The Abstract and Discussion (page not provided) report that Pten deletion promotes axon regeneration in young mice but has a greatly diminished effect in older mice. The paper tests one approach in mice; it does not establish that many approaches often fail in older individuals, and it describes diminished regeneration rather than complete failure. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [26] Yao, K. et al. Restoration of vision after de novo genesis of rod photoreceptors in mammalian retinas. Nature 560, 484–488 (2018). source

      The Abstract describes successful rod-photoreceptor regeneration in mature mouse retinas, with treatment beginning at four weeks of age. Our copy does not compare outcomes in young and older individuals or say that regenerative approaches often fail with age (searched: young versus older regeneration, age-dependent failure). (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    In a HGPS mouse model, cyclic transgene-mediated expression of OSKM alleviates symptoms and extends lifespan.

    “In a premature ageing mouse model of Hutchinson-Gilford progeria syndrome (HGPS), cyclic transgene-mediated expression of these four genes alleviates symptoms and extends lifespan, raising the possibility that OSKM might counteract normal ageing, too16.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [16] Ocampo, A. et al. In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell 167, 1719–1733.e12 (2016). source

  • May combine two claims.

    Premisecitation

    c-Myc is an oncogene that reduces mouse lifespan.

    “Among the Yamanaka factors, c-Myc is an oncogene that reduces mouse lifespan20 and is not required for the initiation of cellular reprogramming21.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [20] Hofmann, J. W. et al. Reduced expression of MYC increases longevity and enhances healthspan. Cell 160, 477–488 (2015). source

  • May combine two claims.

    Premisecitation

    Continuous expression of all four Yamanaka factors in normal mice often induces teratomas or is fatal within days, ostensibly due to tissue dysplasia.

    “Continuous expression of all four factors in normal mice, however, often induces teratomas17–19 or is fatal within days16, ostensibly due to tissue dysplasia18.”
    Quote in the paperSubstantial claim2 of 4 sources checked
    • cites [17] Ohnishi, K. et al. Premature termination of reprogramming in vivo leads to cancer development through altered epigenetic regulation. Cell 156, 663–677 (2014). source
    • cites [18] Abad, M. et al. Reprogramming in vivo produces teratomas and iPS cells with totipotency features. Nature 502, 340–345 (2013). source
    • cites [19] Senís, E. et al. AAV vector-mediated in vivo reprogramming into pluripotency. Nat. Commun. 9, 2651 (2018). source

      The Results report teratomas in wild-type mice given all four OKSM factors, with high-dose mice developing palpable teratomas after 6–13 weeks. The Introduction mentions dysplasia in a separate study of mice with muscle damage, but this paper does not establish tissue dysplasia as the cause of fatality within days. The within-days fatality clause is cited to a different source (16). (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [16] Ocampo, A. et al. In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell 167, 1719–1733.e12 (2016). source

  • May combine two claims.

    Study design and conductcitation

    The ribosomal DNA methylation clock provided the best site coverage (67/72 CpG sites) and was highly correlated with chronological age.

    “The DNAm age of RGCs was calculated based on a ribosomal DNA methylation clock33, which provided the best site coverage (67/72 CpG sites) and was highly correlated with chronological age (Extended Data Fig. 5g).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [33] Wang, M. & Lemos, B. Ribosomal DNA harbors an evolutionarily conserved clock of biological aging. Genome Res. 29, 325–333 (2019). source

      The Results section ('CpGs from the rDNA are sufficient to accurately predict age within species'; page unavailable) reports a 72-CpG rDNA clock and a strong correlation between predicted and chronological age in mouse test subsets (median Spearman’s ρ = 0.92). It does not report coverage of 67 of 72 sites, establish that this clock had the best site coverage in the citing study, or test the correlation in RGCs; those appear to be results of the citing study. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Evidence from yeast and mammals supports an Information Theory of Ageing in which loss of epigenetic information disrupts youthful gene expression, causing cellular dysfunction and senescence.

    “Evidence from yeast and mammals supports an Information Theory of Ageing10,11, in which the loss of epigenetic information disrupts youthful gene expression patterns1–3, leading to cellular dysfunction and senescence12,13.”
    Quote in the paperSubstantial claim1 of 7 sources checked
    • cites [10] Sinclair, D. A. & LaPlante, M. D. Lifespan: Why We Age—and Why We Don’t Have To 13–23, 158–175 (Simon & Schuster, 2019).

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

    • cites [11] Shannon, C. E. A mathematical theory of communication. Bell Syst. Tech. J. 27, 379–423 (1948). source
    • cites [1] Sinclair, D. A., Mills, K. & Guarente, L. Accelerated aging and nucleolar fragmentation in yeast sgs1 mutants. Science 277, 1313–1316 (1997). source
    • cites [2] Imai, S. & Kitano, H. Heterochromatin islands and their dynamic reorganization: a hypothesis for three distinctive features of cellular aging. Exp. Gerontol. 33, 555–570 (1998). source
    • cites [3] Oberdoerffer, P. et al. SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging. Cell 135, 907–918 (2008). source
    • cites [12] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013). source

      The Epigenetic Alterations overview (page not provided) says aging is accompanied by epigenetic changes, and the Transcriptional alterations section reports age-related changes in gene expression. The paper also discusses longevity-related evidence from yeast and mammals. It does not set out an Information Theory of Ageing or establish the claimed causal chain from loss of epigenetic information through disrupted youthful expression to cellular dysfunction and senescence. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [13] Yang, J.-H. et al. Erosion of the epigenetic landscape and loss of cellular identity as a cause of aging in mammals. Preprint at https://doi.org/10.1101/808642 (2019). source

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

    Premisecitation

    Intraocular pressure was measured with a rebound TonoLab tonometer as previously described.

    “IOPs were measured with a rebound TonoLab tonometer (Colonial Medical Supply, Espoo, Finland), as previously described40.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [40] Krishnan, A. et al. Overexpression of soluble Fas ligand following adeno-associated virus gene therapy prevents retinal ganglion cell death in chronic and acute murine models of glaucoma. J. Immunol. 197, 4626–4638 (2016). source

  • Classified as probably not a substantial claim.

    Premisecitation

    Visual acuity of mice was measured using an optomotor reflex-based spatial frequency threshold test.

    “Visual acuity of mice was measured using an optomotor reflex-based spatial frequency threshold test58.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [58] Sun, D., Moore, S. & Jakobs, T. C. Optic nerve astrocyte reactivity protects function in experimental glaucoma and other nerve injuries. J. Exp. Med. 214, 1411-1430 (2017). source

  • Classified as probably not a substantial claim.

    Premisecitation

    Counting CTB-labeled axons at different distances from the crush site estimates the number of regenerating axons in the optic nerve.

    “The number of regenerating axons in the optic nerve was estimated by counting the number of CTB-labeled axons at different distances from the crush site as described previously29.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [29] Park, K. K. et al. Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway. Science 322, 963–966 (2008). source

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

    Findingcitation

    For two entire lifespan multi-tissue clocks, 248 of 582 and 77,342 of 193,651 sites were covered.

    “or 248/582 and 77,342/ 193,651 sites (ridge) of two entire lifespan multi-tissue clocks62.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [62] Thompson, M. J. et al. A multi-tissue full lifespan epigenetic clock for mice. Aging (Albany NY) 10, 2832–2854 (2018). source

      Table 1 in Results (page not provided) lists 582 CpGs for the all-CpGs elastic-net clock and 193,651 for the ridge clock. The paper does not report that 248 or 77,342 of those sites were covered; searches for both coverage figures found no matching passage. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

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

    Premisecitation

    The skin and blood clock for in vitro studies is based on 391 CpGs, and its algorithm and software were previously published.

    “The mathematical algorithm and available software underlying the skin & blood clock for in vitro studies (based on 391 CpGs) was previously published57.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [57] Horvath, S. et al. Epigenetic clock for skin and blood cells applied to Hutchinson Gilford Progeria Syndrome and ex vivo studies. Aging (Albany NY) 10, 1758–1775 (2018). source

  • Classified as probably not a substantial claim.

    Premisecitation

    Differentiated human neurons maintain ageing signatures.

    “We chose to use differentiated human neurons that would maintain ageing signatures53.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [53] Mertens, J. et al. Directly reprogrammed human neurons retain aging-associated transcriptomic signatures and reveal age-related nucleocytoplasmic defects. Cell Stem Cell 17, 705–718 (2015). source

      The Summary reports that directly converted human induced neurons retain aging-associated signatures. It also says that iPSC-derived neurons do not, and the Results section (‘iPSC-Derived iNs Remain Transcriptionally Rejuvenated’) confirms this distinction. The claim is supported only if ‘differentiated human neurons’ means directly converted neurons, not differentiated neurons generally. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

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

    Premisecitation

    PRC2 and H3K27me3 are known to recruit Tet enzymes.

    “Interestingly, the signature CpG sites were associated with genes involved in synaptic and neuronal processes and enriched for the binding of polycomb repressive complex 2 (PRC2) and its histone methyltransferase product H3K27me3, both of which are known to recruit Tet enzymes47,48 (Extended Data Fig 10g–i).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [47] Wu, X., Li, G. & Xie, R. Decoding the role of TET family dioxygenases in lineage specification. Epigenetics Chromatin 11, 58 (2018). source

      The section on maintenance of hypomethylated promoters says that PRC2 and TET proteins can recruit each other, and Fig. 1 explicitly depicts PRC2 recruiting TETs to bivalent promoters. It describes H3K27me3 as a histone mark at these regions, but does not say that H3K27me3 itself recruits TET enzymes. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [48] Neri, F. et al. Genome-wide analysis identifies a functional association of Tet1 and Polycomb repressive complex 2 in mouse embryonic stem cells. Genome Biol. 14, R91 (2013). source

      The Conclusions state that PRC2 recruits Tet1 to H3K27me3 regions in embryonic stem cells (page not specified). The paper does not establish that H3K27me3 itself recruits Tet enzymes, or that this recruitment applies to Tet enzymes generally or to other cell types. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

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

    Findingcitation

    For the whole lifespan multi-tissue clock, 102 of 435 sites were covered.

    “compared to 102/435 sites of the whole lifespan multi-tissue clock61”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [61] Meer, M. V., Podolskiy, D. I., Tyshkovskiy, A. & Gladyshev, V. N. A whole lifespan mouse multi-tissue DNA methylation clock. eLife 7, e40675 (2018). source

      The Results (Construction of a multi-tissue clock; page unavailable) state that the whole-lifespan multi-tissue clock contains 435 CpG sites. The Discussion (page unavailable) reports coverage in other datasets, but neither passage reports 102 covered sites; the cited paper therefore supports the denominator, not the claimed coverage count. (LLM, conf=0.89)

      Experimental — accuracy not yet measured

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

    Premisecitation

    DNA methylation age estimates of neurons tend to be lower than chronological age but remain correlated, in agreement with previous studies.

    “In agreement with previous studies57,63,64, DNAm age estimates of neurons tend to be lower than their chronological age but remain correlated.”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [57] Horvath, S. et al. Epigenetic clock for skin and blood cells applied to Hutchinson Gilford Progeria Syndrome and ex vivo studies. Aging (Albany NY) 10, 1758–1775 (2018). source
    • cites [63] Horvath, S. et al. The cerebellum ages slowly according to the epigenetic clock. Aging (Albany NY) 7, 294–306 (2015). source

      The Introduction and Methods state that DNAm age correlates with chronological age in sorted neurons. The Results report lower age acceleration for cerebellar brain samples, particularly in the oldest subjects, but do not establish that neurons generally have DNAm age estimates below chronological age. No page numbers are available in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [64] Hoshino, A., Horvath, S., Sridhar, A., Chitsazan, A. & Reh, T. A. Synchrony and asynchrony between an epigenetic clock and developmental timing. Sci. Rep. 9, 3770 (2019). source

      The Epigenetic clock analysis section (page unavailable) says DNAm age correlates with chronological age in sorted neurons. It does not say neuronal DNAm age estimates tend to be lower than chronological age; the paper’s own reported correlation concerns fetal retinal tissue, not isolated neurons. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    DNA methylation is likely not the only epigenetic mark involved in this process; other transcription factors and epigenetic modifications such as PRC2 and H3K27me3 are likely involved.

    “That said, we do not wish to imply that DNA methylation is the only epigenetic mark involved in this process. It likely involves other transcription factors and epigenetic modifications, such as the PRC2 complex and H3K27me3, both of which are involved in maintaining stem cell plasticity and are associated with DNAm clock sites4,49,50.”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [4] Horvath, S. DNA methylation age of human tissues and cell types. Genome Biol. 14, 3156 (2013). source

      The section comparing the multi-tissue predictor with other age predictors reports that age-increasing clock CpGs are enriched near Polycomb-group target genes; the Additional file 9 description also links them to SUZ12, EED and H3K27me3 occupancy. The paper does not establish that PRC2, H3K27me3 or other transcription factors participate in the process the citing sentence proposes, or that their role in maintaining stem-cell plasticity explains the clock-site association. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [49] Margueron, R. & Reinberg, D. The Polycomb complex PRC2 and its mark in life. Nature 469, 343–349 (2011). source

      The sections on genome-wide localization and PRC2 pluripotency and differentiation link PRC2 and H3K27me3 to stem-cell chromatin states and plasticity, though they qualify PRC2’s role in maintaining pluripotency. The paper discusses DNA methylation alongside these marks, but it does not address DNAm clock sites or establish their involvement in the citing paper’s specific process. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [50] Mozhui, K. & Pandey, A. K. Conserved effect of aging on DNA methylation and association with EZH2 polycomb protein in mice and humans. Mech. Ageing Dev. 162, 27–37 (2017). source

      The Introduction and Discussion §4.4 identify PRC2 as a potential regulator of age-related DNA methylation, and Results §3.5 reports that PRC2 members associate with age-hypermethylated regions. The passages do not establish the attributed role of H3K27me3 or the claim that both PRC2 and H3K27me3 maintain stem-cell plasticity and are associated with DNA-methylation clock sites. No page numbers are available in our copy. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Efemp1 is a Tet1- and Tet2-regulated gene associated with glaucoma and AMD.

    “Another 196 genes that were up-regulated during ageing are involved in ion transport or neuronal projection development, including Efemp1 (Extended Data Fig. 10b–d), a Tet1- and Tet2-regulated gene associated with glaucoma45 and age-related macular degeneration (AMD)46.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [45] Mackay, D. S., Bennett, T. M. & Shiels, A. Exome sequencing identifies a missense variant in EFEMP1 co-segregating in a family with autosomal dominant primary open-angle glaucoma. PLoS ONE 10, e0132529 (2015). source
    • cites [46] Marmorstein, L. Y. et al. Aberrant accumulation of EFEMP1 underlies drusen formation in Malattia Leventinese and age-related macular degeneration. Proc. Natl Acad. Sci. USA 99, 13067–13072 (2002). source

  • May combine two claims.

    Findingown data

    In 12-month-old mice, OSK treatment doubled RGC survival, similar to 1- and 3-month-old mice.

    “In 12-month-old mice, OSK treatment doubled RGC survival, similar to what was observed in 1- and 3-month-old mice (Extended Data Fig. 4a).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    OSK expression for five days in old mouse fibroblasts causes no apparent loss of cellular identity or induction of Nanog.

    “Even without c-Myc, expression of OSK for five days promoted youthful mRNA profile, with no apparent loss of cellular identity or the induction of Nanog, a transcription factor indicative of pluripotency and oncogenicity (Extended Data Fig. 1a–c).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    After 10-18 months of continuous OSK induction in young and aged mice, there is no increase in tumor incidence or negative effects on overall health.

    “After 10–18 months of continuous OSK induction, no increase in tumor incidence or negative effects on overall health were observed, indicating that cellular identity was maintained in OSK-expressing cells (Extended Data Fig.1 j–n).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Longer duration of OSK induction leads to greater distance of axon extension, with no sign of RGC proliferation.

    “The longer the duration of the OSK induction, the greater the distance the axons extended, with no sign of RGC proliferation (Fig. 2b, c, Extended Data Fig. 5f).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Stat3 mRNA levels robustly increased in response to OSK and were maintained post-injury.

    “The mRNA levels of Stat3, a pro-regeneration gene28, robustly increased in response to OSK and was maintained post-injury (Extended Data Fig. 5a, Supplementary Table 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Even after 15 months of continuous OSK induction, OSK expression did not induce tumors or structural changes in the retina.

    “Even after 15 months of continuous induction, OSK expression did not induce any tumors or structural changes in the retina (Extended Data Fig. 2c–i, Supplementary Videos).”
    Quote in the paperSubstantial claim

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

    Findingown data

    For the ribosomal DNA methylation clock, 67 of 72 sites with at least 10 reads per site were covered.

    “67/72 sites with at least 10 reads per site were covered for the ribosomal DNAm clock”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    mTOR-S6K inhibition does not block OSK-mediated recovery of neurite area, axon number, or axon length.

    “OSK-mediated recovery of neurite area, as well as both the number and length of axons, were blocked by Tet2 knockdown, but not by mTOR-S6K inhibition (Extended Data Fig. 8j–s).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Of 703,583 CpGs considered, 1,226 were selected: 723 trended toward hypermethylation with age and 503 toward hypomethylation with age.

    “Of the 703,583 CpGs that were considered, 1,226 were selected (723 that trended towards hypermethylation with age and 503 that trended towards hypomethylation with age, see Supplementary Table 3).”
    Quote in the paperSubstantial claim

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

    Findingown data

    After filtering, 703,583 CpG sites covered by uniquely mapped reads remained.

    “This resulted in a total of 703,583 sites, covered by uniquely mapped reads.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    OSK-treated glaucomatous eyes experienced a significant increase in visual acuity relative to pre-treatment baseline, restoring about half of visual acuity in the OMR assay.

    “The OSK-treated eyes also experienced a significant increase in visual acuity relative to the pre-treatment function baseline, restoring about half of visual acuity in the optomotor response (OMR) assay (Fig. 3c, d).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Signature CpG sites were associated with genes involved in synaptic and neuronal processes and enriched for binding of PRC2 and H3K27me3.

    “Interestingly, the signature CpG sites were associated with genes involved in synaptic and neuronal processes and enriched for the binding of polycomb repressive complex 2 (PRC2) and its histone methyltransferase product H3K27me3, both of which are known to recruit Tet enzymes47,48 (Extended Data Fig 10g–i).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Accumulated epigenetic noise that disrupts gene expression is a proposed cause of ageing and leads to reduced tissue function and regenerative capacity.

    “A proposed cause of ageing is the accumulation of epigenetic noise that disrupts gene expression patterns, leading to decreases in tissue function and regenerative capacity1–3.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [1] Sinclair, D. A., Mills, K. & Guarente, L. Accelerated aging and nucleolar fragmentation in yeast sgs1 mutants. Science 277, 1313–1316 (1997). source
    • cites [2] Imai, S. & Kitano, H. Heterochromatin islands and their dynamic reorganization: a hypothesis for three distinctive features of cellular aging. Exp. Gerontol. 33, 555–570 (1998). source
    • cites [3] Oberdoerffer, P. et al. SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging. Cell 135, 907–918 (2008). source

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

    Premisecitation

    DNA demethylation is catalyzed by TET1-3, either passively through DNA replication or actively by reversion to cytosine via TDG.

    “DNA demethylation is catalyzed by ten-eleven-translocation methylcytosine dioxygenases (TET1–3), either passively through DNA replication or actively, even in non-replicating cells, by reversion to cytosine via thymine DNA glycosylase (TDG)34.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Wu, X. & Zhang, Y. TET-mediated active DNA demethylation: mechanism, function and beyond. Nat. Rev. Genet. 18, 517–534 (2017). source

  • May combine two claims.

    Interpretationown data

    The ability of OSK to increase RGC survival appears mediated within the RGC and is largely cell-autonomous.

    “Thus, the ability of OSK to increase survival appears to be mediated within the RGC and is largely cell-autonomous.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Attempts to reverse optic nerve damage have been only moderately successful, with no treatments able to restore eyesight in late-stage glaucoma or old age.

    “Attempts to reverse optic nerve damage have been only moderately successful, with no treatments able to restore eyesight either in late-stage glaucoma or in old age23.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23] Roska, B. & Sahel, J. A. Restoring vision. Nature 557, 359–367 (2018). source

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

    Study design and conductnone given

    The SH-SY5Y cells used were confirmed to be negative for mycoplasma.

    “Cells were confirmed as negative for mycoplasma”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    RNA integrity was determined using TapeStation.

    “RNA integrity was determined using TapeStation (Agilent Technologies, Palo Alto, CA, USA).”
    • Also stated in: § Ultra-low input RNA library preparation and multiplexing · plain
      “RNA integrity was ascertained using a 2100 TapeStation (Agilent Technologies, Palo Alto, CA, USA).”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    All animal procedures were approved by the IACUC of the respective institutions and according to appropriate animal welfare regulations.

    “All animal procedures were approved by the IACUC of the respective institutions and according to appropriate animal welfare regulations.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Mice that developed signs of inflammation were excluded.

    “Any mice that developed signs of inflammation (clouding or an edematous cornea) were excluded.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    A sensitivity analysis compared transcription factor and histone enrichment for five sets of 1,226 random CpGs from unselected sites against the selected set.

    “A sensitivity analysis was conducted by performing TF and histone enrichment for five sets of 1,226 random CpGs from the 702,357 unselected sites, which was then compared against the enrichment for our selected set in in order to identify TFs and histone marks that were specific to the selected set but not CpGs in general.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    All cell lines used were mycoplasma negative.

    “All cell lines used were mycoplasma negative.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    In cell cycle analysis, only single cells were gated for analysis.

    “PI-stained samples were analyzed on a BD LSR II analyzer and only single cells were gated for analysis.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Two outliers were excluded because of low intercorrelation within the batch.

    “Two outliers were excluded by low intercorrelation (< 0.93) within the batch (Supplementary Table 5).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Two individuals blinded to the experimental groups performed all retinal ganglion cell counts.

    “Two individuals blinded to the experimental groups performed all RGC counts.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Optomotor response tracking behavior was monitored by a blinded observer who could not see the direction of the moving bars.

    “A blinded observer, unable to see the direction of the moving bars, monitored the tracking behavior of the mouse.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Mice with intravitreal bleeding or inflammation during or after intravitreal injection were excluded from optomotor response and histological analyses.

    “Mice that had intravitreal bleeding or developed signs of inflammation (clouding or an edematous cornea) during or post intravitreal injection were excluded from OMR and histological analyses.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The final sequencing library was assessed with a Qubit fluorometer and an Agilent TapeStation.

    “The final library was assessed by a Qubit 2.0 Fluorometer and an Agilent TapeStation.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    In the mouse retinal ganglion cell DNA methylation analysis, only CpG sites covered in all samples were considered.

    “Only CpG sites covered in all samples were considered for analysis (BioProject PRJNA655981).”
    Quote in the paperNot a substantial claim

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

    Study design and conductreasoning

    Intraocular pressure measurements were taken at the same time of day to account for diurnal variation.

    “All IOPs were taken at the same time of day (between 10:00 and 12:00 hrs) due to the variation of IOP throughout the day.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    All animal work was approved by the IACUCs at Harvard Medical School, Boston Children's Hospital, and the Mass Eye and Ear Institution.

    “All animal work was approved by the Institutional Animal Care and Use Committees (IACUCs) at Harvard Medical School, Boston Children’s Hospital, and the Mass Eye and Ear Institution.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Exclusion criteria were pre-determined before experimentation.

    “Exclusion criteria were pre-determined before experimentation.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Individuals performing axon counts were blinded to the experimental groups.

    “Individuals performing axon counts were blinded to the experimental groups.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Ectopically expressed OSK safely induces in vivo epigenetic restoration of aged CNS neurons without causing loss of cell identity or pluripotency.

    “Using the eye as a model system, we present evidence that ectopically expressed OSK safely induces in vivo epigenetic restoration of aged CNS neurons, without causing a loss of cell identity or pluripotency.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    It is possible to safely reverse the age of a complex tissue and restore its biological function in vivo.

    “Here, we show that it is possible to safely reverse the age of a complex tissue and restore its biological function in vivo.”
    Quote in the paperSubstantial claim

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

    Premisereasoning

    Because ribosomal DNA sequence is repetitive, it is not suitable for whole-genome bisulfite mapping.

    “Due to the repetitive nature of ribosomal DNA sequence, it is not suitable to whole-genome bisulfite mapping.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Optomotor responses were measured before and after treatment by individuals blinded to the animal group and treatment.

    “Responses were measured before and after treatment by individuals blinded to the group of the animal and the treatment.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    To avoid batch effects, subsamples were evaluated separately by batch.

    “To avoid batch effects, subsamples were evaluated separately as 6 mo and 18 mo in Batch 1, and 1 mo, 12 mo, and 30 mo in Batch 2 (Supplementary Table 5).”
    Quote in the paperSubstantial claim
60 of 60

  • The paper relies on this without support.

    DNA methylation patterns are established during embryonic development to set cell type and function.

    “DNA methylation patterns are laid down during embryonic development to establish cell type and function.”

  • The paper relies on this without support.

    During ageing, almost all species experience a decline in regenerative potential.

    “During ageing, almost all species experience a decline in regenerative potential.”

  • The paper relies on this without support.

    Currently, there is no known treatment that can induce robust RGC axon regeneration when started after crush injury.

    “Currently, there is no known treatment that can induce robust RGC axon regeneration when started after crush injury.”

  • The paper relies on this without support.

    Glaucoma is a leading cause of age-related blindness worldwide, characterized by progressive loss of RGCs and their axons and often coinciding with increased intraocular pressure.

    “Glaucoma is a leading cause of age-related blindness worldwide, characterized by a progressive loss of RGCs and their axons and often coinciding with increased intraocular pressure (IOP).”
4 of 4

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?

  • The Information Theory of Aging proposes that a decline in epigenetic information triggers mitochondrial dysfunction, inflammation, and cellular senescence, leading to progressive decline in cell and tissue function.

    “These findings are consistent with the Information Theory of Aging, which proposes that a decline in information, specifically epigenetic information, triggers a cascade of events, including mitochondrial dysfunction, inflammation, and cellular senescence [5, 7–9], leading to a progressive decline in cell and tissue function, manifesting as aging and age-related diseases.”

    From Chemically induced reprogramming to reverse cellular aging (2023) · cites this paper as [8]

    The Abstract (page not provided) describes the Information Theory of Ageing as proposing that loss of epigenetic information disrupts youthful gene expression, leading to cellular dysfunction and senescence; it also links epigenetic noise to declining tissue function. Our copy does not identify mitochondrial dysfunction or inflammation as steps in that cascade. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Numerous tissues, including brain, kidney, and muscle, have been reprogrammed without causing cancer.

    “Numerous tissues, including brain tissue, kidney, and muscle, have now been reprogrammed without causing cancer [7, 8, 22, 24, 25].”

    From Chemically induced reprogramming to reverse cellular aging (2023) · cites this paper as [8]

    The Discussion describes safe OSK-induced reprogramming of retinal neurons, using the eye as a model CNS tissue. The ‘OSK stimulates axon regeneration’ section reports no retinal tumors after 15 months of induction. This paper does not establish cancer-free reprogramming of kidney or muscle tissue, or of brain tissue beyond the retinal CNS model. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Translational applications that aim to reverse aging rely on delivery of genetic material to target tissues.

    “Currently, translational applications that aim to reverse aging, treat injuries, and cure age-related diseases, rely on the delivery of genetic material to target tissues.”

    From Chemically induced reprogramming to reverse cellular aging (2023) · cites this paper as [8]

    The ‘Reset of ageing signatures, not identity’ section describes an AAV system used to deliver OSK genes in mice, and the Abstract reports restoration of youthful markers in mouse retinal cells. This supports genetic delivery as the method in this study, but not the broader claim that translational applications generally rely on it. Page numbers were not provided in our copy. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Ectopic induction of OSK in mammals restores youthful transcript profiles.

    “We have previously shown that the ectopic induction of the Yamanaka factors OCT4, SOX2, and KLF4 (OSK) in mammals can restore youthful DNA methylation patterns, transcript profiles, and tissue function, without erasing cellular identity”

    From Chemically induced reprogramming to reverse cellular aging (2023) · cites this paper as [8]

    Experimental — accuracy not yet measured

  • Ectopic induction of OSK in mammals restores tissue function.

    “We have previously shown that the ectopic induction of the Yamanaka factors OCT4, SOX2, and KLF4 (OSK) in mammals can restore youthful DNA methylation patterns, transcript profiles, and tissue function, without erasing cellular identity”

    From Chemically induced reprogramming to reverse cellular aging (2023) · cites this paper as [8]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Retinal image area conflicts with its stated dimensions

    Major

    An image measuring 248.53 μm on each side covers approximately 0.0618 mm2, not the 0.025 mm2 later assigned to each image. This leaves the area used to calculate RGC density unclear.

1 of 1

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Related

Authors
Lu, Y., Brommer, B., Tian, X., Krishnan, A., Meer, M., Wang, C., Vera, D. L., Zeng, Q., Yu, D., Bonkowski, M. S., Yang, J.-H., Zhou, S., Hoffmann, E. M., Karg, M. M., Schultz, M. B., Kane, A. E., Davidsohn, N., Korobkina, E., Chwalek, K., Rajman, L. A., Church, G. M., Hochedlinger, K., Gladyshev, V. N., Horvath, S., Levine, M. E., Gregory-Ksander, M. S., Ksander, B. R., He, Z., & Sinclair, D. A.
Affiliations
  • Harvard University (US)
  • Boston Children's Hospital (US)
  • Massachusetts Eye and Ear Infirmary (US)
  • Brigham and Women's Hospital (US)
  • Massachusetts General Hospital (US)
  • University of California, Los Angeles (US)
  • Yale University (US)
Corresponding author
Sinclair, David A.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2020-12-02
Volume
588
Issue
7836
Pages
124-129
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-020-2975-4
PMC
PMC7752134
OpenAlex
W3108896277
Semantic Scholar
aa9b261d01ca36831459cb82af4c0c4d460f7d14
Cited by
820
References
72
Citations by year
2026: 125 · 2025: 132 · 2024: 154 · 2023: 172 · 2022: 140 · 2021: 89 · 2020: 7 · 2014: 1
FWCI
33.16
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • National Institutes of Health
  • National Institute on Aging (R01AG067782, R37AG028730, R01AG019719, T32AG023480, K99AG068303, R01AG065403)
  • National Eye Institute (R24EY028767, R21EY030276, R01EY021526, R01EY026939, P30EY012196, P30EY003790, R01EY025794)
  • National Institute of General Medical Sciences (R37GM065204, R01GM065204)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD090255)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
Keywords
cellular reprogramming, epigenetic aging, DNA methylation, Oct4, SOX2, KLF4, Yamanaka factors, retinal ganglion cells, axon regeneration, glaucoma, vision loss, TET1, TET2, demethylation, tissue regeneration, aged mice, epigenetic noise
MeSH terms
Kruppel-Like Factor 4, Dependovirus, Aging, Animals, Axons, Cell Survival, Disease Models, Animal, DNA-Binding Proteins, Eye, Female, Genetic Vectors, Glaucoma, Humans, Mice, Inbred C57BL, Nerve Regeneration, Proto-Oncogene Proteins, Retinal Ganglion Cells, Vision, Ocular, DNA Methylation, Optic Nerve Injuries, Epigenesis, Genetic, Cell Line, Tumor, Dioxygenases, Octamer Transcription Factor-3, Mice, Kruppel-Like Transcription Factors, SOXB1 Transcription Factors, Transcriptome, Cellular Reprogramming

About these checks

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

Claims read under definition version 3 (extract-v3) on 2026-09-28.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-09-28.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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