Telomere dysfunction in ageing and age-related diseases

In the paper

“alleviated plaque formation and disease progression46,118”

What the sources say

• Disputed

  In the section on hypercholesterolemia-induced vascular pathology, the paper reports that senolytic treatment did not affect intimal plaque size or overall plaque lipid content. It found reduced plaque calcification and improved vascular function, but those findings do not establish that treatment alleviated plaque formation or disease progression. (LLM, conf=0.88)

  Checked by a reasoning model — may be wrong.

  cites [46] Roos, C. M. et al. Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell 15, 973–977 (2016). sourceExperimental — accuracy not yet measured
• Supported

  The passage indexed under Abstract reports that removing senescent cells from early fatty streaks led to lesion regression and that clearing them from advanced lesions inhibited plaque growth. Another passage in the same indexed section reports attenuated disease progression in treated atherosclerosis-prone mice. The evidence is from mice, not patients. (LLM, conf=0.93)

  cites [118] Childs, B. G. et al. Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science 354, 472–477 (2016). source

In the paper

“Such short telomeres, however, retain a sufficient number of telomere-binding proteins to inhibit DNA repair and avoid fusions5, and consequently fuel a persistent DNA damage signal that enforces a permanent DNA damage-induced proliferative arrest.”

What the sources say

• Supported

  In “A three-state model of chromosome-end protection” (page unavailable), the paper says intermediate-state telomeres retain TRF2, which prevents end joining despite a DNA damage response. “Telomeres as epigenetic sensors of cellular stress” (page unavailable) describes persistent, unrepaired damage-response foci and cell-cycle arrest at senescence. The paper specifically identifies the inhibited repair process as end joining. (LLM, conf=0.92)

  cites [5] Cesare, A. J. & Karlseder, J. A three-state model of telomere control over human proliferative boundaries. Curr. Opin. Cell Biol. 24, 731–738 (2012). source

In the paper

“Importantly, senescent cells secrete a complex set of pro-inflammatory cytokines, known as the senescence-associated secretory phenotype (SASP). This alters the composition of the extracellular matrix, impairs stem cell functions, promotes cell transdifferentiation and can spread the senescence phenotype to surrounding cells, thereby causing systemic chronic inflammation12.”

What the sources say

• Partly supported

  The Figure 2 passage links the SASP to extracellular-matrix degradation and says it appears to spread between cells. The SASP section says its cytokines can cause epithelial-to-mesenchymal transitions, but describes systemic inflammation as potential and context-dependent. Figure 2 attributes removal from the progenitor/stem-cell pool to senescence, not specifically to SASP-mediated impairment of stem-cell function. (LLM, conf=0.87)

  cites [12] Tchkonia, T., Zhu, Y., van Deursen, J., Campisi, J. & Kirkland, J. L. Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J. Clin. Invest. 123, 966–972 (2013). sourceExperimental — accuracy not yet measured

In the paper

“In addition to irreversible cell cycle arrest, cellular senescence is characterized by changes in chromatin, gene expression, organelles and cell morphology11.”

What the sources say

• Supported

  The Definition and Characteristics section describes senescence as a generally irreversible cell-cycle arrest. The Chromatin Landscape, Senescence-Associated (Epi-)genetic and Gene Expression Changes, and Deregulated Metabolic Profile sections describe changes in chromatin, gene expression, and mitochondria; Challenges to Detect Senescent Cells in Humans describes altered cell size and nuclear morphology. The paper qualifies the arrest as generally, rather than invariably, irreversible. (LLM, conf=0.89)

  cites [11] Gorgoulis, V. et al. Cellular senescence: defining a path forward. Cell 179, 813–827 (2019). source

In the paper

“SASP is both promoted by DDR13 and can promote DDR and TAF formation in an autocrine and paracrine fashion14–16.”

What the sources say

• Supported

  This source is cited for the first clause: that DDR promotes the SASP. The paper reports that DDR signaling drives a subset of SASP factors, including IL-6 and IL-8, while explicitly noting that it does not regulate the entire SASP. The later claim about SASP promoting DDR and TAF formation is attached to citations 14–16, not this source. (LLM, conf=0.91)

  cites [13] Rodier, F. et al. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat. Cell Biol. 11, 973–979 (2009). source
• Partly supported

  The Discussion reports that CXCR2 expression increases DNA damage and that CXCR2 depletion diminishes DDR activation, supporting a link between senescence-associated chemokine signaling and DDR. But it does not report TAF formation, and it says whether secreted CXCR2 ligands act on normal cells in a paracrine fashion requires further investigation. The preceding claim that DDR promotes SASP carries a different citation and is not assessed here. (LLM, conf=0.88)

  cites [14] Acosta, J. C. et al. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 133, 1006–1018 (2008). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results and Discussion report that factors secreted by senescent melanocytes induce a DDR at telomeres and TAF in neighbouring cells, supporting the paracrine part. The Results also suggest autocrine CXCR3 signalling contributes to melanocyte senescence, but do not show that it induces DDR or TAF autocrinely. The claim that DDR promotes SASP is attached to citation 13, not this source. (LLM, conf=0.86)

  cites [15] Victorelli, S. et al. Senescent human melanocytes drive skin ageing via paracrine telomere dysfunction. EMBO J. 38, e101982 (2019). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section, “The SASP promotes telomere dysfunction in a paracrine manner” (page not available), reports that SASP factors induced DDR foci and telomere-associated damage foci in neighboring fibroblasts. The paper supports the paracrine part of the claim, but the passages do not establish that SASP promotes those foci through autocrine signaling. (LLM, conf=0.86)

  cites [16] Razdan, N., Vasilopoulos, T. & Herbig, U. Telomere dysfunction promotes transdifferentiation of human fibroblasts into myofibroblasts. Aging Cell 17, e12838 (2018). sourceExperimental — accuracy not yet measured

In the paper

“As telomeres reach a critical length, they become unable to bind enough telomere-capping proteins and are sensed as exposed DNA ends2, which activates the DDR pathways that, through the induction of the cell cycle inhibitors p21 and p16, arrest proliferation3,4.”

What the sources say

• Partly supported

  In “How Shelterin Solves the End-Protection Problem in Mammals” (page unavailable), the paper says telomeric repeats provide shelterin-binding sites and that shelterin prevents a DNA damage response at chromosome ends. It also reports that loss of TRF2 activates ATM at those ends. It does not establish the claimed critical-length threshold at which shortening leaves too few capping proteins; the p21/p16 portion is cited to other sources in the printed sentence. (LLM, conf=0.84)

  cites [2] de Lange, T. How telomeres solve the end-protection problem. Science 326, 948–952 (2009). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [3] d’Adda di Fagagna, F. et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature 426, 194–198 (2003). source
• ?Not checked — no full text of the sourcecites [4] Herbig, U., Jobling, W. A., Chen, B. P., Chen, D. J. & Sedivy, J. M. Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21CIP1, but not p16INK4a. Mol. Cell 14, 501–513 (2004). source

In the paper

“This initiates and maintains cellular senescence, a key contributor to organismal ageing and multiple age-related diseases6,7.”

What the sources say

• Supported

  The Introduction describes persistent stress signals initiating senescence and mechanisms that maintain its durable growth arrest. The Abstract says accumulating senescent cells contribute to aging-related diseases, while the Conclusions link that accumulation to increased susceptibility to age-associated diseases. The paper does not identify what the citing sentence means by “This,” so it cannot verify that specific antecedent. (LLM, conf=0.88)

  cites [6] He, S. & Sharpless, N. E. Senescence in health and disease. Cell 169, 1000–1011 (2017). source
• Supported

  The “Cellular senescence” section says DNA damage drives cells into senescence and that senescent cells contribute to ageing-associated pathologies, including atherosclerosis and osteoarthritis. “DNA damage-induced epigenetic alterations” describes persistent changes from irreparable DNA lesions that reinforce senescence, supporting its maintenance. Page numbers are unavailable in our copy. (LLM, conf=0.90)

  cites [7] Schumacher, B., Pothof, J., Vijg, J. & Hoeijmakers, J. H. J. The central role of DNA damage in the ageing process. Nature 592, 695–703 (2021). source

In the paper

“In independent cohorts, a shorter telomere length was demonstrated to be a robust independent predictor of disease progression, response to therapy and death55, and to be associated with a shorter time to allograft dysfunction following lung transplant56.”

What the sources say

• Partly supported

  The Results (Association between telomere length and survival time in ILD; Replication Cohorts) show that shorter telomere length independently predicted shorter transplant-free survival in three IPF cohorts. The Discussion says future studies are needed to determine whether telomere-based subgroups predict responsiveness to therapy. This source therefore supports the survival finding, but not the attributed prediction of treatment response or a separately measured disease-progression outcome. The lung-transplant allograft claim is attached to a different citation. (LLM, conf=0.90)

  cites [55] Stuart, B. D. et al. Effect of telomere length on survival in patients with idiopathic pulmonary fibrosis: an observational cohort study with independent validation. Lancet Respir. Med. 2, 557–565 (2014). sourceExperimental — accuracy not yet measured
• Supported

  Citation 56 is attached to the post-transplant allograft-dysfunction finding, not the preceding claims about IPF progression, treatment response, and death. The Results (Lung Allograft Dysfunction; page unavailable) report that lung-transplant recipients with shorter telomeres developed chronic lung allograft dysfunction sooner. The study was limited to patients transplanted for pulmonary fibrosis. (LLM, conf=0.94)

  cites [56] Newton, C. A. et al. Telomere length in patients with pulmonary fibrosis associated with chronic lung allograft dysfunction and post-lung transplantation survival. J. Heart Lung Transplant. 36, 845–853 (2017). sourceExperimental — accuracy not yet measured

In the paper

“Several lung diseases have been associated with ageing50 and causally linked to telomere dysfunction and senescent cell accumulation.”

What the sources say

• Supported

  Citation 50 is attached to the association with ageing, not to the subsequent causal claim. The Age-related pulmonary disease section states that advanced age is a major risk factor for COPD, interstitial fibrotic lung disease, and lung cancer. (LLM, conf=0.93)

  cites [50] Schneider, J. L. et al. The aging lung: physiology, disease, and immunity. Cell 184, 1990–2019 (2021). source

In the paper

“Although we describe diseases individually, grouped by the organs affected, individual patients with telomeropathies often show more than one clinical manifestation, which supports the notion of a “spectrum disorder”49 caused by telomere dysfunction.”

What the sources say

• Supported

  The “Consequences of impaired telomere maintenance” section says that pulmonary fibrosis, aplastic anemia, and liver cirrhosis frequently occur in the same patient at different times. It links these manifestations to impaired telomere maintenance and says they may be considered a single clinical spectrum disorder. (LLM, conf=0.94)

  cites [49] Holohan, B., Wright, W. E. & Shay, J. W. Cell biology of disease: telomeropathies: an emerging spectrum disorder. J. Cell Biol. 205, 289–299 (2014). source

In the paper

“Conversely, TAFs accumulate after chronic inflammation47, obesity37,41, mitochondrial dysfunction36 and impaired autophagy48, which are all known to accelerate ageing.”

What the sources say

• Supported

  The Results section (‘Feedback between inflammation and telomere dysfunction in vivo’) reports higher TAF frequencies in chronically inflamed nfkb1−/− mice and says ibuprofen prevented the increase. The Abstract reports that this chronic inflammation accelerated ageing in mice. Citation 47 is attached to chronic inflammation, not to the other conditions listed in the sentence; page numbers are not provided in our copy. (LLM, conf=0.93)

  cites [47] Jurk, D. et al. Chronic inflammation induces telomere dysfunction and accelerates ageing in mice. Nat. Commun. 2, 4172 (2014). source
• ?Not checked — no full text of the sourcecites [37] Ogrodnik, M. et al. Obesity-induced cellular senescence drives anxiety and impairs neurogenesis. Cell Metab. 29, 1233 (2019). source
• Supported

  The citation is attached to the obesity part of the sentence. In Results (Senescent cell clearance decreases liver fat accumulation; page unavailable), the paper reports that a high-fat diet increased TAF in mouse hepatocytes, supporting the attributed link in this model. (LLM, conf=0.88)

  cites [41] Ogrodnik, M. et al. Cellular senescence drives age-dependent hepatic steatosis. Nat. Commun. 8, 15691 (2017). source
• Supported

  Citation 36 is attached to mitochondrial dysfunction, not the separately cited inflammation, obesity or impaired autophagy. In the Results section, the paper reports increased TAF in cardiomyocytes from Polgmut/mut mice, which it describes as a model of accelerated ageing due to mitochondrial dysfunction. (LLM, conf=0.92)

  cites [36] Anderson, R. et al. Length-independent telomere damage drives post-mitotic cardiomyocyte senescence. EMBO J. 38, e100492 (2019). source
• Supported

  Citation 48 is attached to impaired autophagy. In Results, the paper reports significantly more telomere-associated foci (TAF) in mice with systemic autophagy inhibition and interprets the increase as evidence of accelerated ageing. Page numbers are not provided in our copy. (LLM, conf=0.94)

  cites [48] Cassidy, L. D. et al. Temporal inhibition of autophagy reveals segmental reversal of ageing with increased cancer risk. Nat. Commun. 11, 307 (2020). source

In the paper

“Mice with short telomeres induced by knockout of telomerase components show TAFs, inflammation and fibrosis in lungs59, which is aggravated by cigarette smoke60 or a low dose of bleomycin, a DNA-damaging agent61.”

What the sources say

• Partly supported

  The Results (Fig. 3) report telomere dysfunction-induced foci in alveolar cells, and the Abstract reports inflammation and fibrotic lesions in telomerase-knockout mice. But the paper also says TERC-deficient mice with short telomeres do not show obvious pulmonary fibrosis, so describing the finding simply as lung fibrosis overstates it. Cigarette smoke and bleomycin are attached to separate citations in the citing sentence, not this source. (LLM, conf=0.86)

  cites [59] Chen, R. et al. Telomerase deficiency causes alveolar stem cell senescence-associated low-grade inflammation in lungs. J. Biol. Chem. 290, 30813–30829 (2015). sourceExperimental — accuracy not yet measured
• Partly supported

  Citation 60 is attached to the cigarette-smoke portion of the sentence. The Abstract and Results report that smoke exposure caused additive DNA damage and emphysema in mice with short telomeres. They do not show smoke-aggravated lung fibrosis or increased inflammation specifically in those mice; the Results report no statistically significant difference in alveolar macrophages between the smoke-exposed groups. (LLM, conf=0.89)

  cites [60] Alder, J. K. et al. Telomere length is a determinant of emphysema susceptibility. Am. J. Respir. Crit. Care Med. 184, 904–912 (2011). sourceExperimental — accuracy not yet measured
• Partly supported

  The low-dose-bleomycin results (p. 9) report inflammation and fibrosis in treated mice with short telomeres, but no lung fibrosis in untreated counterparts. Thus, the paper supports bleomycin triggering fibrosis in these mice, not aggravating fibrosis already present. The cigarette-smoke clause carries a different citation and is not assessed here. (LLM, conf=0.86)

  cites [61] Povedano, J. M., Martinez, P., Flores, J. M., Mulero, F. & Blasco, M. A. Mice with pulmonary fibrosis driven by telomere dysfunction. Cell Rep. 12, 286–299 (2015). sourceExperimental — accuracy not yet measured

In the paper

“Patients with IPF accumulate TAFs and senescence markers in lungs that increase with disease severity and activate SASP52.”

What the sources say

• Partly supported

  The Results section, “Senescence biomarkers accumulate in IPF lung” (page unavailable), reports more TAF-positive cells in IPF lungs than controls, p16 expression increasing with disease severity, and elevated expression of SASP components. It does not show that TAF increase with severity or that the markers themselves activate the SASP; the Discussion describes elevated SASP transcription as associated with the senescence markers. (LLM, conf=0.85)

  cites [52] Schafer, M. J. et al. Cellular senescence mediates fibrotic pulmonary disease. Nat. Commun. 8, 14532 (2017). sourceExperimental — accuracy not yet measured

In the paper

“tDDR activation and TAF accumulation are often causally connected to other ageing-associated processes. These include mitochondrial dysfunction, altered nutrient sensing, impaired autophagy, loss of proteostasis and epigenetic dysregulation, which suggests that there is a unifying ‘telomere-centric’ mechanistic rationale for many ageing hallmarks, as also proposed in ref.29.”

What the sources say

• Partly supported

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

  cites [29] Chakravarti, D., LaBella, K. A. & DePinho, R. A. Telomeres: history, health, and hallmarks of aging. Cell 184, 306–322 (2021). sourceExperimental — accuracy not yet measured

In the paper

“Instead, telomere shortening rates and the increase in short telomeres has been proposed to predict lifespan32.”

What the sources say

• Partly supported

  The Conclusions state that telomere shortening rate can predict species life span in the paper’s dataset. The copy does not report an analysis of whether the increase in short telomeres predicts life span; that proposition appears in the title of a different study listed in the References. (LLM, conf=0.85)

  cites [32] Whittemore, K., Vera, E., Martínez-Nevado, E., Sanpera, C. & Blasco, M. A. Telomere shortening rate predicts species life span. Proc. Natl Acad. Sci. USA 116, 15122–15127 (2019). sourceExperimental — accuracy not yet measured

In the paper

“Short telomeres are an established risk factor for IPF, and 37% of familial cases and 25% of sporadic cases show telomere lengths below the tenth percentile for their age, as assessed in circulating leukocytes and alveolar epithelial cells54.”

What the sources say

• Partly supported

  The Discussion reports that 37% of familial probands and 25% of sporadic cases had leukocyte telomere lengths below the age-adjusted tenth percentile. But these figures concern pulmonary fibrosis cases, not exclusively IPF, and the measurements were made in circulating leukocytes, not alveolar epithelial cells. The paper describes an association and says short telomeres may mark increased predisposition; it does not establish them as a risk factor. (LLM, conf=0.90)

  cites [54] Cronkhite, J. T. et al. Telomere shortening in familial and sporadic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 178, 729–737 (2008). sourceExperimental — accuracy not yet measured

In the paper

“Oxidative stress reportedly both induces tDD without telomere shortening and accelerates telomere shortening23–26 by inhibiting telomerase27 and disrupting the recognition by telomere-binding proteins, which contributes to telomere uncapping22,28.”

What the sources say

• Partly supported

  The Results section (page unavailable) says oxidative lesions can disrupt TRF1 and TRF2 binding in vitro and that TRF2 loss causes telomere deprotection, supporting the binding-and-uncapping portion associated with this citation. But this paper did not establish that its induced damage uncapped telomeres: it found no TRF2 loss or substantial increase in telomere-dysfunction markers. The separate shortening and telomerase clauses have other citations in the printed sentence. (LLM, conf=0.86)

  cites [23] Fouquerel, E. et al. Targeted and persistent 8-oxoguanine base damage at telomeres promotes telomere loss and crisis. Mol. Cell 75, 117–130.e6 (2019). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [24] von Zglinicki, T. Oxidative stress shortens telomeres. Trends Biochem. Sci. 27, 339–344 (2002). source
• Partly supported

  The Discussion (page unavailable) says oxidative stress may disrupt the binding of protective shelterin proteins, supporting the telomere-binding part of the claim, but it does not establish that this causes uncapping. Results section 4 reports telomere damage without a statistically significant difference in telomere length in an acute liver-injury model. The separate claim about inhibiting telomerase is attached to citation 27, not this source. (LLM, conf=0.83)

  cites [25] Lagnado, A. et al. Neutrophils induce paracrine telomere dysfunction and senescence in ROS-dependent manner. EMBO J. 40, e106048 (2021). sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion (page unavailable) reports that telomeric oxidative damage causes dysfunction without shortening, and the Introduction associates chronic oxidative stress with accelerated shortening. But the paper does not establish telomerase inhibition; in ‘Acute Telomeric 8oxoG Formation Causes Telomere Fragility But Not Shortening’ (page unavailable), it reports no significant loss of TRF1 or TRF2 from telomeres and attributes the observed dysfunction to replication stress rather than uncapping through shelterin disruption. (LLM, conf=0.90)

  cites [26] Barnes, R. P. et al. Telomeric 8-oxoguanine drives rapid premature senescence in the absence of telomere shortening. Preprint at bioRxiv https://doi.org/10.1101/2021.05.05.442662 (2021). sourceExperimental — accuracy not yet measured
• Supported

  The citation to this paper is attached to the telomerase-inhibition mechanism, not the separate claims about tDD or telomere-binding proteins. The Discussion states that oxidative stress-induced damage to nucleotide pools inhibits telomerase’s ability to maintain telomeres; the Abstract specifies that incorporation of oxidized nucleotides terminates elongation. (LLM, conf=0.90)

  cites [27] Fouquerel, E. et al. Oxidative guanine base damage regulates human telomerase activity. Nat. Struct. Mol. Biol. 23, 1092–1100 (2016). source
• Partly supported

  In the passage beginning “A notable finding,” the paper says oxidative stress shortens telomeres and that oxidation disrupts binding of telomere protective factors and prevents extension by telomerase. It does not say telomere DNA damage occurs without shortening or that oxidative stress inhibits telomerase itself. The relevant passage has no section or page label in our copy. (LLM, conf=0.85)

  cites [22] Jacome Burbano, M. S., Cherfils-Vicini, J. & Gilson, E. Neutrophils: mediating TelOxidation and senescence. EMBO J. 40, e108164 (2021). sourceExperimental — accuracy not yet measured
• Supported

  The citation to this paper attaches to the claim that oxidative damage disrupts recognition by telomere-binding proteins and contributes to uncapping, not to the separately cited telomerase claim. The Discussion reports impaired TRF1/TRF2 binding and links loss of telomere-associated TRF2 to dysfunction even without shortening; it presents the effect on telomere function as a proposed mechanism, not a directly measured uncapping outcome. (LLM, conf=0.86)

  cites [28] Opresko, P. L., Fan, J., Danzy, S., Wilson, D. M. 3rd & Bohr, V. A. Oxidative damage in telomeric DNA disrupts recognition by TRF1 and TRF2. Nucleic Acids Res. 33, 1230–1239 (2005). source

In the paper

“The most prevalent hypothesis is that it is not telomere dysfunction per se that leads to ageing and age-associated diseases but telomere dysfunction-activated tDDR that causes cellular senescence, which, also by SASP, facilitates the age-related loss of tissue functions11.”

What the sources say

• Partly supported

  The Macromolecular Damage section says telomere dysfunction-induced foci activate the DNA damage response and eventually cause cell-cycle arrest. The Secretion section says the SASP can explain some deleterious, pro-aging effects of senescent cells. The paper does not identify this as the “most prevalent hypothesis,” establish that telomere dysfunction itself does not contribute to aging or disease, or specifically trace this pathway to age-related loss of tissue function. (LLM, conf=0.86)

  cites [11] Gorgoulis, V. et al. Cellular senescence: defining a path forward. Cell 179, 813–827 (2019). sourceExperimental — accuracy not yet measured

In the paper

“Lung tissues from these patients show shorter telomeres and increased levels of TAFs and senescence markers69.”

What the sources say

• Supported

  The Results (page not provided) report shorter telomeres, more large-airway epithelial cells containing TAF, and increased p21 in patients with bronchiectasis. The paper defines bronchiectasis here as non–cystic fibrosis bronchiectasis. Its findings concern large-airway epithelium from patients with end-stage disease, rather than all lung tissue or all patients. (LLM, conf=0.90)

  cites [69] Birch, J. et al. Telomere dysfunction and senescence-associated pathways in bronchiectasis. Am. J. Respir. Crit. Care Med. 193, 929–932 (2016). source

In the paper

“Disease severity has been correlated with patient age and leukocyte telomere length71, which is consistent with a recent finding that tDDR activation induced by telomere shortening increases the expression of ACE2, the SARS-CoV-2 receptor on human lung cells72.”

What the sources say

• Partly supported

  The “Major features of COVID-19” section reports worse outcomes among older people and proposes that their comparatively short telomeres may help explain those outcomes. The Abstract describes short telomere length as a potential risk marker, not an established patient-level correlation with disease severity. The ACE2 finding is attached to citation 72, so it is not assessed against this paper. (LLM, conf=0.88)

  cites [71] Aviv, A. Telomeres and COVID-19. FASEB J. 34, 7247–7252 (2020). sourceExperimental — accuracy not yet measured
• Supported

  Citation 72 is attached to the ACE2 mechanism, not the preceding claim about patient age and leukocyte telomere length. In Results and Discussion (page unavailable), the paper reports increased ACE2 mRNA in human bronchial epithelial cells as their telomeres shorten and concludes that telomeric DNA damage response regulates ACE2 expression. Its direct tests of that response also use other cell types and mice. (LLM, conf=0.87)

  cites [72] Sepe, S. et al. DNA damage response at telomeres boosts the transcription of SARS-CoV-2 receptor ACE2 during aging. EMBO Rep. https://doi.org/10.15252/embr.202153658 (2021). source

In the paper

“TAF and p21 levels in hepatocytes positively correlate with NAFLD severity41, and the clearance of senescent cells in aged and obese mice reduced the fraction of TAF-positive hepatocytes and alleviated liver steatosis41.”

What the sources say

• Supported

  In Results, “Hepatocyte senescence correlates with severity of NAFLD” (page not specified), the percentages of TAF- and p21-positive hepatocytes positively correlate with NAFLD activity score in nine patients. In “Senescent cell clearance decreases liver fat accumulation” (page not specified), senescent-cell clearance reduced TAF-positive hepatocytes and hepatic fat deposition in aged mice; AP treatment also reduced senescence markers, including TAF, and fat deposition in high-fat-fed mice. (LLM, conf=0.93)

  cites [41] Ogrodnik, M. et al. Cellular senescence drives age-dependent hepatic steatosis. Nat. Commun. 8, 15691 (2017). source

In the paper

“Around 9% of patients with acquired aplastic anaemia carry mutations in the telomerase components TERC, TERT and DKC1, which are also mutated in inherited aplastic anaemia, as in dyskeratosis congenita74,75.”

What the sources say

• Partly supported

  The Introduction (page unavailable) says TERC and DKC1 mutations occur in dyskeratosis congenita, and Table 2 lists TERC mutations in two patients diagnosed with aplastic anemia. But the paper does not establish a 9% prevalence for acquired aplastic anemia or report TERT mutations. The TERC abnormalities section instead reports three TERC mutations among 210 patients with several marrow-failure diagnoses, approximately 1.5%. (LLM, conf=0.90)

  cites [74] Yamaguchi, H. et al. Mutations of the human telomerase RNA gene (TERC) in aplastic anemia and myelodysplastic syndrome. Blood 102, 916–918 (2003). sourceExperimental — accuracy not yet measured
• Partly supported

  The Mutations section (page not provided) reports TERC mutations in 5 of 205 patients and TERT mutations in 7 of the remaining 200—12 of 205 overall, or about 6%, rather than 9%. It explicitly reports no DKC1 mutations in the patients studied. The background section (page not provided) does link DKC1 and TERC mutations to dyskeratosis congenita. (LLM, conf=0.89)

  cites [75] Yamaguchi, H. et al. Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. N. Engl. J. Med. 352, 1413–1424 (2005). sourceExperimental — accuracy not yet measured

In the paper

“Cigarette smoke (a major risk factor for COPD) induced TAFs, cellular senescence and SASP in cultured primary human airway epithelial cells and fibroblasts34 and reduced telomere protection protein 1 (TPP1) levels in mouse and human lungs, which caused tDDR activation66.”

What the sources say

• Partly supported

  The Results (Fig. 6) report that cigarette smoke extract increased telomere-associated foci (TAF) in cultured primary airway epithelial cells, and induced senescence and SASP markers in MRC5 fibroblasts. They report no significant increase in a senescence marker in the epithelial cells, so the claim overextends those findings to both cell types. The TPP1 clause cites a different source (66) and is not assessed here. (LLM, conf=0.90)

  cites [34] Birch, J. et al. DNA damage response at telomeres contributes to lung aging and chronic obstructive pulmonary disease. Am. J. Physiol. Lung Cell. Mol. Physiol. 309, L1124–L1137 (2015). sourceExperimental — accuracy not yet measured
• Supported

  The citation to this paper is attached to the TPP1 and telomeric DNA damage portion of the sentence, not the earlier TAFs and SASP claim. The Abstract reports reduced TPP1 in cigarette-smoke-exposed mouse lungs and in lungs from smokers and patients with COPD, and states that TPP1 reduction caused telomeric DNA damage. (LLM, conf=0.93)

  cites [66] Ahmad, T. et al. Shelterin telomere protection protein 1 reduction causes telomere attrition and cellular senescence via sirtuin 1 deacetylase in chronic obstructive pulmonary disease. Am. J. Respir. Cell Mol. Biol. 56, 38–49 (2017). source

In the paper

“First, partial depletion of TRF1 in hematopoietic stem and progenitor cells caused TAF formation, cell depletion and a compensatory proliferation, which resulted in rapid telomere attrition and cellular senescence84.”

What the sources say

• Supported

  The Results section reports increased telomere-induced damage foci and progenitor-cell senescence after progressive TRF1 deletion. The Discussion describes progenitor depletion followed by compensatory stem-cell proliferation; with less frequent, long-term deletion, telomeres shortened and replicative senescence developed. The paper studies deletion at a lower frequency across the compartment, rather than partial loss of TRF1 within each cell. (LLM, conf=0.87)

  cites [84] Beier, F., Foronda, M., Martinez, P. & Blasco, M. A. Conditional TRF1 knockout in the hematopoietic compartment leads to bone marrow failure and recapitulates clinical features of dyskeratosis congenita. Blood 120, 2990–3000 (2012). source

In the paper

“Patients with cirrhosis have a higher incidence of telomerase mutations and bear shorter telomeres than unaffected individuals96.”

What the sources say

• Partly supported

  The Abstract reports a higher frequency of telomerase mutations in 521 patients with cirrhosis than in 600 noncirrhosis controls. The Functional Analysis section reports shorter telomeres only in cirrhosis patients carrying telomerase mutations compared with controls without those mutations; it does not establish the telomere comparison for cirrhosis patients generally. Page numbers were not provided in our copy. (LLM, conf=0.86)

  cites [96] Hartmann, D. et al. Telomerase gene mutations are associated with cirrhosis formation. Hepatology 53, 1608–1617 (2011). sourceExperimental — accuracy not yet measured

In the paper

“About one-third of patients with aplastic anaemia show short telomeres in peripheral blood, which suggests that there is a causative link between aplastic anaemia pathology and telomere dysfunction75,76,79.”

What the sources say

• Partly supported

  The paper’s introductory passage (indexed under Abstract; page unavailable) says that approximately one third of patients with *acquired* aplastic anemia have short telomeres in leukocytes, especially those who do not respond to immunosuppressive therapy. Its conclusion says TERT mutations impair telomerase activity and may be risk factors for marrow failure, supporting the suggested link. The citing sentence omits the restriction to acquired aplastic anemia and thus states the one-third figure for a broader population. (LLM, conf=0.84)

  cites [75] Yamaguchi, H. et al. Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. N. Engl. J. Med. 352, 1413–1424 (2005). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [76] Savage, S. A. et al. Genetic variation in telomeric repeat binding factors 1 and 2 in aplastic anemia. Exp. Hematol. 34, 664–671 (2006). source
• ?Not checked — no full text of the sourcecites [79] Brümmendorf, T. H., Maciejewski, J. P., Mak, J., Young, N. S. & Lansdorp, P. M. Telomere length in leukocyte subpopulations of patients with aplastic anemia. Blood 97, 895–900 (2001). source

In the paper

“The use of the androgen receptor agonist danazol in patients with aplastic anaemia with critically short telomeres improved their condition by increasing telomerase expression and lengthening telomeres. This provides support for a causative role of telomere length in this disease83.”

What the sources say

• Partly supported

  The Abstract Results and Discussion (page not provided) report telomere elongation and hematologic improvement during danazol treatment. But the study enrolled patients with a range of telomere diseases, not only aplastic anaemia, and the Discussion says telomerase activity could not be reliably measured. It does not establish that increased telomerase expression caused the improvement or that telomere length was the causal factor. (LLM, conf=0.88)

  cites [83] Townsley, D. M. et al. Danazol treatment for telomere diseases. N. Engl. J. Med. 374, 1922–1931 (2016). sourceExperimental — accuracy not yet measured

In the paper

“Patients with shorter telomeres at diagnosis show a more severe disease, a poorer response to treatments, an increased risk of relapse and development of myelodysplastic syndrome (MDS; see below) and a lower survival rate75,80,81.”

What the sources say

• Partly supported

  The introductory passage reports short telomeres in patients with acquired aplastic anemia, especially those who do not respond to immunosuppressive therapy; the discussion also notes poor response among patients with TERT mutations. The paper does not establish that telomere length at diagnosis predicts disease severity, relapse, development of MDS, or survival. Its treatment-response evidence is narrower than the full claim. (LLM, conf=0.86)

  cites [75] Yamaguchi, H. et al. Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. N. Engl. J. Med. 352, 1413–1424 (2005). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results (Response and relapse according to telomere length; Clonal evolution and survival according to telomere length) associate shorter pretreatment telomeres with relapse, clonal evolution and lower survival. They do not establish more severe disease at diagnosis, and explicitly report no correlation between telomere length and response to initial immunosuppressive treatment. The paper reports clonal evolution, including changes associated with myelodysplasia, rather than a separate MDS risk estimate. (LLM, conf=0.91)

  cites [80] Scheinberg, P. et al. Association of telomere length of peripheral blood leukocytes with hematopoietic relapse, malignant transformation, and survival in severe aplastic anemia. JAMA 304, 1358–1364 (2010). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results (page unavailable) show that children with shorter telomeres at diagnosis responded less often to immunosuppressive therapy. They report no statistical tendency linking telomere length to relapse, clonal evolution or overall survival, and do not establish that shorter telomeres indicate more severe disease. The Introduction attributes the relapse, MDS and survival associations to an earlier study, rather than to this paper's findings. (LLM, conf=0.90)

  cites [81] Sakaguchi, H. et al. Peripheral blood lymphocyte telomere length as a predictor of response to immunosuppressive therapy in childhood aplastic anemia. Haematologica 99, 1312–1316 (2014). sourceExperimental — accuracy not yet measured

In the paper

“MDS can also be secondary to chemotherapy or radiation or be associated with inherited abnormalities in DNA repair and telomere maintenance genes89.”

What the sources say

• Partly supported

  In “Dyskeratosis congenita – a direct connection between germline telomere biology and human disease” (Table 2; page unavailable), the paper links the telomere-biology gene TERT with MDS. “Telomeres and cancer” also reports increased MDS risk in patients with telomere biology disorders. The passages do not address MDS secondary to chemotherapy or radiation, or its association with inherited DNA-repair abnormalities. (LLM, conf=0.88)

  cites [89] Savage, S. Beginning at the ends: telomeres and human disease [version 1; peer review: 4 approved]. F1000Res. https://doi.org/10.12688/f1000research.14068.1 (2018). sourceExperimental — accuracy not yet measured

In the paper

“COPD exhibits accelerated lung ageing characterized by inflammation of parenchyma and airways, chronic remodelling of the peripheral bronchi and inter-alveolar septa disruption towards emphysema.”

What the sources say

• ?Could not verify

  The Results section reports COPD prevalence, incidence, and years lived with disability, while the Discussion’s “Emerging trends” section addresses respiratory-disease burden in older people. Searches for accelerated lung ageing, airway remodelling, and emphysema found no passage in our copy addressing the claimed pathological changes. (LLM, conf=0.76)

  cites [65] James, S. L. et al. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 392, 1789–1858 (2018). sourceExperimental — accuracy not yet measured

In the paper

“Consistently, expression of telomerase using adeno-associated vectors (AAVs) in alveolar epithelial type II cells led to TAF reduction, decreased inflammation and improved lung function in telomerase-mutant and wild-type aged mice63,64.”

What the sources say

• Partly supported

  The Results report that AAV9-Tert preferentially targeted alveolar type II cells, reduced lung inflammation, and improved lung function. They also report less DNA damage in those cells, but do not identify that measurement as a reduction in telomere-associated foci (TAFs). The Materials and methods describe young telomerase-deficient mice, not aged wild-type mice, for the treatment experiment. (LLM, conf=0.88)

  cites [63] Povedano, J. M. et al. Therapeutic effects of telomerase in mice with pulmonary fibrosis induced by damage to the lungs and short telomeres. eLife 7, e31299 (2018). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results report that AAV9-Tert reduced inflammatory markers in both aged wild-type and telomerase-deficient mice, and improved pulmonary surfactant activity in both groups. They report fewer γ-H2AX-positive lung cells, but do not establish a reduction in telomere-associated foci (TAFs); surfactant activity is not a direct measure of lung function. The Discussion says ATII-cell transduction was shown previously, rather than established in this treatment experiment. (LLM, conf=0.87)

  cites [64] Pineiro-Hermida, S. et al. Telomerase treatment prevents lung profibrotic pathologies associated with physiological aging. J. Cell Biol. https://doi.org/10.1083/jcb.202002120 (2020). sourceExperimental — accuracy not yet measured

In the paper

“MDS is a heterogeneous group of clonal haematopoietic disorders characterized by ineffective haematopoiesis and DNA damage accumulation in haematopoietic stem and progenitor cells87.”

What the sources say

• Partly supported

  The Introduction describes MDS as a group of HSC-based disorders characterized by ineffective differentiation, and the genomic-instability section discusses accumulating genetic alterations. But the paper does not establish DNA damage accumulation in MDS haematopoietic stem and progenitor cells as a defining characteristic; its direct evidence of increased DNA damage concerns bone marrow cells in MDS mouse models (DNA repair > Double strand break repair; page unavailable). (LLM, conf=0.84)

  cites [87] Zhou, T. et al. Myelodysplastic syndrome: an inability to appropriately respond to damaged DNA? Exp. Hematol. 41, 665–674 (2013). sourceExperimental — accuracy not yet measured

In the paper

“The clearance of senescent cells in aged mice improves heart functions and reduces the fraction of TAF-positive cardiomyocytes without a significant effect on mean telomere length36.”

What the sources say

• Partly supported

  The Results section, “Senescent-cell clearance reduces cardiac hypertrophy and fibrosis” (page unavailable), reports reduced TAF in cardiomyocytes after senescent-cell clearance, with no detected difference in telomere FISH signals. It does not support improved heart function: ejection fraction was unchanged after genetic clearance, and navitoclax had no significant impact on cardiac function. The reported improvements were in hypertrophy and fibrosis. (LLM, conf=0.93)

  cites [36] Anderson, R. et al. Length-independent telomere damage drives post-mitotic cardiomyocyte senescence. EMBO J. 38, e100492 (2019). sourceExperimental — accuracy not yet measured

In the paper

“CKD shows several features of accelerated ageing, including decreased kidney weight, atrophy, sclerosis, fibrosis and a CKD-associated secretory phenotype, which is similar to SASP135.”

What the sources say

• Supported

  The Introduction describes CKD as a form of renal ageing and lists decreased kidney weight, renal cortical and tubular atrophy, glomerular and vascular sclerosis, and interstitial fibrosis among changes shared by CKD and the ageing kidney. The section comparing CKD- and senescence-associated secretory phenotypes says CASP and SASP have prominent similarities. Page numbers are not provided in our copy. (LLM, conf=0.93)

  cites [135] Wang, W. J., Cai, G. Y. & Chen, X. M. Cellular senescence, senescence-associated secretory phenotype, and chronic kidney disease. Oncotarget 8, 64520–64533 (2017). source

In the paper

“Late-generation telomerase-deficient mice show severe left ventricular loss of function, increased cardiomyocyte hypertrophy and decreased number of cardiomyocytes111.”

What the sources say

• Supported

  The Results and discussion section reports severe left ventricular failure in fifth-generation (G5) Terc–/– mice. It also reports cellular hypertrophy and a statistically significant 49% decrease in left ventricular cardiomyocyte number compared with wild-type mice. Page numbers were not provided in the supplied copy. (LLM, conf=0.94)

  cites [111] Leri, A. et al. Ablation of telomerase and telomere loss leads to cardiac dilatation and heart failure associated with p53 upregulation. EMBO J. 22, 131–139 (2003). source

In the paper

“cultured chondrocytes isolated from areas close to the osteoarthritis lesions from the hips of patients have shorter mean telomere length and increased levels of senescence markers than those from distal sites in the same joint126”

What the sources say

• Supported

  The Abstract reports that cultured chondrocytes near an OA lesion had more SA-β-gal-positive cells and shorter mean telomeres than cells from distal sites in the same joint. The Analysis figure caption identifies the cartilage as human hip cartilage. (LLM, conf=0.94)

  cites [126] Price, J. S. et al. The role of chondrocyte senescence in osteoarthritis. Aging Cell 1, 57–65 (2002). source

In the paper

“This is associated with the induction of p16 and p21 and a cardiac-specific form of SASP that contributes to cardiac hypertrophy and fibrosis36.”

What the sources say

• Supported

  The Discussion (page not provided) links telomere dysfunction in cardiomyocytes to p16 and p21 pathways and describes a non-classical secretory phenotype that promotes myofibroblast activation and cardiomyocyte hypertrophy. The Results section on aged cardiomyocytes (page not provided) reports increased p16 and p21 expression and identifies secreted factors that activate fibroblasts and enlarge cardiomyocytes, supporting the paraphrase about hypertrophy and fibrosis. (LLM, conf=0.91)

  cites [36] Anderson, R. et al. Length-independent telomere damage drives post-mitotic cardiomyocyte senescence. EMBO J. 38, e100492 (2019). source

In the paper

“DNA damage and DDR markers have been observed in models of Alzheimer’s disease154,155 and in neurons in postmortem brains from patients with the disease156.”

What the sources say

• ?Not checked — no full text of the sourcecites [154] Fielder, E., von Zglinicki, T. & Jurk, D. The DNA damage response in neurons: die by apoptosis or survive in a senescence-like state? J. Alzheimers Dis. 60, S107–S131 (2017). source
• ?Could not verify

  The indexed passages are labeled as a Parkinson’s disease paper, despite the supplied Alzheimer’s disease title. Its Results section reports DNA-damage markers in postmortem PD neurons, while its Discussion only briefly mentions a previous study of 53BP1 in AD brain tissue. Searches for AD models and postmortem AD neurons did not retrieve a passage establishing the attributed claim in our copy. (LLM, conf=0.75)

  cites [155] Thadathil, N. et al. DNA double-strand break accumulation in Alzheimer’s disease: evidence from experimental models and postmortem human brains. Mol. Neurobiol. 58, 118–131 (2021). sourceExperimental — accuracy not yet measured
• Supported

  Citation 156 is attached to the claim about neurons in postmortem brains, not the separate claim about Alzheimer’s disease models. The Discussion reports that immunostaining postmortem brain sections showed greater accumulation of neuronal DNA double-strand breaks in patients with Alzheimer’s disease than in cognitively normal controls, using γH2AX foci as a marker. Page numbers are not provided in our copy. (LLM, conf=0.93)

  cites [156] Shanbhag, N. M. et al. Early neuronal accumulation of DNA double strand breaks in Alzheimer’s disease. Acta Neuropathol. Commun. 7, 77 (2019). source

In the paper

“In aged mice, clearance of senescent cells reduced glomerulosclerosis and retained blood urea nitrogen levels”

What the sources say

• Supported

  The “Renal epithial cell senescence and glomerulosclerosis” section (page not provided) reports that AP-mediated clearance of senescent cells markedly reduced glomerulosclerosis in aged mice. It also reports attenuated age-related increases in blood urea nitrogen, consistent with the claim that treatment preserved those levels. (LLM, conf=0.93)

  cites [147] Baker, D. J. et al. Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature 530, 184–189 (2016). source

In the paper

“Kidneys in patients with CKD exhibited an increased number of tubules positive for the DDR marker γH2AX, which was inversely correlated with the estimated glomerular filtration rate, and a greater number of phosphorylated ATR-positive cells137.”

What the sources say

• Supported

  The Results (Figure 1B–D) report more γH2AX/KIM-1 double-positive tubules in CKD kidney tissue, an inverse correlation between their number and eGFR, and more phosphorylated ATR-positive cells in injured tubule cells. These findings support the citing sentence. (LLM, conf=0.94)

  cites [137] Kishi, S. et al. Proximal tubule ATR regulates DNA repair to prevent maladaptive renal injury responses. J. Clin. Invest. 129, 4797–4816 (2019). source

In the paper

“Senescent cells accumulate with age in the murine brain and is exacerbated in late-generation telomerase-deficient mice150”

What the sources say

• Partly supported

  The Results report that frequencies of neurons positive for senescence-associated markers increased with age, and the Abstract says the phenotype was aggravated in brains of late-generation TERC−/− mice. The paper describes this as evidence suggesting a senescence-like phenotype in neurons, rather than establishing that senescent cells generally accumulate in the brain. (LLM, conf=0.85)

  cites [150] Jurk, D. et al. Postmitotic neurons develop a p21-dependent senescence-like phenotype driven by a DNA damage response. Aging Cell 11, 996–1004 (2012). sourceExperimental — accuracy not yet measured

In the paper

“telomerase activators led to decreased levels of pathological α-synuclein protein and improved motor symptoms in a mouse model of Parkinson’s disease171”

What the sources say

• Supported

  The Discussion reports that both telomerase activators improved walking speed and gait in the transgenic Parkinson’s disease mouse model. It also reports reduced α-synuclein levels, including reductions in phosphorylated and aggregated forms, particularly with TA-65. (LLM, conf=0.94)

  cites [171] Wan, T., Weir, E. J., Johnson, M., Korolchuk, V. I. & Saretzki, G. C. Increased telomerase improves motor function and alpha-synuclein pathology in a transgenic mouse model of Parkinson’s disease associated with enhanced autophagy. Prog. Neurobiol. 199, 101953 (2021). source

In the paper

“androgen therapy, based on the clinical use of danazol, a synthetic testosterone, has been part of clinical practice for many years in the treatment of aplastic anaemia with some efficacy83”

What the sources say

• Partly supported

  The Discussion says androgens have been used for marrow failure syndromes since the 1960s, and the References include studies of androgen treatment for aplastic anemia. The Methods identify danazol as a synthetic sex hormone with androgenic properties, and the Results report hematologic responses in patients with telomere diseases. The paper does not establish that danazol itself has been used for many years to treat aplastic anemia or that its efficacy was demonstrated in that population. (LLM, conf=0.84)

  cites [83] Townsley, D. M. et al. Danazol treatment for telomere diseases. N. Engl. J. Med. 374, 1922–1931 (2016). sourceExperimental — accuracy not yet measured

In the paper

“A natural plant compound named TA-65 has been reported to boost telomerase activity and lengthen telomeres in mice189.”

What the sources say

• Partly supported

  The Results section on mouse embryonic fibroblasts reports increased telomerase activity after TA-65 treatment. The Results section on dietary supplementation in mice reports fewer very short telomeres, but not a significant increase in average telomere length; it reports increased telomerase expression in liver rather than a direct measurement of activity in treated mice. The claim therefore omits important limits on both findings. (LLM, conf=0.88)

  cites [189] de Jesus, B. B. et al. The telomerase activator TA-65 elongates short telomeres and increases health span of adult/old mice without increasing cancer incidence. Aging Cell 10, 604–621 (2011). sourceExperimental — accuracy not yet measured

In the paper

“Telomere shortening and damage are recognized causes of cellular senescence and ageing.”

In the paper

“Endogenous or exogenous DNA damage is constantly generated, and the fraction that occurs at telomeres, which is less efficiently repaired, thus accumulates and induces a senescence-like phenotype (Fig. 1a).”

In the paper

“As standard DNA polymerases cannot fully replicate linear DNA templates in the absence of telomerase, a DNA-template-independent DNA polymerase, and because of nucleolytic processing, DNA replication results in the generation of chromosomes with progressively shortened telomeres1.”

What the sources say

• ?Not checked — no full text of the sourcecites [1] Harley, C. B., Futcher, A. B. & Greider, C. W. Telomeres shorten during ageing of human fibroblasts. Nature 345, 458–460 (1990). source

In the paper

“Across species, however, short telomeres do not necessarily predict short lifespan—that is, humans have shorter telomeres but longer lifespans than rodents.”

In the paper

“Primary biliary cirrhosis, an autoimmune disease with chronic, progressive cholestasis and liver failure, is associated with short telomeres, DDR activation and senescence marker accumulation in biliary epithelial cells98.”

What the sources say

• ?Not checked — no full text of the sourcecites [98] Sasaki, M., Ikeda, H., Yamaguchi, J., Nakada, S. & Nakanuma, Y. Telomere shortening in the damaged small bile ducts in primary biliary cirrhosis reflects ongoing cellular senescence. Hepatology 48, 186–195 (2008). source

In the paper

“Both telomere shortening and telomere damage have been reported as hallmarks and potential drivers of heart diseases and as indicators of therapeutic outcomes105.”

What the sources say

• ?Not checked — no full text of the sourcecites [105] Boniewska-Bernacka, E., Pańczyszyn, A. & Klinger, M. Telomeres and telomerase in risk assessment of cardiovascular diseases. Exp. Cell. Res. 397, 112361 (2020). source

In the paper

“Telomere shortening has been implicated in hepatocyte senescence94 and in disease progression in patients with liver cirrhosis95.”

What the sources say

• ?Not checked — no full text of the sourcecites [94] Wiemann, S. U. et al. Hepatocyte telomere shortening and senescence are general markers of human liver cirrhosis. FASEB J. 16, 935–942 (2002). source
• ?Not checked — no full text of the sourcecites [95] Kitada, T., Seki, S., Kawakita, N., Kuroki, T. & Monna, T. Telomere shortening in chronic liver diseases. Biochem. Biophys. Res. Commun. 211, 33–39 (1995). source

In the paper

“Short telomeres in adipose tissues are associated with metabolic disease progression, and causality was demonstrated by telomerase inactivation in mouse adipocyte precursors that led to hypertrophy and inflammation93.”

What the sources say

• ?Not checked — no full text of the sourcecites [93] Gao, Z. et al. Age-associated telomere attrition in adipocyte progenitors predisposes to metabolic disease. Nat. Metab. 2, 1482–1497 (2020). source

In the paper

“long telomeres in a female cohort were associated with high bone mineral density and reduced risk of osteoporosis131”

What the sources say

• ?Not checked — no full text of the sourcecites [131] Valdes, A. M. et al. Telomere length in leukocytes correlates with bone mineral density and is shorter in women with osteoporosis. Osteoporos. Int. 18, 1203–1210 (2007). source

In the paper

“Cats with CKD also show shortened telomeres and increased numbers of senescent cells in the kidney148.”

What the sources say

• ?Not checked — no full text of the sourcecites [148] Quimby, J. M. & Lunn, K. F. Mirtazapine as an appetite stimulant and anti-emetic in cats with chronic kidney disease: a masked placebo-controlled crossover clinical trial. Vet. J. 197, 651–655 (2013). source

In the paper

“Cellular senescence markers have been reported in neurons and astrocytes from patients with Alzheimer’s disease and in cultured human astrocytes exposed to β-amyloid153.”

What the sources say

• ?Not checked — no full text of the sourcecites [153] Saez-Atienzar, S. & Masliah, E. Cellular senescence and Alzheimer disease: the egg and the chicken scenario. Nat. Rev. Neurosci. 21, 433–444 (2020). source

In the paper

“β-amyloid can induce telomere shortening and inhibit telomerase activity167.”

What the sources say

• ?Not checked — no full text of the sourcecites [167] Wang, J. et al. New insights in amyloid beta interactions with human telomerase. J. Am. Chem. Soc. 137, 1213–1219 (2015). source

In the paper

“a woman with dyskeratosis congenita, a telomeropathy associated with a reduced ovarian reserve, responded poorly to hormonal treatment before in vitro fertilization and her oocytes contained critically short telomeres181”

What the sources say

• ?Not checked — no full text of the sourcecites [181] Robinson, L. G. Jr et al. Impaired reproductive function and fertility preservation in a woman with a dyskeratosis congenita. J. Assist. Reprod. Genet. 37, 1221–1225 (2020). source

In the paper

“both TERT expression and tASO approaches, by acting upstream in the pathological cascade, are expected, and some have demonstrated, to make a promising impact on the many consequences of telomere dysfunction, such as impaired proliferation, inflammation and fibrosis.”

In the paper

“the use of immunogenic viral vectors such as AAV may reduce the possibility of repeated treatments.”

In the paper

“patients with premature ovarian insufficiency have shorter telomeres and reduced telomerase activity in leukocytes and granulosa cells than healthy individuals179”

What the sources say

• ?Not checked — no full text of the sourcecites [179] Xu, X. et al. Impaired telomere length and telomerase activity in peripheral blood leukocytes and granulosa cells in patients with biochemical primary ovarian insufficiency. Hum. Reprod. 32, 201–207 (2017). source

In the paper

“Antisense oligonucleotides (ASOs) are an emerging class of drugs targeting RNAs, with eight products presently on the market and many more in advanced clinical trials197.”

What the sources say

• ?Not checked — no full text of the sourcecites [197] Crooke, S. T., Baker, B. F., Crooke, R. M. & Liang, X. H. Antisense technology: an overview and prospectus. Nat. Rev. Drug Discov. https://doi.org/10.1038/s41573-021-00162-z (2021). source

In the paper

“Limitations of their use may lie in their tissue distribution, the need for safety evaluations and their relatively less-studied mechanism of action.”

In the paper

“An advantage of this approach is its broad activity independent from the genetic defects underlying telomere dysfunction, its ability to act at both critically short and damaged telomeres and in non-proliferating cells, and its nonviral delivery.”