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Cited by 104Telomeres, Telomerase, and SenescenceGenetics, Aging, and Longevity in Model OrganismsEpigenetics and DNA Methylation

The DOI matches its Crossref record; 89 of the 89 references it cites were found in a registry or an index; 48 of the 73 sources its claims cite were checked for support.

TERT activation targets DNA methylation and multiple aging hallmarks

Open access
Shim, Hong Seok, Iaconelli, Jonathan, Shang, Xiaoying, Li, Jiexi, Lan, Zheng D., Jiang, Shan, Nutsch, Kayla, Beyer, Brittney A., Lairson, Luke L., Boutin, Adam T., Bollong, Michael J., Schultz, Peter G., DePinho, Ronald A.·2024·Cell
DOI 10.1016/j.cell.2024.05.048PMC PMC11552617
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Abstract

Insufficient telomerase activity, stemming from low telomerase reverse transcriptase (TERT) gene transcription, contributes to telomere dysfunction and aging pathologies. Besides its traditional function in telomere synthesis, TERT acts as a transcriptional co-regulator of genes pivotal in aging and age-associated diseases. Here, we report the identification of a TERT activator compound (TAC) that upregulates TERT transcription via the MEK/ERK/AP-1 cascade. In primary human cells and naturally aged mice, TAC-induced elevation of TERT levels promotes telomere synthesis, blunts tissue aging hallmarks with reduced cellular senescence and inflammatory cytokines, and silences p16 INK4a expression via upregulation of DNMT3B-mediated promoter hypermethylation. In the brain, TAC alleviates neuroinflammation, increases neurotrophic factors, stimulates adult neurogenesis, and preserves cognitive function without evident toxicity, including cancer risk. Together, these findings underscore TERT's critical role in aging processes and provide preclinical proof of concept for physiological TERT activation as a strategy to mitigate multiple aging hallmarks and associated pathologies.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

A high-throughput screen identified a small molecule TERT activator compound (TAC) that upregulates TERT transcription via MEK/ERK/AP-1. In human cells and naturally aged mice, TAC promoted telomere synthesis, reduced senescence and inflammation, silenced p16INK4a via DNMT3B-mediated promoter hypermethylation, and improved neurogenesis and cognition without evident toxicity.

Key findings

  • Screening ~653,000 compounds in hTERT-Rluc transgenic mouse ear fibroblasts identified TAC, which dose-dependently induced TERT mRNA in primary human MRC-5 fibroblasts, increased H3K27ac and reduced H3K9me3 at the TERT promoter, and after i.p. injection of 6 mg/kg increased human TERT reporter activity in brain, heart, and skeletal muscle of hTERT-Rluc mice.
  • TAC activated MEK/ERK/AP-1 signaling: phospho-kinase arrays showed increased ERK and S6 kinase phosphorylation; the MEK inhibitor trametinib abolished TAC-induced ERK phosphorylation and TERT upregulation; FOS was the most significantly induced common gene in human fibroblasts and iPSC-derived neurons; two AP-1 sites were identified in the 4-kb human TERT promoter, with the conserved site required for TAC-induced promoter activity, and AP-1 inhibitor T-5224 impaired TAC-induced TERT expression.
  • In middle-aged mice, one-week TAC (6 mg/kg/day i.p.) reduced p16Ink4a and SASP components (Il-1α, Il-1β, Mmp-3, Vegf) in PBMCs and decreased p16Ink4a in brain, skeletal muscle, kidney, heart, and liver; this repression was abolished in Tert-null mice. TAC increased methylated CpG sites at the p16Ink4a promoter, and 6-month treatment in 26–27-month-old mice reduced senescent cell burden and IL-1β/IL-6.
  • In the brain, TAC increased mature BDNF and neurogenesis markers (DCX+ newborn neurons, PSA-NCAM+ immature neurons), reduced IBA1+ activated microglia and Il-1β, Il-6, Tnf-α, and in 20–21-month-old mice treated for six months improved Barnes maze, Y-maze, novel-location recognition, rotarod, and grip strength without overt adverse effects.

Methods

  • Cell-based high-throughput screen using adult mouse ear fibroblasts from hTERT-Rluc BAC transgenic reporter mice, screening ~653,000 compounds at 5 μM; hits confirmed by Renilla luciferase, then characterized in primary human MRC-5 and Werner syndrome fibroblasts, human iPSC-derived neurons, and mouse primary cells.
  • Molecular and biochemical assays included phospho-kinase arrays, RNA-seq (human fibroblasts/iPSC neurons treated with 0.5 μM TAC for 1 hr; mouse PBMCs after 1 week; mouse hippocampus after 3 weeks), ChIP-qPCR and ChIP-seq, TERT promoter luciferase reporters with AP-1 deletions, methylation-specific PCR for p16Ink4a, telomere FISH and qPCR, ELISA, immunohistochemistry/immunofluorescence, SA-β-gal staining, and behavioral tests.
  • Animal studies used male C57BL/6 mice, hTERT-Rluc transgenic mice, and Tert-deficient mice; TAC was administered i.p. at 6 mg/kg/day or 6 mg/kg three times per week in mice aged 10–12, 12–14, 20–21, and 26–27 months; pharmacokinetics were measured by mass spectrometry; statistical analyses used GraphPad Prism 8.

Limitations

  • The paper states that TAC’s impact on lifespan extension remains undetermined; dose optimization, dosing schedules, maximum tolerated dose, and drug metabolites/liabilities were not assessed; species differences require toxicity studies in non-human primates and humans; and cancer incidence should be monitored in clinical trials of sustained TAC administration.
  • The paper states that additional molecular mediators may be involved because most biologically active small molecules exhibit polypharmacology, and future chemical proteomics with structural and functional validation are needed to identify TAC’s precise target(s).
  • The text also makes evident that sample sizes were not statistically predetermined, normality was assumed but not formally tested, investigators were generally not blinded to allocation or outcome assessment, and animal studies used male mice only.

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

Integrity signals

Registry

Crossref · 10.1016/j.cell.2024.05.048

Cites

89 of 89 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

48 of 73 cited sources checked · 18 supported · 1 flagged · accuracy not yet measured

  • Premisecitation

    Insufficient telomerase activity due to low TERT gene transcription contributes to telomere dysfunction and aging pathologies.

    “Insufficient telomerase activity, stemming from low telomerase reverse transcriptase (TERT) gene transcription, contributes to telomere dysfunction and aging pathologies.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [9] Vulliamy, 2001, The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita, Nature source
    • cites [10] Yamaguchi, 2005, Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia, N. Engl. J. Med. source

      The Functional Analysis results (page unavailable) report reduced telomerase activity from disease-associated TERT mutations, but explicitly say the loss of function was not due to altered TERT transcription: mutant and wild-type RNA expression levels were similar. The paper links impaired telomere maintenance to aplastic anemia and marrow failure, rather than establishing low TERT transcription as the cause of aging pathologies. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [11] Armanios, 2007, Telomerase mutations in families with idiopathic pulmonary fibrosis, N. Engl. J. Med. source

      The Impaired Activity of Mutant Telomerase section (page not available in our copy) reports reduced activity of mutant TERT, and the paper links telomerase mutations to short telomeres and pulmonary fibrosis. It does not attribute the reduced activity to low TERT gene transcription; the mechanisms it describes are mutations affecting protein function or splicing. The claim also extends the paper’s disease finding to aging pathologies generally. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Premisecitation

    TERT acts as a transcriptional co-regulator of genes pivotal in aging and age-associated diseases.

    “Besides its traditional function in telomere synthesis, TERT acts as a transcriptional co-regulator of genes pivotal in aging and age-associated diseases.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [15] Jaskelioff, 2011, Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice, Nature source

      The Abstract reports that telomerase reactivation extended telomeres and reversed degenerative phenotypes in mice. Searches for transcriptional co-regulation and TERT-mediated gene-expression regulation found no passage in our copy addressing the claimed role of TERT as a transcriptional co-regulator. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
    • cites [16] Shim, 2021, Telomerase Reverse Transcriptase Preserves Neuron Survival and Cognition in Alzheimer's Disease Models, Nat Aging source
  • Premisecitation

    Telomeres undergo progressive attrition during aging-associated tissue renewal, leading to loss of their capping function.

    “Telomeres, specialized chromatin structures that preserve chromosomal integrity, undergo progressive attrition during aging-associated tissue renewal, leading to loss of their capping function.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [2] Chakravarti, 2021, Telomeres: history, health, and hallmarks of aging, Cell source
    • cites [7] Sahin, 2010, Linking functional decline of telomeres, mitochondria and stem cells during ageing, Nature source
  • Premisecitation

    Natural or synthetic compounds that induce TERT expression promote cellular survival and metabolic fitness.

    “Accordingly, natural or synthetic compounds that induce TERT expression have been shown to promote cellular survival and metabolic fitness.17–19”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [17] Bernardes de Jesus, 2011, The telomerase activator TA-65 elongates short telomeres and increases health span of adult/old mice without increasing cancer incidence, Aging Cell source

      The Results report that TA-65 increased TERT expression in mouse liver, reduced TUNEL-positive epidermal cells, and improved glucose tolerance in treated mice. The Methods identify TA-65 as plant-derived. These findings support benefits from this compound, but do not establish that natural or synthetic TERT-inducing compounds generally promote cellular survival and metabolic fitness; the metabolic results are measured in mice, not cells. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [18] Eitan, 2012, Novel telomerase-increasing compound in mouse brain delays the onset of amyotrophic lateral sclerosis, EMBO Mol. Med. source

      The Results section reports that AGS-499 increased telomerase activity and improved survival of human cells exposed to oxidative stress; the benefit was absent when TERT was suppressed. The Discussion links TERT itself to improved respiratory-chain efficiency, but the paper does not show that AGS-499 improves metabolic fitness or establish the claim for natural compounds. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [19] Wan, 2021, Increased telomerase improves motor function and alpha-synuclein pathology in a transgenic mouse model of Parkinson's disease associated with enhanced autophagy, Prog. Neurobiol. source

      The Results section reports that the natural compound TA-65 and synthetic compound GRN510 increased Tert expression in mouse brain and cultured neurons. However, only TA-65 significantly reduced mitochondrial ROS in the treated mice; the paper does not establish that both compounds promote cellular survival or metabolic fitness. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Premisecitation

    Age-associated repression of TERT is reminiscent of other key longevity-associated genes, where epigenetic alterations altering chromatin structure and accessibility accumulate in cis-regulatory sequences during aging, leading to changes in transcriptional regulation of genes governing aging.

    “The age-associated repression of TERT is reminiscent of other key longevity-associated genes, where epigenetic alterations altering chromatin structure and accessibility accumulate in the cis-regulatory sequences during aging, leading changes in the transcriptional regulation of genes governing aging.41,42”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [41] Fraga, 2007, Epigenetics and aging: the targets and the marks, Trends Genet. source
    • cites [42] Cavalli, 2019, Advances in epigenetics link genetics to the environment and disease, Nature source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
  • Probably not a substantial claim. 22
  • It may state two separate claims as one. 40

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisecitation

    Age-associated epigenomic alterations can induce significant transcriptional drift and initiate cellular aging processes, implicating altered epigenetic signatures in aging pathophysiology and aging-related diseases.

    “In particular, age-associated epigenomic alterations can induce significant transcriptional drift and initiate cellular aging processes, implicating altered epigenetic signatures in aging pathophysiology and aging-related diseases.4,5”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [4] Frenk, 2018, Gene expression hallmarks of cellular ageing, Biogerontology source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites [5] Booth, 2016, The Aging Epigenome, Mol. Cell source

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

    Premisecitation

    Telomere dysfunction can contribute to other hallmarks such as genome instability, stem cell exhaustion, mitochondrial dysfunction and cellular senescence.

    “Telomere dysfunction is itself an aging hallmark and can also contribute to other hallmarks such as genome instability, stem cell exhaustion, mitochondrial dysfunction and cellular senescence.2,7”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [2] Chakravarti, 2021, Telomeres: history, health, and hallmarks of aging, Cell source
    • cites [7] Sahin, 2010, Linking functional decline of telomeres, mitochondria and stem cells during ageing, Nature source

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

    Premisecitation

    Defects in telomerase activity due to germ-line mutations in core telomerase components are linked to premature loss of tissue renewal and premature death, such as dyskeratosis congenita, aplastic anemia and idiopathic pulmonary fibrosis.

    “Indeed, defects in telomerase activity due to germ-line mutations in core telomerase components are linked to the premature loss of tissue renewal and premature death, such as dyskeratosis congenita,9 aplastic anemia10 and idiopathic pulmonary fibrosis.11”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [9] Vulliamy, 2001, The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita, Nature source
    • cites [10] Yamaguchi, 2005, Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia, N. Engl. J. Med. source

      The Abstract and the section headed “Functional Analysis of TERT Mutations” link TERT mutations to reduced telomerase activity and diminished marrow regenerative capacity, supporting the aplastic-anemia example attached to this citation. Our copy does not establish premature death in affected people; its reference to a shortened life span concerns cells, not patients. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [11] Armanios, 2007, Telomerase mutations in families with idiopathic pulmonary fibrosis, N. Engl. J. Med. source

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

    Premisecitation

    Modulating chromatin modifier activity has shown promise in mitigating multiple aging risk factors and associated disease phenotypes on the organismal level.

    “Notably, modulating chromatin modifier activity has shown promise in mitigating multiple aging risk factors and associated disease phenotypes on the organismal level.6”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [6] Benayoun, 2015, Epigenetic regulation of ageing: linking environmental inputs to genomic stability, Nat. Rev. Mol. Cell Biol. source

      The Concluding remarks report that drugs targeting chromatin modifiers increase lifespan in model organisms, supporting promise at the organismal level. But they describe treating age-related diseases as a possibility requiring further testing, not as a demonstrated mitigation of multiple disease phenotypes or ageing risk factors. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Premisecitation

    In post-mitotic neurons, restoration of physiological TERT levels improves capacity for neural stem cell regeneration, enhances synaptic plasticity and preserves cognitive function in two models of Alzheimer's Disease.

    “Indeed, in post-mitotic neurons, restoration of physiological TERT levels improve capacity for neural stem cell regeneration, enhance synaptic plasticity and preserve cognitive function in two models of Alzheimer’s Disease.15,16”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [15] Jaskelioff, 2011, Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice, Nature source

      The neural stem-cell and SVZ passages (Figures 3–4; page not provided) report improved progenitor proliferation and neurogenic capacity after telomerase reactivation in telomerase-deficient mice. The paper does not report restoration specifically in post-mitotic neurons, enhanced synaptic plasticity, or preserved cognitive function in two Alzheimer’s disease models; its reported functional test concerns olfactory avoidance. (LLM, conf=0.89)

      Experimental — accuracy not yet measured
    • cites [16] Shim, 2021, Telomerase Reverse Transcriptase Preserves Neuron Survival and Cognition in Alzheimer's Disease Models, Nat Aging source

      The Discussion reports that neuronal TERT expression improved dendritic spine formation and cognitive function in aging AD mice. The Results document cognitive benefit in the 3xTg-AD model, while the two-model finding concerns reduced amyloid levels. The Introduction attributes restoration of neural stem-cell pools to earlier work in TERT-deficient mice with severe telomere dysfunction, not to TERT restoration in post-mitotic neurons in these AD models. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim.

    Premisecitation

    Telomere dysfunction has been causally implicated as a rate-limiting pathogenetic step in age-related diseases including premature aging syndromes, cardiovascular diseases, inflammatory bowel disease, pulmonary fibrosis, metabolic diseases and neurological diseases.

    “Telomere dysfunction has been causally implicated as a rate-limiting pathogenetic step in age-related diseases including premature aging (progeroid) syndromes, cardiovascular diseases, inflammatory bowel disease, pulmonary fibrosis, metabolic diseases and neurological diseases.2,7,8”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites [2] Chakravarti, 2021, Telomeres: history, health, and hallmarks of aging, Cell source

      The Introduction and the section on telomere dysfunction in inflammatory diseases link telomere dysfunction to progeroid syndromes, pulmonary fibrosis, and inflammatory bowel disease. The age-related diseases and altered nutrient sensing sections also discuss cardiovascular, neurological, and metabolic effects. But the inflammatory-diseases section says telomere dysfunction may amplify and cooperate with primary disease drivers; it does not establish it as a causal, rate-limiting step across all the listed diseases. Page numbers were not provided in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [7] Sahin, 2010, Linking functional decline of telomeres, mitochondria and stem cells during ageing, Nature source

      The “Telomeres and ageing” section describes limiting telomeres as pathogenetic elements in degenerative disease and links telomere defects to premature-ageing syndromes and idiopathic pulmonary fibrosis. It does not establish telomere dysfunction as a causal, rate-limiting step for every disease listed: its cardiovascular discussion is largely associative, and the passages found do not make that claim for inflammatory bowel, metabolic or neurological diseases. No page numbers are available in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [8] Sharpless, 2007, How stem cells age and why this makes us grow old, Nat. Rev. Mol. Cell Biol. source

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisecitation

    Telomere dysfunction is a primary hallmark of aging, causing molecular and cellular damage and serving as a driver or amplifier of the molecular circuitries driving the aging process and associated diseases.

    “Telomere dysfunction is a primary hallmark of aging, causing molecular and cellular damage and serving as a driver or amplifier of the molecular circuitries driving the aging process and associated diseases.1,2,7”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [1] López-Otín, 2013, The hallmarks of aging, Cell source
    • cites [2] Chakravarti, 2021, Telomeres: history, health, and hallmarks of aging, Cell source
    • cites [7] Sahin, 2010, Linking functional decline of telomeres, mitochondria and stem cells during ageing, Nature source

      The Abstract (page unavailable) describes telomeres and p53-mediated DNA-damage signalling as core components of stem-cell depletion and age-related tissue degeneration. The Telomeres and ageing section also identifies limiting telomeres as drivers of degenerative disease. But the paper does not designate telomere dysfunction a “primary hallmark” of ageing, and it explicitly calls the broader connection to mitochondrial dysfunction a speculative model rather than an established molecular circuitry. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Age-matched male mice were used because they have been widely used for aging studies and shown to correspond more closely to the phenotype of human aging.

    “Age-matched male mice were used in this study as these have been widely used for the aging studies and shown to correspond more closely to the phenotype of human aging55,56 and were ten to twenty seven months of age as described in the corresponding figure legends.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [55] Chakravarti, 2020, Telomere dysfunction activates YAP1 to drive tissue inflammation, Nat. Commun. source

      The Methods sections on Mice and Animal Experiment describe the mouse models and their ages, but do not say they were male or explain a preference for male mice in aging studies. The Results section on gut inflammation describes premature aging in telomere-deficient mice, but does not compare male mice with human aging phenotypes. Searches for male mice and correspondence to human aging found no supporting passage in our copy. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [56] Anders, 2015, HTSeq--a Python framework to work with high-throughput sequencing data, Bioinformatics source

      The HTSEQ-COUNT section describes a tool for counting RNA-seq reads, and the Discussion addresses sequencing-data analysis; neither discusses mouse aging studies. Searches for age-matched male mice and for their resemblance to human aging found no relevant passage in our copy. No page numbers were supplied for these sections. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Premisecitation

    TERT levels are tightly regulated in normal adult somatic cells and further repressed in aged tissues and in the Alzheimer's Disease brain.

    “TERT levels are tightly regulated in normal adult somatic cells and further repressed in aged tissues and in the Alzheimer’s Disease brain.16”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [16] Shim, 2021, Telomerase Reverse Transcriptase Preserves Neuron Survival and Cognition in Alzheimer's Disease Models, Nat Aging source

      The Results section on neuronal Tert downregulation reports reduced Tert expression in cortical and hippocampal tissue from two mouse models of Alzheimer’s disease compared with matched controls. The Results section on human neurons also reports decreased TERT expression in an AD patient-derived neuron model. These findings support repression in AD models, but the cited passages do not establish tight regulation across normal adult somatic cells or further repression in aged tissues generally. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • Rests on an assumption: Telomerase activity is tightly regulated in most adult somatic cells, primarily due to transcriptional repression of TERT.

  • It may state two separate claims as one.

    Findingown data

    TAC treatment concurrently induced signatures of organism growth and natural killer cell activation in PBMCs.

    “Conversely, TAC treatment concurrently induced signatures of organism growth and natural killer cell activation (Figure 3C), which are known to decline with age.25”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [25] Brauning, 2022, Aging of the Immune System: Focus on Natural Killer Cells Phenotype and Functions, Cells source

      Section 5 reports an age-related decline in NK-cell cytotoxicity and changes in activating receptors, supporting the age-related NK-cell portion of the cited clause. Section 9 reports declining IGF-1 levels, but does not establish that an organism-growth signature declines with age. The TAC-induced PBMC signatures are presented as the citing study’s own Figure 3C result, not as a finding of this source. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Premisecitation

    Genetic re-activation of TERT can restore neurogenic and cognitive capacities in rodent models of premature aging and Alzheimer's Disease and can increase levels of mature BDNF.

    “Genetic re-activation of TERT can restore the neurogenic and cognitive capacities in rodent models of premature aging and Alzheimer’s Disease and can increase levels of mature brain-derived neurotrophic factor (BDNF), a key molecule promoting the growth, survival and differentiation of newborn neurons in the normal mouse brain.14–16”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [14] Bernardes de Jesus, 2012, Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer, EMBO Mol. Med. source

      The Introduction reports that telomerase reactivation reversed some age-associated phenotypes in a mouse model of premature aging. The Results report increased cyclin D1-positive cells in neurogenic brain areas, but only a nonsignificant trend toward improved memory in the paper’s adult and old mice. The copy does not establish restored neurogenic or cognitive capacity in Alzheimer’s disease models or increased mature BDNF. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [15] Jaskelioff, 2011, Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice, Nature source

      The paper’s SVZ findings and discussion (page not provided) report restored neurogenesis in adult telomerase-deficient mice and improved odor detection in innate avoidance tests after TERT reactivation. They do not establish restored cognitive capacity or address an Alzheimer’s disease model or increased mature BDNF levels. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [16] Shim, 2021, Telomerase Reverse Transcriptase Preserves Neuron Survival and Cognition in Alzheimer's Disease Models, Nat Aging source

      The Introduction (page unavailable) reports that TERT reactivation restored neural stem-cell pools, newborn-neuron formation, and learning and memory in mice with severe telomere dysfunction. The Results report that TERT activation prevented learning and memory dysfunction in AD mice, but do not show restored neurogenesis in those mice. They also report reduced mature BDNF with TERT deficiency and increased BDNF gene expression after induction in human neurons, not a measured increase in mature BDNF after reactivation. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

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

    Study design and conductcitation

    The sample sizes used were similar to those reported in previous publications.

    “our sample sizes are similar to those reported in previous publications.15,24,86”
    Quote in the paperNot a substantial claim3 of 3 sources checked
    • cites [15] Jaskelioff, 2011, Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice, Nature source
    • cites [24] Sahin, 2011, Telomere dysfunction induces metabolic and mitochondrial compromise, Nature source

      The Methods Summary describes the experiments and says some mouse models and protocols were described previously, but it does not compare sample sizes with earlier publications. Searches for comparable sample sizes and numbers of mice per group found no passage addressing that comparison. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
    • cites [86] Iaccarino, 2016, Gamma frequency entrainment attenuates amyloid load and modifies microglia, Nature source

  • It may state two separate claims as one.

    Premisecitation

    TERT reactivation in aged inducible-TERT mice was shown to reverse aging phenotypes without causing an increase in cancer.

    “Correspondingly, TERT reactivation in aged inducible-TERT mice was shown to reverse aging phenotypes without causing an increase in cancer.15”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [15] Jaskelioff, 2011, Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice, Nature source

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

    Premisecitation

    ERK signaling has been linked to the cognitive-enhancing effects of plant secondary metabolites, such as curcumin and apigenin.

    “Along these lines, it is intriguing that ERK signaling has been linked to the cognitive-enhancing effects of plant secondary metabolites, such as curcumin and apigenin.46,47”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [46] Zhang, 2015, Curcumin Improves Amyloid beta-Peptide (1-42) Induced Spatial Memory Deficits through BDNF-ERK Signaling Pathway, PLoS One source
    • cites [47] Venigalla, 2015, Curcumin and Apigenin - novel and promising therapeutics against chronic neuroinflammation in Alzheimer's disease, Neural Regen. Res. source

      The Apigenin > Animal studies section reports improved learning and memory in apigenin-treated Alzheimer’s-model mice alongside restoration of a cortical ERK/CREB/BDNF pathway involved in learning and memory. The Curcumin > Mechanistic pathways and cellular studies section separately describes memory-enhancing actions and MAPK-related anti-inflammatory effects, but does not link ERK signaling to curcumin’s cognitive effects. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Fine-tuning of MEK/ERK pathway activation by natural bioactive compounds, such as flavonoids, appears to promote physiological responses of gene transcription/translation and cell growth/survival and, in turn, advance human health as neuroprotectants and cognitive enhancers.

    “Although sustained hyperactivation of MEK/ERK signaling is a prerequisite for malignant transformation or progression, the fine-tuning of this pathway activation by natural bioactive compounds, such as flavonoids, appears to promote physiological responses of gene transcription/translation and cell growth/survival and, in turn, advance human health as neuroprotectants and cognitive enhancers.48–51”
    Quote in the paperNot a substantial claim3 of 4 sources checked
    • cites [48] Steelman, 2011, Roles of the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways in controlling growth and sensitivity to therapy-implications for cancer and aging, Aging (Albany, NY) source

      Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [49] Chappell, 2011, Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR inhibitors: rationale and importance to inhibiting these pathways in human health, Oncotarget source

      Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured
    • cites [50] Deschênes-Simard, 2014, ERKs in cancer: friends or foes?, Cancer Res. source
    • cites [51] Ayaz, 2019, Flavonoids as Prospective Neuroprotectants and Their Therapeutic Propensity in Aging Associated Neurological Disorders, Front. Aging Neurosci. source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Findingown data

    TAC treatment led to accumulation of H3K27ac and loss of H3K9me3 upstream of the TERT transcription start site.

    “Consistent with TAC-induced TERT gene expression, TAC treatment led to the accumulation of the active enhancer/promoter mark H3K27ac and loss of repressive mark H3K9me3 upstream of the transcriptional start site of the TERT gene (Figure 1E), indicating that TAC can override the repressive chromatin state of the human TERT locus.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    TAC preserves cognitive function without evident toxicity, including cancer risk.

    “In the brain, TAC alleviates neuroinflammation, increases neurotrophic factors, stimulates adult neurogenesis and preserves cognitive function without evident toxicity, including cancer risk.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    TAC-induced elevation of TERT levels blunts tissue aging hallmarks with reduced cellular senescence and inflammatory cytokines in primary human cells and naturally aged mice.

    “In primary human cells and naturally aged mice, TAC-induced elevation of TERT levels promotes telomere synthesis, blunts tissue aging hallmarks with reduced cellular senescence and inflammatory cytokines, and silences p16INK4a expression via upregulation of DNMT3B-mediated promoter hypermethylation.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Following an initial screen of 653,000 compounds, approximately 100 hits were further characterized, yielding several TACs capable of modestly inducing TERT gene transcription activity.

    “Following an initial screen of 653,000 compounds from the California Institute for Biomedical Research (Calibr)’s library, approximately 100 hits were further characterized by measuring reporter bioluminescence, yielding several TACs capable of modestly inducing the transcription activity of TERT gene (Figure S1B).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    TAC-treated Werner syndrome fibroblasts exhibited a marked reduction in telomere dysfunction-induced DNA damage foci (TIFs) and an enhancement in proliferative potential relative to vehicle control.

    “TAC-treated WS fibroblasts also exhibited a marked reduction in telomere dysfunction-induced DNA damage foci (TIFs) and an enhancement in proliferative potential relative to the vehicle control group (Figure S1H and S1I), suggesting that DNA damage at short telomeres is repaired efficiently by TAC/TERT-mediated telomere addition and that human primary fibroblasts retain the proliferative capacity.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Two AP-1 binding sites reside within the 4-kb upstream regulatory region of the human TERT gene, with one well conserved between human and mouse.

    “We identified two AP-1 binding sites residing within the 4-kb upstream regulatory region of the human TERT gene, with one of these binding motifs well conserved between human and mouse (Figures 2H and 2I).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Only two genes, FOS and SOGA3, exhibited significant upregulation in both human fibroblasts and iPSC-derived neurons following TAC treatment (≥2-fold cutoff; P<0.05), with FOS most significantly regulated.

    “Strikingly, only two genes, FOS and SOGA3, exhibited significant upregulation in both cell types following treatment (≥ 2-fold cutoff; P < 0.05), with FOS, encoding a major constituent of the activator protein 1 (AP-1) transcriptional complex, identified as the gene most significantly regulated by TAC in both cells (Figures 2E–2G).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Inhibition of ERK with the MEK inhibitor trametinib abolished TAC-induced ERK phosphorylation and TERT upregulation in MRC-5 cells.

    “Accordingly, inhibition of ERK with the MEK inhibitor trametinib abolished TAC-induced ERK phosphorylation and TERT upregulation in MRC-5 cells (Figures 2C and S2A).”
    Quote in the paperSubstantial claim

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

    Findingown data

    No change in body weight was detected between TAC and control groups throughout the study.

    “No change in body weight was detected between the two groups throughout the study (Figure S5E).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    TAC-treated aged mice showed improved rotarod performance and grip strength.

    “In addition, TAC-treated aged mice showed improved rotarod performance and grip strength (Figures S5H and S5I, respectively), which are known to decline with advancing age,40 consistent with improved motor coordination and muscle strength.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [40] Bellantuono, 2020, A toolbox for the longitudinal assessment of healthspan in aging mice, Nat. Protoc. source

      Checked before — its earlier verdict is held back until a new check runs.

  • It may state two separate claims as one.

    Findingown data

    TAC treatment significantly reduces the presence of senescent cells in diverse tissues along with DNMT3B-mediated repression of p16Ink4a, in a TERT-dependent manner.

    “Notably, TAC treatment significantly reduces the presence of senescent cells in diverse tissues along with DNMT3B-mediated repression of the master cellular mortality gene p16Ink4a, in a TERT-dependent manner.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Quantitative RT-PCR confirmed marked down-regulation of Dnmt3b levels in Tert+/− mouse brains which was further reduced in Tert−/− mice.

    “Quantitative RT-PCR analysis of Tert+/+, Tert+/− and Tert−/− mouse brains confirmed marked down-regulation of Dnmt3b levels in Tert+/− mice which was further reduced in Tert−/− mice (Figure 3F), indicating a positive correlation between TERT levels and Dnmt3b expression in vivo.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    TAC exhibited central nervous system exposure, with approximately two-fold partitioning of the compound in the CNS relative to plasma.

    “Notably, TAC exhibited central nervous system exposure, with approximately two-fold partitioning of the compound in the central nervous system (CNS) relative to plasma.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    TAC is cleared from plasma by 3 hr with plasma levels tracking those in the brain.

    “TAC is cleared from the plasma by 3 hr with plasma levels tracking those in the brain (Figures S3C and S3D).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Chronic administration of TAC for 6 months reduced senescence cell burden and production of pro-inflammatory IL-1β and IL-6 SASP factors in multiple tissues of naturally aged (26~27-month-old) mice.

    “Furthermore, chronic administration of TAC for 6 months reduced senescence cell burden, as well as the production of pro-inflammatory IL-1β and IL-6 SASP factors in multiple tissues of naturally aged (26~27-month-old) mice (Figures 3I, S4G–S4J).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Long-term administration of brain-penetrant TAC in aged mice reduces neuroinflammation and inflammatory cytokines, enhances rejuvenation-associated gene signatures, promotes adult neurogenesis and preserves cognitive function without overt side effects.

    “Additionally, long-term administration of brain-penetrant TAC in aged mice reduces neuroinflammation and inflammatory cytokines, enhances rejuvenation-associated gene signatures, promotes adult neurogenesis and preserves cognitive function without overt side effects.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    In genetically engineered mice, TERT reactivation has a dual role in reversal of aging via telomere synthesis in proliferative tissues and via gene expression modulation in post-mitotic tissues in a telomere-independent manner.

    “Moreover, in genetically engineered mice, TERT reactivation studies revealed the dual role of TERT in the reversal of aging via telomere synthesis in proliferative tissues as well as via gene expression modulation in post-mitotic tissues in a telomere-independent manner.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [15] Jaskelioff, 2011, Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice, Nature source
    • cites [16] Shim, 2021, Telomerase Reverse Transcriptase Preserves Neuron Survival and Cognition in Alzheimer's Disease Models, Nat Aging source

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisecitation

    FOS encodes a critical component of the AP-1 transcription factor complex, which binds to specific cis-acting elements on gene promoters to stimulate expression of target genes.

    “The FOS gene encodes a critical component of AP-1 transcription factor complex, which binds to specific cis-acting elements on gene promoters stimulating the expression of these target genes.22”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] Angel, 1991, The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation, Biochim. Biophys. Acta source

  • It may state two separate claims as one.

    Interpretationown data

    TAC treatment specifically induces TERT expression and its downstream transcriptional effects without affecting general mRNA translation.

    “providing evidence that TAC treatment specifically induces TERT expression and its downstream transcriptional effects without affecting general mRNA translation.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    DNA damage at short telomeres is repaired efficiently by TAC/TERT-mediated telomere addition and human primary fibroblasts retain proliferative capacity.

    “suggesting that DNA damage at short telomeres is repaired efficiently by TAC/TERT-mediated telomere addition and that human primary fibroblasts retain the proliferative capacity.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    Enforced expression of TERT stabilizes endogenous telomeres, reduces senescence-associated markers and restores proliferative lifespan in mammals.

    “Conversely, enforced expression of TERT stabilizes endogenous telomeres, reduces senescence-associated markers and restores the proliferative lifespan in mammals.12–14”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [12] Bodnar, 1998, Extension of life-span by introduction of telomerase into normal human cells, Science source
    • cites [13] Tomás-Loba, 2008, Telomerase reverse transcriptase delays aging in cancer-resistant mice, Cell source
    • cites [14] Bernardes de Jesus, 2012, Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer, EMBO Mol. Med. source

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

    Premisecitation

    Small molecule therapeutics may offer advantages over biologics due to their lower immunogenic and cost-effectiveness.

    “In the setting of aging and chronic disease, small molecule therapeutics may offer advantages over biologics due to their lower immunogenic and cost-effectiveness.43,44”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [43] Pérez-Jeldres, 2019, Targeting Cytokine Signaling and Lymphocyte Traffic via Small Molecules in Inflammatory Bowel Disease: JAK Inhibitors and S1PR Agonists, Front. Pharmacol. source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites [44] Olivera, 2017, Next generation of small molecules in inflammatory bowel disease, Gut source

  • It may state two separate claims as one.

    Interpretationreasoning

    TERT exerts anti-aging activity not only by preserving telomere integrity but also by modulating gene expression and cellular signaling pathways governing cellular survival, senescence, neurogenesis, stress resistance, among other processes.

    “Our findings reinforce the view that TERT exerts anti-aging activity not only by preserving telomere integrity but also by modulating gene expression and cellular signaling pathways governing cellular survival, senescence, neurogenesis, stress resistance, among other processes.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationcitation

    TAC may reduce cancer incidence given that insufficient telomerase and resultant telomere dysfunction, coupled with loss of p53-dependent DNA checkpoint control, is a major driver of chromosomal instability and cancer genesis in the aged.

    “Along these lines, it is worth noting that TAC may reduce cancer incidence given that insufficient telomerase and resultant telomere dysfunction, coupled with loss of p53-dependent DNA checkpoint control, is a major driver of chromosomal instability and cancer genesis in the aged.53”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [53] Artandi, 2000, Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice, Nature source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductnone given

    Mice and cells were randomly assigned to control or experimental groups, except in experiments that required specific genotypes and ages.

    “The mice and cells were randomly assigned to control or experimental groups, except in experiments that required specific genotypes and ages.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Physiological activation of somatic TERT expression and activity sustains cellular replicative potential via telomere maintenance and enhances tissue-level physiology by modulating multiple aging-relevant pathophysiological processes, including senescence and inflammation.

    “Physiological activation of somatic TERT expression and activity not only sustains cellular replicative potential via telomere maintenance but also enhances tissue-level physiology by modulating multiple aging-relevant pathophysiological processes, including senescence and inflammation.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Interpretationreasoning

    The multifaceted organismal and functional benefits may arise from a combination of TERT's canonical and non-canonical functions.

    “The multifaceted organismal and functional benefits may arise from a combination of TERT’s canonical and non-canonical functions.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    TAC possesses a low molecular weight (<400 Da) and lipophilicity that favor drug uptake across all tissues, including the CNS.

    “TAC possesses a low molecular weight (<400 Da) and lipophilicity that favor drug uptake across all tissues, including the CNS.45”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] Bharate, 2018, Why Are the Majority of Active Compounds in the CNS Domain Natural Products? A Critical Analysis, J. Med. Chem. source

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

    Study design and conductnone given

    All animal procedures used in this study were reviewed and approved by the University of Texas MD Anderson Cancer Center Institutional Animal Care and Use Committee.

    “All animal procedures used in this study were reviewed and approved by the University of Texas MD Anderson Cancer Center Institutional Animal Care and Use Committee.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationown data

    TAC effectively counteracts the epigenetic silencing of the TERT gene in adult somatic cells, thereby influencing the expression of genes governing aging hallmarks.

    “TAC effectively counteracts the epigenetic silencing of the TERT gene in adult somatic cells, thereby influencing the expression of genes governing aging hallmarks.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Study design and conductnone given

    Naturally aged (20~21-month-old) C57BL/6 mice were randomized into TAC and vehicle treatment groups.

    “Naturally aged (20~21-month-old) C57BL/6 mice were randomized into TAC and vehicle treatment groups.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    This study highlights the significant regenerative capacity of aging organ systems and the ability to pharmacologically modulate aging hallmarks during natural aging.

    “This study highlights the significant regenerative capacity of aging organ systems as well as the ability to pharmacologically modulate aging hallmarks during natural aging.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    No animal or sample was excluded from the analysis.

    “No animal or sample was excluded from the analysis.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Mutations in the human TERT reporter constructs were confirmed by sequencing.

    “The mutations were confirmed by sequencing.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Modest TAC-induced increase in endogenous TERT levels improves hippocampal-dependent cognitive function and enhances neuromuscular function in aged mice without any overt adverse consequences.

    “Together, these findings demonstrated that the modest TAC-induced increase in endogenous TERT levels improves not only hippocampal-dependent cognitive function but also enhances neuromuscular function in aged mice without any overt adverse consequences.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationreasoning

    The engagement of diverse aging mechanisms by TERT makes TAC treatment a viable strategy for aging per se and for specific associated age-related diseases, particularly those characterized by impaired telomerase/telomere function.

    “In this light, the engagement of diverse aging mechanisms by TERT makes TAC treatment a viable strategy for aging per se and for specific associated age-related diseases, particularly those characterized by impaired telomerase/telomere function.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Pharmacological activation of TERT induces rejuvenation-associated gene signatures and stimulates adult neurogenesis in the hippocampus of adult mice.

    “Thus, pharmacological activation of TERT induces rejuvenation-associated gene signatures and stimulates adult neurogenesis in the hippocampus of adult mice.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    TAC-driven TERT upregulation reduces age-dependent tissue senescence and regulates major genetic drivers of cellular senescence, including p16Ink4a and SASP components.

    “Thus, TAC-driven TERT upregulation reduces age-dependent tissue senescence and regulates major genetic drivers of cellular senescence, including p16Ink4a and SASP components.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    No statistical methods were used to predetermine sample sizes.

    “No statistical methods were used to predetermine sample sizes”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The investigators were generally not blinded to allocation during experiments and outcome assessment.

    “The investigators were generally not blinded to allocation during experiments and outcome assessment.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    For ChIP-seq, control immunoprecipitation was done in parallel without antibodies.

    “For ChIP-seq, control immunoprecipitation was done in parallel without antibodies.”
    Quote in the paperNot a substantial claim
56 of 56

  • The paper relies on this without support.

    Telomerase activity is tightly regulated in most adult somatic cells, primarily due to transcriptional repression of TERT.

    “While essential for cell viability in normal healthy tissues, telomerase activity is tightly regulated in most adult somatic cells, primarily due to transcriptional repression of the core catalytic subunit of telomerase, TERT.”

  • The paper relies on this without support.

    Development of compounds that induce TERT expression has been hampered by a lack of understanding of their downstream mechanisms of action.

    “While promising, the development of these compounds has been hampered by a lack of understanding of their downstream mechanisms of action.”

  • The paper relies on this without support.

    The importance of each pathway and associated promoter binding elements in regulating TERT transcription in human adult somatic tissues remains unclear.

    “In addition, while numerous pathways regulate TERT gene transcription, the importance of each pathway and their associated promoter binding elements in regulating the transcription of TERT in human adult somatic tissues remains unclear.”

  • The paper relies on this without support.

    TERT protein half-life is 2–3 hours.

    “Moreover, while the half-life of TAC is short, TERT protein half-life is 2–3 hours and its actions can be more enduring via such actions as DNMT3B-mediated silencing of the p16INK4a promoter.”

  • The authors state this as an assumption.

    All data distributions were assumed to be normal, although this was not formally tested.

    “All data distributions were assumed to be normal, but this was not formally tested.”
5 of 5

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Metadata

Authors
Shim, H. S., Iaconelli, J., Shang, X., Li, J., Lan, Z. D., Jiang, S., Nutsch, K., Beyer, B. A., Lairson, L. L., Boutin, A. T., Bollong, M. J., Schultz, P. G., & DePinho, R. A.
Affiliations
  • The University of Texas MD Anderson Cancer Center (US)
  • Scripps Research Institute (US)
Corresponding author
DePinho, Ronald A.
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2024-07
Volume
187
Issue
15
Pages
4030-4042.e13
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2024.05.048
PMC
PMC11552617
OpenAlex
W4399886291
Cited by
104
References
88
Citations by year
2026: 45 · 2025: 48 · 2024: 11
FWCI
15.79
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Digital Commons-TMC (Texas Medical Center) (submittedVersion)
Funders
  • National Institutes of Health (R01 CA084628, P30 CA016672, S10 RR029552)
  • G. Harold and Leila Y. Mathers Foundation
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Keywords
telomerase reverse transcriptase, telomere maintenance, hallmarks of aging, cellular senescence, neuroinflammation, adult neurogenesis, cognitive function, p16INK4a, DNMT3B, DNA methylation, transcriptional co-regulation, age-related diseases
MeSH terms
DNA Methyltransferase 3B, Aging, Animals, Brain, DNA (Cytosine-5-)-Methyltransferases, Humans, Male, Mice, Inbred C57BL, Promoter Regions, Genetic, Telomere, Cellular Senescence, Transcription Factor AP-1, Telomerase, DNA Methylation, Cyclin-Dependent Kinase Inhibitor p16, Mice, Neurogenesis

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