The DOI matches its Crossref record; 89 of the 89 references it cites were found in a registry or an index; 53 of the 73 sources its claims cite were checked for support.
TERT activation targets DNA methylation and multiple aging hallmarks
Open accessAbstract
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
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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.
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Claims the paper makes
49 Own result · 23 Own interpretation · 20 Partly supported · 8 Own method · 6 No full text of the sources · 5 Supported · 2 Supported so far · 1 Mixed support · 1 Couldn’t confirm · 1 Not checked yet · 1 No basis given · accuracy not yet measured
Some cited sources support this claim and some don’t — read each source’s verdict below.
In the paper
“Insufficient telomerase activity, stemming from low telomerase reverse transcriptase (TERT) gene transcription, contributes to telomere dysfunction and aging pathologies.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > Abstract
What the sources say
- Not checked — no full text of the sourcecites [9] Vulliamy, 2001, The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita, Nature source
- Disputedcites [10] Yamaguchi, 2005, Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia, N. Engl. J. Med. sourceExperimental — accuracy not yet measured
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.
- Partly supportedcites [11] Armanios, 2007, Telomerase mutations in families with idiopathic pulmonary fibrosis, N. Engl. J. Med. sourceExperimental — accuracy not yet measured
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)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Besides its traditional function in telomere synthesis, TERT acts as a transcriptional co-regulator of genes pivotal in aging and age-associated diseases.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > Abstract
What the sources say
- Could not verifycites [15] Jaskelioff, 2011, Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice, Nature sourceExperimental — accuracy not yet measured
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)
- Supportedcites [16] Shim, 2021, Telomerase Reverse Transcriptase Preserves Neuron Survival and Cognition in Alzheimer's Disease Models, Nat Aging source
The Results section ('TERT as a novel transactivation component in AD neurons') reports that TERT associates with transcriptional regulators and occupies gene promoters alongside β-Catenin and TCF7. The Results section ('TERT activation alleviates amyloid pathology') also reports altered expression of aging- and AD-associated genes. These findings support the paraphrase, principally in the context of the AD neurons studied. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Could not verify
Every source the paper cites for this claim was checked and supports it.
In the paper
“Telomeres, specialized chromatin structures that preserve chromosomal integrity, undergo progressive attrition during aging-associated tissue renewal, leading to loss of their capping function.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > INTRODUCTION
What the sources say
- Supportedcites [2] Chakravarti, 2021, Telomeres: history, health, and hallmarks of aging, Cell source
In “Telomere dysfunction and telomerase in age-related diseases” (page not provided), the review says continual renewal of highly proliferative tissues causes progressive telomere attrition over decades. It also says telomere shortening generates dysfunction-induced foci and discusses uncapping, supporting the paraphrase that attrition compromises telomeres’ protective function. (LLM, conf=0.88)
- Supportedcites [7] Sahin, 2010, Linking functional decline of telomeres, mitochondria and stem cells during ageing, Nature source
The ‘Telomeres and ageing’ section describes telomeres as chromosome-protecting caps and says cell division causes progressive attrition; further erosion triggers chromosomal instability. It also reports declining telomere reserves with increased tissue turnover and discusses capping status, supporting the paraphrase about renewal-associated attrition and loss of protection. No page number is available in our copy. (LLM, conf=0.86)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Accordingly, natural or synthetic compounds that induce TERT expression have been shown to promote cellular survival and metabolic fitness.17–19”
§ TERT activation targets DNA methylation and multiple aging hallmarks > INTRODUCTION
What the sources say
- Partly supportedcites [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 sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [18] Eitan, 2012, Novel telomerase-increasing compound in mouse brain delays the onset of amyotrophic lateral sclerosis, EMBO Mol. Med. sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [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. sourceExperimental — accuracy not yet measured
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)
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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”
§ TERT activation targets DNA methylation and multiple aging hallmarks > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites [41] Fraga, 2007, Epigenetics and aging: the targets and the marks, Trends Genet. source
- Partly supportedcites [42] Cavalli, 2019, Advances in epigenetics link genetics to the environment and disease, Nature sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
plaindirect- Asserted: passes — The authors put it forward as true.
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The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Remarkably, TAC treatment induced a significant increase in the expression of genes positively associated with adult hippocampus neurogenesis and brain function,30–35 including Eomes, a driver of immune cell development & neurogenesis, Dlk1, a mediator of adult hippocampal neurogenesis and cognition, Gdnf, a neurotrophic factor, Dcx, a marker for new-born neurons, Sox1/2, critical determinants of”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > Chronic TAC administration ameliorates brain aging.
What the sources say
- Partly supportedcites [30] Christian, 2014, Functions and dysfunctions of adult hippocampal neurogenesis, Annu. Rev. Neurosci. sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
- Partly supportedcites [31] Flavell, 2008, Signaling mechanisms linking neuronal activity to gene expression and plasticity of the nervous system, Annu. Rev. Neurosci. sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
- Not checked — no full text of the sourcecites [32] Glebova, 2005, Growth and survival signals controlling sympathetic nervous system development, Annu. Rev. Neurosci. source
- Not checked — no full text of the sourcecites [33] Hevner, 2006, Transcription factors in glutamatergic neurogenesis: conserved programs in neocortex, cerebellum, and adult hippocampus, Neurosci. Res. source
- Supportedcites [34] Grassi, 2022, Emerging Roles of DLK1 in the Stem Cell Niche and Cancer Stemness, J. Histochem. Cytochem. source
Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
- Partly supportedcites [35] Schafer, 2019, The influence of GDF11 on brain fate and function, GeroScience sourceExperimental — accuracy not yet measured
Split into 2 atoms — 1 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
plaindirect- Asserted: passes — The authors put it forward as true.
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- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“These results are consistent with previous findings that TERT can act as a transcriptional modulator not only in highly proliferating cells but also in terminally differentiated cells.16,27”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > TAC attenuates multiple aging hallmarks in vivo.
What the sources say
- Supportedcites [16] Shim, 2021, Telomerase Reverse Transcriptase Preserves Neuron Survival and Cognition in Alzheimer's Disease Models, Nat Aging source
The Results section, “TERT as a novel transactivation component in AD neurons” (page not available), reports prior evidence linking TERT to WNT/β-catenin signaling in proliferating cells and finds that TERT associates with transcriptional machinery and promotes transcriptional activation in postmitotic neurons. This supports the claim that TERT can modulate transcription in terminally differentiated cells as well as proliferating cells. (LLM, conf=0.88)
- Partly supportedcites [27] Park, 2009, Telomerase modulates Wnt signalling by association with target gene chromatin, Nature sourceExperimental — accuracy not yet measured
The Abstract and Conclusions describe TERT as a transcriptional modulator, and the section ‘TERT activates the Wnt axis in vivo and in ES cells’ shows enhanced Wnt transcriptional output in intestinal progenitor cells. The passages do not establish that TERT acts as a transcriptional modulator in terminally differentiated cells; the claim extends beyond the cell types shown here. (LLM, conf=0.85)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Indeed, our recent study provided additional genetic evidence that somatic TERT maintenance restrains the pathological hallmarks of Alzheimer’s Disease, including amyloid pathology, dendritic spine deficits and cognitive decline.16”
§ TERT activation targets DNA methylation and multiple aging hallmarks > DISCUSSION
What the sources say
- Supportedcites [16] Shim, 2021, Telomerase Reverse Transcriptase Preserves Neuron Survival and Cognition in Alzheimer's Disease Models, Nat Aging source
The Discussion reports that increased neuronal TERT reduced Aβ levels and improved dendritic spine formation and cognitive function in AD mouse models. The Results also report greater dendritic spine density after TERT induction. These findings support the cited claim in the models studied; page numbers were not provided. (LLM, conf=0.94)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Transcriptomic analysis of the brains of adult Tert+/+ and first generation (G1) Tert−/− mice (with intact telomeres)16 showed significant and specific reduction in the expression of Dnmt3b (Figures S4E and S4F), a DNA methyltransferase responsible for the hypermethylation of p16Ink4a promoter.26”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > TAC attenuates multiple aging hallmarks in vivo.
What the sources say
- Supportedcites [16] Shim, 2021, Telomerase Reverse Transcriptase Preserves Neuron Survival and Cognition in Alzheimer's Disease Models, Nat Aging source
The Results section (‘Tert insufficiency induces APP and reduces BDNF in mouse brain’; page unavailable) describes transcriptomic analysis of adult Tert+/+ and first-generation Tert−/− brains and explicitly says the G1 mice had intact telomeres. Citation 16 is attached to that description; the Dnmt3b reduction is presented as the citing authors’ own result in Figures S4E and S4F, not as a finding attributed to this source. (LLM, conf=0.91)
- Not checked — no full text of the sourcecites [26] Rhee, 2002, DNMT1 and DNMT3b cooperate to silence genes in human cancer cells, Nature source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Conversely, cytokines and inflammatory response, whose over-activation or dysregulation is known to contribute to age-related diseases and aging itself,36 were downregulated with TAC administration (Figure 4B).”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > Chronic TAC administration ameliorates brain aging.
What the sources say
- Supportedcites [36] Rea, 2018, Age and Age-Related Diseases: Role of Inflammation Triggers and Cytokines, Front. Immunol. source
Citation 36 is attached to the background statement about cytokine dysregulation and aging, not to the TAC result. The Pro-Inflammatory Cytokines in Aging and Age-Related Disease section says major pro-inflammatory cytokines contribute to inflamm-aging and play a major role in age-related diseases. The source does not need to report the TAC experiment to support the cited portion of the sentence. (LLM, conf=0.93)
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“A selective AP-1 inhibitor T-5224 that specifically blocks FOS/AP-1 binding to DNA without affecting their expression23 impaired TAC-induced expression of TERT (Figures 2K and S2C).”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > TAC activates the MEK/ERK/AP-1 cascade to directly upregulate TERT gene transcription.
What the sources say
- Not checked — no full text of the sourcecites [23] Aikawa, 2008, Treatment of arthritis with a selective inhibitor of c-Fos/activator protein-1, Nat. Biotechnol. source
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In addition, TAC treatment did not elicit any significant change in the global translation rate (Figure S2B), providing evidence that TAC treatment specifically induces TERT expression and its downstream transcriptional effects without affecting general mRNA translation.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > TAC activates the MEK/ERK/AP-1 cascade to directly upregulate TERT gene transcription.
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In the brain, TAC alleviates neuroinflammation, increases neurotrophic factors, stimulates adult neurogenesis and preserves cognitive function without evident toxicity, including cancer risk.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“TAC treatment resulted in a dose-dependent induction of TERT mRNA in primary human fibroblasts MRC-5 (Figures 1C and 1D).”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > Identification of a small molecule activator of TERT expression.
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Moreover, TAC (intraperitoneal (i.p.) injection of 6 mg/kg) increased human TERT gene expression across multiple tissues of hTERT-Rluc transgenic mice including brain, heart and skeletal muscle (Figure 1F).”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > Identification of a small molecule activator of TERT expression.
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“We found that TAC (0.5 μM) was able to induce TERT expression in WS fibroblasts (Figures 1G and S1G).”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > Identification of a small molecule activator of TERT expression.
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Further, our comprehensive survey demonstrates that TAC up-regulates human TERT transcription independently of cell- or tissue-types.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > Identification of a small molecule activator of TERT expression.
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Consistent with our observation of endogenous TERT levels, TAC induced TERT reporter activity in human fibroblasts (Figure 2I).”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > TAC activates the MEK/ERK/AP-1 cascade to directly upregulate TERT gene transcription.
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Chromatin immunoprecipitation followed by real-time quantitative PCR (ChIP-qPCR) analysis showed that TAC treatment led to recruitment of endogenous FOS, a subunit of AP-1 complex, to two AP-1 binding motifs in the endogenous TERT promoter (Figure 2J).”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > TAC activates the MEK/ERK/AP-1 cascade to directly upregulate TERT gene transcription.
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Through transcriptome profiling of human normal fibroblasts and induced pluripotent stem cell (iPSC)-derived neurons, we observed that acute treatment with TAC (0.5 μM for 1 hr) resulted in the significant induction of only a limited number of common genes in both human cell types (Figure 2D).”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > TAC activates the MEK/ERK/AP-1 cascade to directly upregulate TERT gene transcription.
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Immunoblot analysis demonstrated that the screening hit TAC induced the highest level of protein expression and therefore it was chosen for further analyses (Figure S1C).”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > Identification of a small molecule activator of TERT expression.
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In the paper
“Here, we report the identification of a TERT activator compound (TAC) that upregulates TERT transcription via the MEK/ERK/AP-1 cascade.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Further analysis of cell-type-specific effects in primary cells revealed that TAC (0.5 μM) can trigger expression of endogenous Tert gene in both mouse proliferating and post-mitotic cells within the physiological range (Figures S1D, S1E and S1F).”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > Identification of a small molecule activator of TERT expression.
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Of note, single and double deletions including the AP-1 binding motif common in the promoters of both mouse and human significantly abolished TAC-induced TERT promoter activity (Figure 2I), highlighting that the conserved AP-1 cis-element has a more prominent function in inducing TERT transcription compared to the other.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > TAC activates the MEK/ERK/AP-1 cascade to directly upregulate TERT gene transcription.
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In the brain, TAC alleviates neuroinflammation, increases neurotrophic factors, stimulates adult neurogenesis and preserves cognitive function without evident toxicity, including cancer risk.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > Abstract
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In the paper
“In the brain, TAC alleviates neuroinflammation, increases neurotrophic factors, stimulates adult neurogenesis and preserves cognitive function without evident toxicity, including cancer risk.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“We found that phosphorylation of extracellular signal-regulated kinase (ERK) and its downstream effector S6 kinase was consistently increased by TAC treatment in primary human MRC-5 cells (Figures 2A and 2B).”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > TAC activates the MEK/ERK/AP-1 cascade to directly upregulate TERT gene transcription.
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Our biochemical and cell-based assays show that TAC fine-tunes MEK/ERK/FOS signaling pathway, resulting in transient upregulation of TERT expression in the physiological range.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > DISCUSSION
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In the paper
“Further confirmation of TAC-induced adult neurogenesis was obtained with the immature neuron marker PSA-NCAM, revealing a higher number of DCX+ PSA-NCAM+ immature neurons in TAC-treated mice relative to controls (Figures 4E and S5D).”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > Chronic TAC administration ameliorates brain aging.
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“We report the discovery of a novel small molecule telomerase activator that induces the physiological expression of TERT in both human and mouse somatic tissues.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > DISCUSSION
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In the paper
“Specifically, relative to vehicle-treated controls, TAC-treated PBMCs exhibited repression of p16Ink4a, a key driver and biomarker of in vivo senescence and aging, as well as other senescence-associated secretory phenotype (SASP) components – Il-1α, Il-1β, Mmp-3 and Vegf (Figure 3B).”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > TAC attenuates multiple aging hallmarks in vivo.
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In the paper
“TAC-treated animals displayed a prominent reduction in the cell density and soma size of IBA1-positive microglia in the hippocampus.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > Chronic TAC administration ameliorates brain aging.
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Intraperitoneal administration of TAC, followed by the time-dependent quantification of TAC levels by mass spectrometry-based pharmacokinetics, demonstrated favorable plasma exposure for TAC (T1/2: 0.568 h, AUC: 285 h·ng/ml) (Figures S3A and S3B).”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > TAC attenuates multiple aging hallmarks in vivo.
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Real-time methylation-specific PCR (MSR) was used to detect the methylation of CpG islands flanking the translation start site of murine p16Ink4a 28,29, revealing a significant increase in methylated CpG sites at the promoter region of p16Ink4a in middle-aged mouse tissues after TAC treatment compared with vehicle controls (Figure 3H).”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > TAC attenuates multiple aging hallmarks in vivo.
What the sources say
- Not checked — no full text of the sourcecites [28] Sharpless, 2001, Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis, Nature source
- Not checked — no full text of the sourcecites [29] Lo, 1999, Quantitative analysis of aberrant p16 methylation using real-time quantitative methylation-specific polymerase chain reaction, Cancer Res.
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Following a six-month treatment course (i.p. injection of either vehicle or 6 mg/kg/day of TAC, three times a week), 26~27-month-old (aged) mice treated with TAC showed improved performance on three hippocampal-dependent cognitive tests – Barnes maze, Y-maze and novel-location recognition tasks (Figures 4H, 4I, S5F and S5G).”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > Chronic TAC administration ameliorates brain aging.
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In the paper
“Consistent with a crucial role for activated microglia as the primary source of pro-inflammatory cytokines in the brain,39 the age-related increases in expression of pro-inflammatory cytokines including Il-1β, Il-6, and Tnf-α were also attenuated in TAC-treated hippocampus relative to vehicle-treated controls (Figure 4G).”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > Chronic TAC administration ameliorates brain aging.
What the sources say
- Not checked — no full text of the sourcecites [39] Lynch, 2009, The multifaceted profile of activated microglia, Mol. Neurobiol. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Consistent with previous in vivo experiments, TERT protein levels were significantly increased in PBMCs from middle-aged mice treated with TAC (Figure S4A).”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > TAC attenuates multiple aging hallmarks in vivo.
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“TAC administration significantly attenuated the levels of IBA1-positive activated microglia in the brains of aging mice relative to vehicle-treated controls (Figure 4F).”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > Chronic TAC administration ameliorates brain aging.
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Consistent with these reports, immunoblotting and mature BDNF (mBDNF)-specific enzyme-linked immunosorbent assay (ELISA) demonstrated a marked increase in the levels of mature BDNF as well as TERT in adult hippocampus following one-week administration of TAC (Figures S5A, S5B and S5C).”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > Chronic TAC administration ameliorates brain aging.
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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“While it is encouraging that long-term TAC treatment was well-tolerated without any overt or histological adverse effects including carcinogenesis.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > DISCUSSION
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In the paper
“Moreover, pathway enrichment analysis revealed that TAC treatment resulted in the activation of pathways associated with synaptic potential, axon guidance, hippocampus/stem cell development, telomere maintenance, neuroblast proliferation, dopaminergic neurogenesis/CNS neuron differentiation, and MAPK family signaling cascades in the hippocampus of middle-aged mice (Figure 4B).”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > Chronic TAC administration ameliorates brain aging.
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Notably, immunohistochemical and immunofluorescent analyses demonstrated that TAC treatment for 4 weeks markedly increased the number of doublecortin (DCX)-expressing newborn neurons in the hippocampal dentate gyrus (DG) (Figures 4C and 4D), indicating that TAC can indeed enhance the regenerative capacity of the aged brain.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > Chronic TAC administration ameliorates brain aging.
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Correspondingly, chromatin IP followed by sequencing (ChIP-Seq) analysis demonstrated that TERT bound to the DNMT3b promoter in human iPSC-derived neurons (Figure 3G).”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > TAC attenuates multiple aging hallmarks in vivo.
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Following a one-week treatment course (daily i.p. injection of 6 mg/kg/day), transcriptome analysis revealed a reduction in aging gene signatures including cell cycle arrest and PML body, which are established key cellular changes associated with aging PBMCs of middle-aged C57BL/6 mice (Figure 3A).”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > TAC attenuates multiple aging hallmarks in vivo.
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Across a wide range of tissues, a one-week course of TAC treatment decreased expression of the classical senescence marker p16Ink4a, but not p21Cip1, in the brain, skeletal muscle, kidney, heart and liver of middle-aged (10~12-month-old) mice (Figures 3D, S4B–S4D).”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > TAC attenuates multiple aging hallmarks in vivo.
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This CNS exposure corresponded to an increase in the signaling cascade upstream of TERT transcription within 0.5 to 3 hr post-administration, mirroring the rapid induction of hTERT promoter activity observed in brain tissues of TAC-treated transgenic mice (Figure 1F).”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > TAC attenuates multiple aging hallmarks in vivo.
plaindirect- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“this human hTERT reporter transgene is capable of mirroring and recapitulating the key transcriptional and functional aspects of the regulation of TERT gene expression in normal mouse somatic tissues, thus providing a useful tool for preclinical drug screening.20”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > Identification of a small molecule activator of TERT expression.
What the sources say
- Not checked yetcites [20] Jia, 2011, A BAC transgenic reporter recapitulates in vivo regulation of human telomerase reverse transcriptase in development and tumorigenesis, FASEB J. source
Checked before — its earlier verdict is held back until a new check runs.
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Not checked yet
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“highlighting that the conserved AP-1 cis-element has a more prominent function in inducing TERT transcription compared to the other.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > TAC activates the MEK/ERK/AP-1 cascade to directly upregulate TERT gene transcription.
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > Abstract
boosteddirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“indicating that TAC can override the repressive chromatin state of the human TERT locus.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > Identification of a small molecule activator of TERT expression.
hedgeddirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > Abstract
boosteddirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“indicating that TAC can indeed enhance the regenerative capacity of the aged brain.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > Chronic TAC administration ameliorates brain aging.
hedgeddirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, physiological TERT activation hold promise in assuaging aging phenotypes during natural aging in mice (Figure 5).”
§ TERT activation targets DNA methylation and multiple aging hallmarks > DISCUSSION
hedgedconditional- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Somatic TERT de-repression via TAC administration confers cellular and organismal benefits via canonical and non-canonical telomerase functions.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and that fine-tuning of the ERK-AP-1-TERT signaling axis induces beneficial effects on biological aging.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Together, these data indicate that TAC specifically activates the transcriptional activation of TERT via the MEK/ERK/AP-1 pathway.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > TAC activates the MEK/ERK/AP-1 cascade to directly upregulate TERT gene transcription.
hedgeddirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Nevertheless, our findings provide ample evidence that the ERK/AP-1 cascade functions as a prime genetic switch regulating TAC-induced somatic TERT expression and that fine-tuning of the ERK-AP-1-TERT signaling axis induces beneficial effects on biological aging.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > DISCUSSION
boosteddirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“indicating a positive correlation between TERT levels and Dnmt3b expression in vivo.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > TAC attenuates multiple aging hallmarks in vivo.
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“indicating the requirement of TERT for TAC-induced silencing of p16Ink4a.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > TAC attenuates multiple aging hallmarks in vivo.
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- It may state two separate claims as one. 40
- Probably not a substantial claim. 22
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > INTRODUCTION
What the sources say
- Partly supportedcites [15] Jaskelioff, 2011, Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice, Nature sourceExperimental — accuracy not yet measured
The Abstract and main-text tissue analyses (page unavailable) report that TERT reactivation extended telomeres and reversed degeneration in highly proliferative organs of telomerase-deficient mice. The brain analyses also report restored neural progenitor proliferation and telomere elongation in the subventricular zone. They do not establish a second, telomere-independent mechanism involving gene-expression modulation in post-mitotic tissues. (LLM, conf=0.88)
- Partly supportedcites [16] Shim, 2021, Telomerase Reverse Transcriptase Preserves Neuron Survival and Cognition in Alzheimer's Disease Models, Nat Aging sourceExperimental — accuracy not yet measured
The Introduction reports that TERT reactivation improved outcomes in telomere-dysfunctional mice and that post-mitotic cells showed improved function, but says a mechanism unrelated to telomere synthesis is suggested, not established. The Discussion describes telomere synthesis in proliferative cells and gene-expression modulation in post-mitotic tissues; it does not establish both as mechanisms by which reactivation reversed aging in those mice. Page numbers are unavailable in our copy. (LLM, conf=0.85)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“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”
§ TERT activation targets DNA methylation and multiple aging hallmarks > INTRODUCTION
What the sources say
- Not checked yetcites [4] Frenk, 2018, Gene expression hallmarks of cellular ageing, Biogerontology source
Checked before — its earlier verdict is held back until a new check runs.
- Supportedcites [5] Booth, 2016, The Aging Epigenome, Mol. Cell source
The Aging Epigenomic Regulatory Landscape section says age-associated epigenomic changes contribute to changes in gene expression, which can change drastically during aging. The Introduction says these changes may give rise to aging phenotypes and diseases, and that evidence suggests they can occur early and be causative. This supports the claim’s qualified wording that they can initiate aging processes. (LLM, conf=0.89)
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
- Not checked yet
Every source the paper cites for this claim was checked and supports it.
In the paper
“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”
§ TERT activation targets DNA methylation and multiple aging hallmarks > INTRODUCTION
What the sources say
- Supportedcites [2] Chakravarti, 2021, Telomeres: history, health, and hallmarks of aging, Cell source
The “Crosstalk between Dysfunctional Telomeres and the Hallmarks of Cellular Aging” section identifies telomere dysfunction as a hallmark and says it can drive or amplify other hallmarks. Its subsections link telomere dysfunction to genomic instability, stem cell exhaustion, and mitochondrial dysfunction; the “Telomere dysfunction and telomerase in age-related diseases” section says telomere attrition can trigger senescence. (LLM, conf=0.93)
- Supportedcites [7] Sahin, 2010, Linking functional decline of telomeres, mitochondria and stem cells during ageing, Nature source
The Abstract links telomere damage to stem-cell decline and mitochondrial dysfunction, presenting the mitochondrial connection as a proposed model. The “Telomeres and ageing” section links telomere erosion to cellular senescence and chromosomal instability. Together, these passages support the claim’s qualified wording, “can contribute.” (LLM, conf=0.90)
plainconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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”
§ TERT activation targets DNA methylation and multiple aging hallmarks > INTRODUCTION
What the sources say
- Not checked — no full text of the sourcecites [9] Vulliamy, 2001, The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita, Nature source
- Partly supportedcites [10] Yamaguchi, 2005, Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia, N. Engl. J. Med. sourceExperimental — accuracy not yet measured
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)
- Supportedcites [11] Armanios, 2007, Telomerase mutations in families with idiopathic pulmonary fibrosis, N. Engl. J. Med. source
The Abstract reports that germ-line mutations in the core telomerase components hTERT and hTR occur in some families with idiopathic pulmonary fibrosis, a progressive and often fatal disease. The Discussion links short telomeres to limited renewal of bronchoalveolar epithelium. The paper supports a link in a subset of familial cases, not all idiopathic pulmonary fibrosis. (LLM, conf=0.91)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Conversely, enforced expression of TERT stabilizes endogenous telomeres, reduces senescence-associated markers and restores the proliferative lifespan in mammals.12–14”
§ TERT activation targets DNA methylation and multiple aging hallmarks > INTRODUCTION
What the sources say
- Not checked — no full text of the sourcecites [12] Bodnar, 1998, Extension of life-span by introduction of telomerase into normal human cells, Science source
- Not checked — no full text of the sourcecites [13] Tomás-Loba, 2008, Telomerase reverse transcriptase delays aging in cancer-resistant mice, Cell source
- Partly supportedcites [14] Bernardes de Jesus, 2012, Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer, EMBO Mol. Med. sourceExperimental — accuracy not yet measured
The Results report longer telomeres and fewer short telomeres in tissues of TERT-treated mice, as well as reduced p16, a senescence marker, in most organs studied. The Discussion interprets lower p16 as a sign of extended renewal and proliferative capacity, but the paper does not demonstrate restoration of proliferative lifespan; its experiments were in mice, not mammals generally. Our copy provides no page numbers for these passages. (LLM, conf=0.87)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Notably, modulating chromatin modifier activity has shown promise in mitigating multiple aging risk factors and associated disease phenotypes on the organismal level.6”
§ TERT activation targets DNA methylation and multiple aging hallmarks > INTRODUCTION
What the sources say
- Partly supportedcites [6] Benayoun, 2015, Epigenetic regulation of ageing: linking environmental inputs to genomic stability, Nat. Rev. Mol. Cell Biol. sourceExperimental — accuracy not yet measured
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)
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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”
§ TERT activation targets DNA methylation and multiple aging hallmarks > INTRODUCTION
What the sources say
- Partly supportedcites [15] Jaskelioff, 2011, Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice, Nature sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [16] Shim, 2021, Telomerase Reverse Transcriptase Preserves Neuron Survival and Cognition in Alzheimer's Disease Models, Nat Aging sourceExperimental — accuracy not yet measured
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)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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”
§ TERT activation targets DNA methylation and multiple aging hallmarks > INTRODUCTION
What the sources say
- Partly supportedcites [2] Chakravarti, 2021, Telomeres: history, health, and hallmarks of aging, Cell sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [7] Sahin, 2010, Linking functional decline of telomeres, mitochondria and stem cells during ageing, Nature sourceExperimental — accuracy not yet measured
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)
- Not checked — no full text of the sourcecites [8] Sharpless, 2007, How stem cells age and why this makes us grow old, Nat. Rev. Mol. Cell Biol. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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”
§ TERT activation targets DNA methylation and multiple aging hallmarks > INTRODUCTION
What the sources say
- Supportedcites [1] López-Otín, 2013, The hallmarks of aging, Cell source
The Telomere Attrition section identifies telomere dysfunction as a hallmark of aging and links telomere damage to senescence, apoptosis, and premature disease. Conclusions and Perspectives classifies telomere loss among the primary hallmarks and describes primary hallmarks as potential initiating triggers that accelerate other, interconnected hallmarks. (LLM, conf=0.88)
- Supportedcites [2] Chakravarti, 2021, Telomeres: history, health, and hallmarks of aging, Cell source
The Introduction describes telomeres as an instigator or amplifier of circuitry driving aging and associated diseases. The Crosstalk section identifies telomere dysfunction as a hallmark of aging, while its Genomic instability subsection describes chromosomal damage caused by dysfunctional telomeres. The copy calls it one of nine hallmarks, rather than using the word “primary.” (LLM, conf=0.91)
- Partly supportedcites [7] Sahin, 2010, Linking functional decline of telomeres, mitochondria and stem cells during ageing, Nature sourceExperimental — accuracy not yet measured
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)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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”
§ TERT activation targets DNA methylation and multiple aging hallmarks > DISCUSSION
What the sources say
- Partly supportedcites [43] Pérez-Jeldres, 2019, Targeting Cytokine Signaling and Lymphocyte Traffic via Small Molecules in Inflammatory Bowel Disease: JAK Inhibitors and S1PR Agonists, Front. Pharmacol. sourceExperimental — accuracy not yet measured
The Introduction section, “Differences Between Small Molecules and Monoclonal Antibodies” (page unavailable), identifies non-immunogenicity and usually lower manufacturing costs as advantages of small molecules. It does not establish that they are cost-effective relative to biologics; lower manufacturing cost alone does not demonstrate cost-effectiveness. (LLM, conf=0.84)
- Not checked — no full text of the sourcecites [44] Olivera, 2017, Next generation of small molecules in inflammatory bowel disease, Gut source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > Chronic TAC administration ameliorates brain aging.
What the sources say
- Partly supportedcites [40] Bellantuono, 2020, A toolbox for the longitudinal assessment of healthspan in aging mice, Nat. Protoc. sourceExperimental — accuracy not yet measured
The Anticipated Results section says rotarod time declines with age in mice. It says grip strength measured with a grip-strength meter may decline with age, but not every group has observed this; thus the unqualified statement that both measures are known to decline overstates the source. The TAC-treated mice’s improvements are attributed to the citing paper’s own figures, not to this source. (LLM, conf=0.84)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources that could be checked couldn’t confirm or dispute this claim.
In the paper
“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.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > STAR★METHODS > RESOURCE AVAILABILITY
What the sources say
- Could not verifycites [55] Chakravarti, 2020, Telomere dysfunction activates YAP1 to drive tissue inflammation, Nat. Commun. sourceExperimental — accuracy not yet measured
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)
- Could not verifycites [56] Anders, 2015, HTSeq--a Python framework to work with high-throughput sequencing data, Bioinformatics sourceExperimental — accuracy not yet measured
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)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Could not verify
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“TERT levels are tightly regulated in normal adult somatic cells and further repressed in aged tissues and in the Alzheimer’s Disease brain.16”
§ TERT activation targets DNA methylation and multiple aging hallmarks > DISCUSSION
What the sources say
- Partly supportedcites [16] Shim, 2021, Telomerase Reverse Transcriptase Preserves Neuron Survival and Cognition in Alzheimer's Disease Models, Nat Aging sourceExperimental — accuracy not yet measured
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)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Telomerase activity is tightly regulated in most adult somatic cells, primarily due to transcriptional repression of TERT.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Conversely, TAC treatment concurrently induced signatures of organism growth and natural killer cell activation (Figure 3C), which are known to decline with age.25”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > TAC attenuates multiple aging hallmarks in vivo.
What the sources say
- Partly supportedcites [25] Brauning, 2022, Aging of the Immune System: Focus on Natural Killer Cells Phenotype and Functions, Cells sourceExperimental — accuracy not yet measured
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)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > Chronic TAC administration ameliorates brain aging.
What the sources say
- Partly supportedcites [14] Bernardes de Jesus, 2012, Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer, EMBO Mol. Med. sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [15] Jaskelioff, 2011, Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice, Nature sourceExperimental — accuracy not yet measured
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)
- Partly supportedcites [16] Shim, 2021, Telomerase Reverse Transcriptase Preserves Neuron Survival and Cognition in Alzheimer's Disease Models, Nat Aging sourceExperimental — accuracy not yet measured
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)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“our sample sizes are similar to those reported in previous publications.15,24,86”
§ TERT activation targets DNA methylation and multiple aging hallmarks > STAR★METHODS > METHOD DETAILS
What the sources say
- Supportedcites [15] Jaskelioff, 2011, Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice, Nature source
The cited paper reports sample sizes, providing a previous-publication example for the citing sentence. Its Figure 5 legend lists n≥10 for brain weights, n=2 for g-ratio measurements, and n=4 for olfactory tests; the Innate olfactory avoidance test section also specifies n=4 per experimental condition. (LLM, conf=0.86)
- Could not verifycites [24] Sahin, 2011, Telomere dysfunction induces metabolic and mitochondrial compromise, Nature sourceExperimental — accuracy not yet measured
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)
- Supportedcites [86] Iaccarino, 2016, Gamma frequency entrainment attenuates amyloid load and modifies microglia, Nature source
The Methods (Analysis of electrophysiology recordings) state that the paper's sample size was consistent with previous publications and that the sample size for each experiment is specified in its figure legend. This source is itself a previous publication reporting sample sizes, so it supports the citation's use as an example. (LLM, conf=0.88)
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Correspondingly, TERT reactivation in aged inducible-TERT mice was shown to reverse aging phenotypes without causing an increase in cancer.15”
§ TERT activation targets DNA methylation and multiple aging hallmarks > DISCUSSION
What the sources say
- Supportedcites [15] Jaskelioff, 2011, Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice, Nature source
The Abstract reports reversal of degenerative phenotypes in late-generation inducible TERT-ER mice. The discussion says the brief course of telomerase reactivation was not sufficient to promote carcinogenesis, while cautioning that longer treatment or treatment later in life might do so. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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”
§ TERT activation targets DNA methylation and multiple aging hallmarks > DISCUSSION
What the sources say
- Supportedcites [46] Zhang, 2015, Curcumin Improves Amyloid beta-Peptide (1-42) Induced Spatial Memory Deficits through BDNF-ERK Signaling Pathway, PLoS One source
The Discussion (page not provided) reports that curcumin improved cognition in Aβ-treated rats and that an ERK inhibitor blocked the improvement. This supports the curcumin portion of the sentence; the separate citation alongside this one appears to serve the apigenin example. (LLM, conf=0.93)
- Partly supportedcites [47] Venigalla, 2015, Curcumin and Apigenin - novel and promising therapeutics against chronic neuroinflammation in Alzheimer's disease, Neural Regen. Res. sourceExperimental — accuracy not yet measured
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)
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“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”
§ TERT activation targets DNA methylation and multiple aging hallmarks > DISCUSSION
What the sources say
- Partly supportedcites [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) sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
- Partly supportedcites [49] Chappell, 2011, Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR inhibitors: rationale and importance to inhibiting these pathways in human health, Oncotarget sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
- Not checked — no full text of the sourcecites [50] Deschênes-Simard, 2014, ERKs in cancer: friends or foes?, Cancer Res. source
- Partly supportedcites [51] Ayaz, 2019, Flavonoids as Prospective Neuroprotectants and Their Therapeutic Propensity in Aging Associated Neurological Disorders, Front. Aging Neurosci. sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Partly supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > Identification of a small molecule activator of TERT expression.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In the brain, TAC alleviates neuroinflammation, increases neurotrophic factors, stimulates adult neurogenesis and preserves cognitive function without evident toxicity, including cancer risk.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > Identification of a small molecule activator of TERT expression.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > Identification of a small molecule activator of TERT expression.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > TAC activates the MEK/ERK/AP-1 cascade to directly upregulate TERT gene transcription.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > TAC activates the MEK/ERK/AP-1 cascade to directly upregulate TERT gene transcription.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > TAC activates the MEK/ERK/AP-1 cascade to directly upregulate TERT gene transcription.
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“No change in body weight was detected between the two groups throughout the study (Figure S5E).”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > Chronic TAC administration ameliorates brain aging.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > TAC attenuates multiple aging hallmarks in vivo.
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Notably, TAC exhibited central nervous system exposure, with approximately two-fold partitioning of the compound in the central nervous system (CNS) relative to plasma.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > TAC attenuates multiple aging hallmarks in vivo.
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“TAC is cleared from the plasma by 3 hr with plasma levels tracking those in the brain (Figures S3C and S3D).”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > TAC attenuates multiple aging hallmarks in vivo.
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > TAC attenuates multiple aging hallmarks in vivo.
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > TAC activates the MEK/ERK/AP-1 cascade to directly upregulate TERT gene transcription.
What the sources say
- Not checked — no full text of the sourcecites [22] Angel, 1991, The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation, Biochim. Biophys. Acta source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“providing evidence that TAC treatment specifically induces TERT expression and its downstream transcriptional effects without affecting general mRNA translation.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > TAC activates the MEK/ERK/AP-1 cascade to directly upregulate TERT gene transcription.
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > Identification of a small molecule activator of TERT expression.
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“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”
§ TERT activation targets DNA methylation and multiple aging hallmarks > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites [53] Artandi, 2000, Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice, Nature source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The mice and cells were randomly assigned to control or experimental groups, except in experiments that required specific genotypes and ages.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > STAR★METHODS > METHOD DETAILS
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The multifaceted organismal and functional benefits may arise from a combination of TERT’s canonical and non-canonical functions.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > DISCUSSION
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“TAC possesses a low molecular weight (<400 Da) and lipophilicity that favor drug uptake across all tissues, including the CNS.45”
§ TERT activation targets DNA methylation and multiple aging hallmarks > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites [45] Bharate, 2018, Why Are the Majority of Active Compounds in the CNS Domain Natural Products? A Critical Analysis, J. Med. Chem. source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > STAR★METHODS > RESOURCE AVAILABILITY
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“TAC effectively counteracts the epigenetic silencing of the TERT gene in adult somatic cells, thereby influencing the expression of genes governing aging hallmarks.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Naturally aged (20~21-month-old) C57BL/6 mice were randomized into TAC and vehicle treatment groups.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > Chronic TAC administration ameliorates brain aging.
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This study highlights the significant regenerative capacity of aging organ systems as well as the ability to pharmacologically modulate aging hallmarks during natural aging.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“No animal or sample was excluded from the analysis.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > STAR★METHODS > METHOD DETAILS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The mutations were confirmed by sequencing.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > STAR★METHODS > METHOD DETAILS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > Chronic TAC administration ameliorates brain aging.
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, pharmacological activation of TERT induces rejuvenation-associated gene signatures and stimulates adult neurogenesis in the hippocampus of adult mice.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > Chronic TAC administration ameliorates brain aging.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, TAC-driven TERT upregulation reduces age-dependent tissue senescence and regulates major genetic drivers of cellular senescence, including p16Ink4a and SASP components.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > RESULTS > TAC attenuates multiple aging hallmarks in vivo.
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“No statistical methods were used to predetermine sample sizes”
§ TERT activation targets DNA methylation and multiple aging hallmarks > STAR★METHODS > METHOD DETAILS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The investigators were generally not blinded to allocation during experiments and outcome assessment.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > STAR★METHODS > METHOD DETAILS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“For ChIP-seq, control immunoprecipitation was done in parallel without antibodies.”
§ TERT activation targets DNA methylation and multiple aging hallmarks > STAR★METHODS > METHOD DETAILS
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
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.”
Citations
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Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2
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The Sequence Alignment/Map format and SAMtools
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Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625
Ultrafast and memory-efficient alignment of short DNA sequences to the human genome.
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HTSeq—a Python framework to work with high-throughput sequencing data
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Model-based Analysis of ChIP-Seq (MACS)
Zhang, Y., Liu, T., Meyer, C. A., Eeckhoute, J., Johnson, D. S., Bernstein, B. E., Nusbaum, C., Myers, R. M., Brown, M., Li, W., et al. (2008) · Genome Biology · doi:10.1186/gb-2008-9-9-r137 · Cited by 18,386
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Mootha, V. K., Lindgren, C. M., Eriksson, K.-F., Subramanian, A., Sihag, S., Lehar, J., Puigserver, P., Carlsson, E., Ridderstråle, M., Laurila, E., et al. (2003) · Nature Genetics · doi:10.1038/ng1180 · Cited by 10,197
Extension of Life-Span by Introduction of Telomerase into Normal Human Cells
Bodnar, A. G., Ouellette, M., Frolkis, M., Holt, S. E., Chiu, C.-P., Morin, G. B., Harley, C. B., Shay, J. W., Lichtsteiner, S., & Wright, W. E. (1998) · Science · doi:10.1126/science.279.5349.349 · Cited by 4,975
Telomere measurement by quantitative PCR
Cawthon, R. (2002) · Nucleic Acids Research · doi:10.1093/nar/30.10.e47 · Cited by 3,550
Cited by
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Epigenetic ageing clocks: statistical methods and emerging computational challenges
Teschendorff, A. E., & Horvath, S. (2025) · Nature Reviews Genetics · doi:10.1038/s41576-024-00807-w · Cited by 226
Wu, Z., Qu, J., & Liu, G.-H. (2024) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00775-3 · Cited by 118
Liu, B., Peng, Z., Zhang, H., Zhang, N., Liu, Z., Xia, Z., Huang, S., Luo, P., & Cheng, Q. (2025) · Molecular Cancer · doi:10.1186/s12943-025-02284-z · Cited by 86
Immune Alterations with Aging: Mechanisms and Intervention Strategies
Yu, W., Yu, Y., Sun, S., Lu, C., Zhai, J., Lei, Y., Bai, F., Wang, R., & Chen, J. (2024) · Nutrients · doi:10.3390/nu16223830 · Cited by 53
Biomarkers of ageing of humans and non-human primates
Wu, Z., Qu, J. T., Zhang, W., Bao, Z., Bi, Y., Cai, J.-P., Cai, S.-Q., Cao, C.-M., Cao, F., Cao, Z., et al. (2025) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-025-00883-8 · Cited by 52
Self-citation
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)
- 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
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 389 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- 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
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.
A language model drew the claims from the paper on 2026-11-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-11-09 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (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.
What counts as a claim ›How we measure confidence ›How we check this ›
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