Telomere dysfunction in ageing and age-related diseases

In the paper

“In these models, telomere shortening progressively causes tDDR activation and cellular senescence, which recapitulates features of ageing and age-related diseases30,31.”

What the sources say

• Supported

  The Introduction states that critically shortened, dysfunctional telomeres induce DNA-damage responses that can lead to senescence, and describes degenerative phenotypes in late-generation telomerase-knockout mice. The Abstract and Discussion report that tert-knockout zebrafish develop shorter telomeres, DNA-damage markers, and later accumulation of senescent cells alongside premature tissue degeneration. The paper reports the mouse findings as background rather than as its own experiments. (LLM, conf=0.86)

  cites [30] Henriques, C. M., Carneiro, M. C., Tenente, I. M., Jacinto, A. & Ferreira, M. G. Telomerase is required for zebrafish lifespan. PLoS Genet. 9, e1003214 (2013). source
• Disputed

  The paper’s Abstract reports progressive telomere shortening in telomerase-deficient mice, but its discussion of primary mouse-cell cultures says they showed no difference in overcoming senescence/crisis across the generations tested. It concludes that telomere length is not a primary determinant of senescence/crisis in mouse cells, contrary to the claim that shortening progressively causes senescence in these models. The cited paper does not study fish or establish tDDR activation. (LLM, conf=0.88)

  Checked by a reasoning model — may be wrong.

  cites [31] Blasco, M. A. et al. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 91, 25–34 (1997). sourceExperimental — accuracy not yet measured

In the paper

“Nevertheless, TAFs and senescence have been reported in ageing post-mitotic cells, including cardiomyocytes, adipocytes, neurons, osteocytes and osteoblasts17.”

What the sources say

• Partly supported

  The section ‘Can postmitotic cells become “senescent”?’ reports senescence-associated findings in neurons, adipocytes, osteocytes and cardiomyocytes, including telomeric dysfunction in osteocytes and persistent telomeric DNA damage in cardiomyocytes (page unavailable). It does not report TAFs in all the listed cell types: DNA-damage accumulation was not reported for adipocytes, and the cited passages do not address osteoblasts. The adipocyte finding was also in mice subjected to excessive caloric intake, rather than specifically ageing mice. (LLM, conf=0.90)

  cites [17] Di Micco, R., Krizhanovsky, V., Baker, D. & d’Adda di Fagagna, F. Cellular senescence in ageing: from mechanisms to therapeutic opportunities. Nat. Rev. Mol. Cell Biol. 22, 75–95 (2021). sourceExperimental — accuracy not yet measured

In the paper

“These observations can be explained by an evolutionary perspective by which telomere-binding proteins inhibit DNA repair in cis18,19 to maintain the linear structure of chromosomes and to prevent fusions.”

What the sources say

• ?Not checked — no full text of the sourcecites [18] Bae, N. S. & Baumann, P. A RAP1/TRF2 complex inhibits nonhomologous end-joining at human telomeric DNA ends. Mol. Cell 26, 323–334 (2007). source
• Supported

  The Results (‘Persistent DDR foci are localized at telomeres’; page not provided) say that telomeres are coated by proteins that inhibit DNA repair to prevent chromosome fusions, and propose that telomeric factors also inhibit repair along telomeric repeats. The Discussion (page not provided) links this resistance to repair with maintaining linear chromosome structure. (LLM, conf=0.92)

  cites [19] Fumagalli, M. et al. Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nat. Cell Biol. 14, 355–365 (2012). source

In the paper

“In addition to being hard to repair, telomeric DNA is hyper-sensitive to oxidative DNA damage, a phenomenon recently named TelOxidation22.”

What the sources say

• Supported

  The discussion states that telomeres are particularly sensitive to oxidative stress and calls this process TelOxidation. It also explains that telomeric DNA’s high guanine content makes it susceptible to oxidation. (LLM, conf=0.94)

  cites [22] Jacome Burbano, M. S., Cherfils-Vicini, J. & Gilson, E. Neutrophils: mediating TelOxidation and senescence. EMBO J. 40, e108164 (2021). source

In the paper

“As a consequence, DNA damage that occurs within telomeric repeats (tDD) resists repair, which causes persistent tDDR signalling and TAF formation also at long telomeres19–21.”

What the sources say

• Supported

  The Results section states that damage at telomeres resists repair and produces persistent DDR foci. It also reports that these foci do not preferentially occur at short telomeres, supporting their formation at longer telomeres (page not provided). (LLM, conf=0.93)

  cites [19] Fumagalli, M. et al. Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nat. Cell Biol. 14, 355–365 (2012). source
• Partly supported

  The Discussion reports a persistent DNA damage response at telomeres irrespective of telomere length and proposes that repair inhibition could allow it to persist. But it explicitly says the authors could not determine whether the damage occurred within telomeric repeats or at chromosome ends. The claim presents that proposed location and causal mechanism as established. (LLM, conf=0.89)

  cites [20] Hewitt, G. et al. Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence. Nat. Commun. 3, 708–708 (2012). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section ('DDR signaling persists for years after cellular senescence establishment'; page unavailable) reports persistent DDR foci in telomere-initiated senescent cells. The paper also cites irreparable DNA damage as a driver of persistent DDR, but its own reported foci are not identified as TAF at long telomeres, and it does not establish repair resistance specifically within long telomeric repeats. (LLM, conf=0.84)

  cites [21] Fumagalli, M., Rossiello, F., Mondello, C. & d’Adda di Fagagna, F. Stable cellular senescence is associated with persistent DDR activation. PLoS ONE 9, e110969 (2014). sourceExperimental — accuracy not yet measured

In the paper

“Following telomere dysfunction, some cell types may also undergo cell death by apoptosis8,9 or autophagy10.”

What the sources say

• ?Not checked — no full text of the sourcecites [8] d’Adda di Fagagna, F. Living on a break: cellular senescence as a DNA-damage response. Nat. Rev. Cancer 8, 512–522 (2008). source
• ?Not checked — no full text of the sourcecites [9] Karlseder, J., Broccoli, D., Dai, Y., Hardy, S. & de Lange, T. p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2. Science 283, 1321–1325 (1999). source
• Supported

  Citation 10 is attached to autophagy, not apoptosis. The paper’s Abstract states that telomere dysfunction specifically triggers autophagy and that autophagy has a dominant role in the death of fibroblasts and epithelial cells during replicative crisis. (LLM, conf=0.93)

  cites [10] Nassour, J. et al. Autophagic cell death restricts chromosomal instability during replicative crisis. Nature 565, 659–663 (2019). source

In the paper

“Indeed, the levels of DDR markers and TAFs increase during ageing in different mammalian tissues.”

What the sources say

• Supported

  The Results section (“TAF increase with age irrespective of telomere length”; page not provided) reports age-dependent increases in DNA damage foci in mouse tissues and shows that TAF per cell increase with age in both liver hepatocytes and intestinal crypt enterocytes. This supports the claim across different mammalian tissues. (LLM, conf=0.91)

  cites [20] Hewitt, G. et al. Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence. Nat. Commun. 3, 708–708 (2012). source
• Supported

  The Introduction (labeled Abstract in our copy; page unavailable) reports that telomeres colocalizing with DDR proteins increase with age in baboon skin and mouse liver, brain, and gut. The Results (page unavailable) also report age-related increases in TAF in mouse small-airway epithelial cells. (LLM, conf=0.87)

  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). source
• Partly supported

  The Results (page unavailable) report substantially more telomere dysfunction-induced foci (TIFs) in osteocytes from old mice than in those from young mice, and higher p53 expression in some aged bone-cell populations. The paper does not establish that DDR markers and telomere-associated foci increase across different mammalian tissues; its findings are centered on the mouse bone microenvironment. (LLM, conf=0.84)

  cites [35] Farr, J. N. et al. Identification of senescent cells in the bone microenvironment. J. Bone Miner. Res. 31, 1920–1929 (2016). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section ('Length-independent telomere damage in aged cardiomyocytes in vivo'; page not provided) reports that TAF increase with age in mouse and human hearts, as well as in skeletal muscle myocytes and hippocampal neurons. It does not support a general increase in DDR markers: total γH2A.X foci did not change with age in cardiomyocytes, and non-TAF did not increase in the other post-mitotic cells examined. (LLM, conf=0.90)

  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
• ?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

In the paper

“First, interventions known to increase health span such as dietary restriction41, exercise42, rapamycin43,44 and 17β-oestradiol45 can reduce the frequency of cells with TAFs.”

What the sources say

• Supported

  The citation is attached to dietary restriction, not to the other interventions listed. In Results, “DR protects against hepatocyte senescence,” the paper reports that dietary restriction kept the frequency of hepatocytes with three or more TAF low, while it rose with age in ad-libitum-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
• Supported

  The Results section reports that exercised nfkb1-/- mice had fewer hepatocytes with telomere-associated DNA damage foci (TAFs) than sedentary mice. This supports the exercise portion of the citing sentence, which is the portion attributed to this source; the other interventions have separate citations. (LLM, conf=0.93)

  cites [42] Bianchi, A. et al. Moderate exercise inhibits age-related inflammation, liver steatosis, senescence, and tumorigenesis. J. Immunol. 206, 904–916 (2021). source
• Supported

  This source is cited for rapamycin, not for the other listed interventions. In the Results section (‘mTORC1‐PGC‐1β regulates mitochondrial content and contributes to senescence in vivo’), the authors report that rapamycin-fed mice had fewer telomere-associated foci in liver tissue than expected from the age-dependent increase. (LLM, conf=0.93)

  cites [43] Correia-Melo, C. et al. Mitochondria are required for pro-ageing features of the senescent phenotype. EMBO J. 35, 724–742 (2016). source
• Supported

  The citation supports the rapamycin portion of the sentence, not the other interventions. In the Results section, rapamycin reduced the percentage of TAF-positive lung airway epithelial cells and hepatocytes in nfκb1−/− mice; the Discussion links reduced TAF with improved healthspan in those mice. (LLM, conf=0.93)

  cites [44] Correia-Melo, C. et al. Rapamycin improves healthspan but not inflammaging in nfκb1–/– mice. Aging Cell 18, e12882 (2019). source
• Partly supported

  The Results section (‘17α-E2 Reverses Age-related Lipid Redistribution and Restores Metabolic Flexibility’; page unavailable) reports reduced hepatocyte telomere-associated DNA damage foci after 17α-estradiol treatment in mice. The cited claim instead names 17β-oestradiol; the paper uses 17β-estradiol in other assays but does not report that it reduces cells with TAFs. (LLM, conf=0.88)

  cites [45] Stout, M. B. et al. 17α-Estradiol alleviates age-related metabolic and inflammatory dysfunction in male mice without inducing feminization. J. Gerontol. A Biol. Sci. Med. Sci. 72, 3–15 (2017). sourceExperimental — accuracy not yet measured

In the paper

“Consistently, one or a few critically short telomeres are sufficient to trigger a DDR and impose cellular senescence in vivo, regardless of a majority of otherwise long telomeres33.”

What the sources say

• Partly supported

  The Discussion says individual critically short telomeres, rather than average length, trigger cellular responses; the Results describe mice with short telomeres despite also inheriting long ones. But the paper reports chromosome instability, cell-cycle arrest, and apoptosis—not a demonstration that one or a few short telomeres trigger a DNA-damage response and impose cellular senescence in vivo. Its cross gave offspring 50% short and 50% long telomeres, rather than a majority of long telomeres. (LLM, conf=0.87)

  cites [33] Hemann, M. T., Strong, M. A., Hao, L.-Y. & Greider, C. W. The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability. Cell 107, 67–77 (2001). sourceExperimental — accuracy not yet measured

In the paper

“Damaged telomeres also increase in the brain, liver and skin of aged baboons19,38.”

What the sources say

• Supported

  The Results section reports that telomere-associated DNA-damage-response foci accumulate with age in baboon hippocampal neurons and liver hepatocytes. The Discussion also reports DDR foci in skin fibroblasts of old baboons and relates them to telomeres. Page numbers are unavailable in our copy. (LLM, conf=0.86)

  cites [19] Fumagalli, M. et al. Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nat. Cell Biol. 14, 355–365 (2012). source
• ?Not checked — no full text of the sourcecites [38] Herbig, U., Ferreira, M., Condel, L., Carey, D. & Sedivy, J. M. Cellular senescence in aging primates. Science 311, 1257 (2006). source

In the paper

“Causality of telomere dysfunction in familial and sporadic IPF is indicated by the detection of germline mutations in genes involved in telomere maintenance57,58.”

What the sources say

• Partly supported

  The Abstract reports germline mutations in hTERT or hTR in six probands from a familial pulmonary fibrosis registry, and the Discussion links mutant telomerase and short telomeres to familial IPF. This paper does not report germline mutations in sporadic IPF; it only suggests that acquired telomere shortening may contribute to disease in people without telomerase mutations. The passages provide evidence for a causal role in a subgroup of familial cases, but not the claimed evidence from germline mutations in both familial and sporadic IPF. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  cites [57] Armanios, M. Y. et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. N. Engl. J. Med. 356, 1317–1326 (2007). sourceExperimental — accuracy not yet measured
• Partly supported

  The Abstract (page unavailable) reports inherited PARN and RTEL1 mutations in familial pulmonary fibrosis, shortened telomeres in mutation carriers, and a strengthened link between fibrosis and telomere dysfunction. It separately notes short telomeres in sporadic IPF, but does not show that germline mutations establish telomere dysfunction as causal in sporadic IPF. (LLM, conf=0.87)

  cites [58] Stuart, B. D. et al. Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening. Nat. Genet. 47, 512–517 (2015). sourceExperimental — accuracy not yet measured

In the paper

“Although most human data on telomeres are based on studies of leukocytes, a recent study of telomere length in tissues from 952 individuals concluded that 21 out of the 24 tissues studied show age-dependent telomere shortening40.”

What the sources say

• Supported

  The Abstract reports tissue samples from 952 individuals. In “TL is correlated with age in most tissues,” the paper reports negative correlations with age in 21 of 24 tissues; it qualifies that only 14 of those correlations were statistically significant (p < 0.05). (LLM, conf=0.91)

  cites [40] Demanelis, K. et al. Determinants of telomere length across human tissues. Science 369, eaaz6876 (2020). source

In the paper

“Clearance of senescent cells with senolytic strategies reduces TAF numbers in vivo36,37,41,46.”

What the sources say

• Supported

  In Results, “Senescent-cell clearance reduces cardiac hypertrophy and fibrosis” (page not available), clearing p16-positive cells in aged mice significantly reduced TAF in cardiomyocytes. The same section reports that the senolytic navitoclax reduced cardiomyocyte telomere dysfunction in aged mice. (LLM, conf=0.93)

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

  In Results, under “Senescent cell clearance decreases liver fat accumulation” (Fig. 3b; Supplementary Fig. 3d), the paper reports that both the senolytic combination D+Q and AP-mediated clearance reduced TAF-positive hepatocytes and the average number of TAF per hepatocyte in aged mice. (LLM, conf=0.94)

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

  In the age-related vascular pathology section, the paper reports that TAF-positive nuclei in the aortas of aged mice were markedly reduced after dasatinib-plus-quercetin treatment. The Abstract also reports fewer TAF-positive cells in the aortic medial layer of aged and hypercholesterolemic mice, while noting no reduction in intimal atherosclerotic plaques. (LLM, conf=0.92)

  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). source

In the paper

“Although senescence may occur independently of telomere dysfunction17 (for example, during development), the differential contribution of telomere-dependent and -independent cellular senescence to ageing and age-related disorders remains to be determined.”

What the sources say

• Supported

  The ‘Cellular senescence of stem cells’ section says senescence occurs during mammalian embryonic development mainly through p21, p15 and SASP mediators rather than overt DNA-damage-response signalling. This supports the hedged claim that developmental senescence may occur independently of telomere dysfunction. (LLM, conf=0.88)

  cites [17] Di Micco, R., Krizhanovsky, V., Baker, D. & d’Adda di Fagagna, F. Cellular senescence in ageing: from mechanisms to therapeutic opportunities. Nat. Rev. Mol. Cell Biol. 22, 75–95 (2021). source

In the paper

“Moreover, circulating leukocytes and alveolar epithelial cells show shorter telomeres than age-matched individuals53.”

What the sources say

• Supported

  The Results report shorter peripheral-blood telomeres in IIP patients than in age-matched controls, with no detected difference between IPF and non-IPF IIP patients. They also report shorter telomeres in the alveolar epithelium of IPF patients than in age-matched controls. (LLM, conf=0.93)

  cites [53] Alder, J. K. et al. Short telomeres are a risk factor for idiopathic pulmonary fibrosis. Proc. Natl Acad. Sci. USA 105, 13051–13056 (2008). source

In the paper

“Mice, despite having long telomeres and ubiquitous telomerase expression, show an age-dependent increase in dysfunctional telomeres in both proliferating and non-proliferating tissues20,34–37.”

What the sources say

• Partly supported

  The Results section ('TAF increase with age irrespective of telomere length'; page unavailable) reports that telomere-associated damage foci increase with age in proliferative intestinal crypts and in liver, where few hepatocytes proliferate. The paper describes the mice as having long telomeres and active telomerase, but does not establish that telomerase expression is ubiquitous. (LLM, conf=0.85)

  cites [20] Hewitt, G. et al. Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence. Nat. Commun. 3, 708–708 (2012). sourceExperimental — accuracy not yet measured
• Supported

  The Results (page unavailable) state that mice have long telomeres and ubiquitous telomerase expression, and report that telomere-associated foci accumulate with age in liver and intestine. The paper also reports age-related increases in telomere-associated DNA-damage foci in mouse brain and gut, and its Results document an increase in small-airway epithelial cells. Together, these support the claim across proliferating and non-proliferating tissues. (LLM, conf=0.88)

  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). source
• Partly supported

  The Results report substantially more telomere dysfunction-induced foci in osteocytes from old mice than in those from young mice, supporting an age-related increase in this non-proliferating cell type. The paper does not establish the claimed increase across both proliferating and non-proliferating tissues, or state the premises about long mouse telomeres and ubiquitous telomerase expression. Page numbers were not available in our copy. (LLM, conf=0.88)

  cites [35] Farr, J. N. et al. Identification of senescent cells in the bone microenvironment. J. Bone Miner. Res. 31, 1920–1929 (2016). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section (page unavailable) reports an age-dependent increase in telomere-associated damage foci in mouse cardiomyocytes, skeletal muscle myocytes, and hippocampal neurons, supporting the claim for non-proliferating tissues. It does not establish the same age-dependent increase in proliferating tissues or say that mice have ubiquitous telomerase expression; it reports only that telomerase activity in the heart was unaffected by age. (LLM, conf=0.86)

  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
• ?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

In the paper

“In humans, TAFs increase with age in the absence of telomere shortening in skin melanocytes15 and CD8+ T cells, together with other senescence markers39.”

What the sources say

• Supported

  Citation 15 is attached to the skin-melanocyte finding; the CD8+ T-cell finding is separately cited to reference 39. The Results report that TAF increase in melanocytes in older human skin, without significant telomere shortening, alongside increased p16 and reduced HMGB1—other senescence markers. (LLM, conf=0.94)

  cites [15] Victorelli, S. et al. Senescent human melanocytes drive skin ageing via paracrine telomere dysfunction. EMBO J. 38, e101982 (2019). source
• Partly supported

  The Results section reports that human CD8+ T cells with senescence markers have telomere dysfunction-induced foci and that cells with these features become more common with age. It does not establish that this occurs without telomere shortening; the reported foci measurements do not measure telomere length. Skin melanocytes are attached to a different citation in the citing sentence. (LLM, conf=0.87)

  cites [39] Martinez-Zamudio, R. I. et al. Senescence-associated β-galactosidase reveals the abundance of senescent CD8+ T cells in aging humans. Aging Cell 20, e13344 (2021). sourceExperimental — accuracy not yet measured

In the paper

“Fibrosis in human ageing lungs has been associated with telomere shortening, DDR and cellular senescence51.”

What the sources say

• Supported

  The Abstract reports pro-fibrotic changes in aging human lungs alongside telomere shortening, DNA damage foci, and cellular senescence. The Results section, “Quantitation of telomere length,” explicitly links telomere attrition to a DNA damage response and senescence markers. Page numbers are not provided in our copy. (LLM, conf=0.90)

  cites [51] Lee, S. et al. Molecular programs of fibrotic change in aging human lung. Nat. Commun. 12, 6309 (2021). source

In the paper

“Treatment of a mouse model of biliary liver fibrosis with a senolytic drug reduced fibrosis99.”

What the sources say

• Supported

  The Results section reports that Mdr2−/− mice treated with the Bcl-xL inhibitor A-1331852 had significantly less periductal fibrosis than vehicle-treated controls. The paper also reports a reduction in senescent cholangiocytes, consistent with the citing sentence’s description of senolytic treatment. Page numbers are not supplied in our copy. (LLM, conf=0.94)

  cites [99] Moncsek, A. et al. Targeting senescent cholangiocytes and activated fibroblasts with B-cell lymphoma-extra large inhibitors ameliorates fibrosis in multidrug resistance 2 gene knockout (Mdr2−/−) mice. Hepatology 67, 247–259 (2018). source

In the paper

“Telomere dysfunction, specifically induced in alveolar epithelial type II cells through the deletion of the telomere proteins TRF1 or TRF2, led to impaired regeneration, inflammation and fibrosis61,62.”

What the sources say

• Partly supported

  The Results (pp. 5–7) show that deleting TRF1 in alveolar type II cells caused cell loss and pulmonary fibrosis, and report an inflammatory response in TRF1-deficient lungs (p. 6). The Discussion (p. 12) and Figure 7 (p. 13) propose impaired regeneration as part of the mechanism rather than establishing it as a measured outcome. This paper does not report deletion of TRF2 in those cells. (LLM, conf=0.88)

  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
• ?Not checked — no full text of the sourcecites [62] Alder, J. K. et al. Telomere dysfunction causes alveolar stem cell failure. Proc. Natl Acad. Sci. USA 112, 5099–5104 (2015). source

In the paper

“Leukocyte telomere length in the donor, but not in the recipient, positively correlates with survival following allogenic haematopoietic cell transplantation82.”

What the sources say

• Partly supported

  The Conclusions and Results report that longer donor leukocyte telomere length was associated with better survival, while recipient telomere length was not. The study was limited to patients with severe aplastic anemia receiving unrelated-donor allogeneic HCT; the citing sentence leaves out that population and donor restriction. (LLM, conf=0.86)

  cites [82] Gadalla, S. M. et al. Association between donor leukocyte telomere length and survival after unrelated allogeneic hematopoietic cell transplantation for severe aplastic anemia. JAMA 313, 594–602 (2015). sourceExperimental — accuracy not yet measured

In the paper

“Short telomeres were also observed in lungs and circulating leukocytes of patients with COPD66,67.”

What the sources say

• Supported

  The Results report significantly reduced telomere length in the lungs of patients with COPD. The Discussion reports prior studies finding telomere attrition in patients with COPD, and reference 19 identifies circulating leukocytes as the tissue studied; the paper does not present leukocyte measurements as its own result. (LLM, conf=0.90)

  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
• ?Not checked — no full text of the sourcecites [67] Houben, J. M. et al. Telomere shortening in chronic obstructive pulmonary disease. Respir. Med. 103, 230–236 (2009). source

In the paper

“Compared with unaffected individuals, small airway epithelial cells from patients with COPD show higher levels of TAFs and senescence markers34.”

What the sources say

• Supported

  The Results report significantly more small airway epithelial cells positive for TAF in COPD patients than in controls, alongside increased p16 expression. They also report higher Sen-β-Gal positivity, although that difference was not statistically significant; p21 did not differ. (LLM, conf=0.88)

  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). source

In the paper

“Senescent cell clearance improved glucose homeostasis and insulin sensitivity in obese and aged mice103.”

What the sources say

• Partly supported

  The Adipose Tissue Senescence and Inflammation section reports that senolytics significantly improve glucose tolerance and insulin sensitivity in mice on a high-fat diet, supporting the claim for obese mice. The copy does not report those improvements following senescent-cell clearance in aged mice; its discussion of old mice concerns senescence markers and insulin resistance. Page numbers are unavailable in the indexed passages. (LLM, conf=0.88)

  cites [103] Narasimhan, A., Flores, R. R., Robbins, P. D. & Niedernhofer, L. J. Role of cellular senescence in type II diabetes. Endocrinology https://doi.org/10.1210/endocr/bqab136 (2021). sourceExperimental — accuracy not yet measured

In the paper

“Similar to the other conditions contributing to it, obesity is associated with increased TAFs in various organs and tissues37,41,92.”

What the sources say

• ?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
• Partly supported

  The Results section, “Senescent cell clearance decreases liver fat accumulation” (page unavailable), reports increased TAF in hepatocytes of high-fat-diet mice and an increased fraction of TAF-containing cells in db/db mice. The paper supports the association in liver, but does not establish increased TAF across various organs and tissues. (LLM, conf=0.85)

  cites [41] Ogrodnik, M. et al. Cellular senescence drives age-dependent hepatic steatosis. Nat. Commun. 8, 15691 (2017). sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion (page unavailable) reports increased senescent cells in the adipose tissue, liver, and brain of obese mice. It does not say that TAF specifically increased in those tissues. The bone-quality results report increased TAF only in osteocytes of mice with type 2 diabetes compared with controls, not obesity alone. (LLM, conf=0.84)

  cites [92] Eckhardt, B. A. et al. Accelerated osteocyte senescence and skeletal fragility in mice with type 2 diabetes. JCI Insight 5, e135236 (2020). sourceExperimental — accuracy not yet measured

In the paper

“Additionally, genetic or pharmacological clearance of senescent cells improved lung function and health in a mouse model of bleomycin-induced IPF52.”

What the sources say

• Supported

  The Discussion (Fig. 4; page not supplied) states that eliminating senescent cells by suicide-gene or senolytic strategies attenuated bleomycin-induced impairments in lung function and physical health in mice. It identifies the strongest benefits when treatment began at disease onset. (LLM, conf=0.94)

  cites [52] Schafer, M. J. et al. Cellular senescence mediates fibrotic pulmonary disease. Nat. Commun. 8, 14532 (2017). source

In the paper

“Moreover, late-generation telomerase-deficient mice recapitulate myelodysplastic features that can be reversed by telomerase reactivation91.”

What the sources say

• Supported

  In Results, “Telomere dysfunctional mice exhibit hallmarks of human MDS” reports that late-generation G4/G5 mice developed cytopenias, marrow dysplasia, and excess blasts. In Results, “Telomerase reactivation rescues impaired progenitor cell differentiation,” reactivation restored myeloid differentiation and improved several associated marrow abnormalities. The paper does not claim that every abnormality was reversed. (LLM, conf=0.92)

  cites [91] Colla, S. et al. Telomere dysfunction drives aberrant hematopoietic differentiation and myelodysplastic syndrome. Cancer Cell 27, 644–657 (2015). source

In the paper

“Similarly, transplantation of bone marrow from late-generation Tert-knockout mice in irradiated wild-type recipients resulted in aplastic anaemia85.”

What the sources say

• Supported

  The Introduction describes transplanting bone marrow from third-generation Tert-knockout mice into irradiated wild-type recipients. The Discussion calls this a second mouse model of aplastic anemia, while noting that aplastic anemia from Tert deficiency has variable penetrance. Page numbers are unavailable in our copy. (LLM, conf=0.90)

  cites [85] Bär, C. et al. Telomerase gene therapy rescues telomere length, bone marrow aplasia, and survival in mice with aplastic anemia. Blood 127, 1770–1779 (2016). source

In the paper

“Nucleated blood cells show the shortest telomeres among human tissues40.”

What the sources say

• Supported

  In “TL varies across (and correlates among) human tissue types” (page unavailable), the paper reports that average relative telomere length was shortest in whole blood among the tissues studied. The paper describes whole-blood telomere measurements as coming from leukocytes, supporting the claim about nucleated blood cells. (LLM, conf=0.93)

  cites [40] Demanelis, K. et al. Determinants of telomere length across human tissues. Science 369, eaaz6876 (2020). source

In the paper

“Alcoholic liver disease and chronic viral hepatitis have also been associated with telomere dysfunction in human liver biopsies100,101.”

What the sources say

• ?Not checked — no full text of the sourcecites [100] Ikeda, H. et al. Large cell change of hepatocytes in chronic viral hepatitis represents a senescent-related lesion. Hum. Pathol. 40, 1774–1782 (2009). source
• Partly supported

  In Results, under “Neutrophils promote hepatocellular telomere damage” (page unavailable), the paper reports telomere-associated DNA damage in hepatocytes from human alcoholic liver disease tissue, compared with negligible damage in normal liver. It does not report the corresponding finding for chronic viral hepatitis, so only the alcoholic liver disease portion is supported. (LLM, conf=0.88)

  cites [101] Wilson, C. L. et al. NFκB1 is a suppressor of neutrophil-driven hepatocellular carcinoma. Nat. Commun. 6, 6818 (2015). sourceExperimental — accuracy not yet measured

In the paper

“At least two mouse models have demonstrated a causative role of telomere dysfunction in bone marrow failure.”

What the sources say

• Supported

  The Discussion (page unavailable) reports that mice with TRF1 deletion developed bone marrow failure and links the outcome to dysfunctional telomeres. It also describes a separate POT1b-deficient mouse model in which telomere dysfunction accompanied bone marrow failure. Together, these support the claim about at least two mouse models. (LLM, conf=0.90)

  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). sourceExperimental — accuracy not yet measured
• Supported

  The Introduction describes two mouse models with short telomeres: one involving Trf1 deletion and another using marrow from telomerase-deficient mice. The Discussion reports bone marrow aplasia in both models and improved outcomes after telomerase treatment, supporting a causal role for telomere dysfunction. Page numbers were not available in our copy. (LLM, conf=0.92)

  cites [85] Bär, C. et al. Telomerase gene therapy rescues telomere length, bone marrow aplasia, and survival in mice with aplastic anemia. Blood 127, 1770–1779 (2016). sourceExperimental — accuracy not yet measured

In the paper

“Telomerase mutations are a risk factor for emphysema among patients with COPD68.”

What the sources say

• Partly supported

  The Discussion reports that germline telomerase mutations are a risk factor for severe emphysema in smokers and says cigarette smoke exposure is a necessary second hit. The cited finding supports the risk-factor claim, but the citing sentence omits those limits and states it for COPD patients generally. (LLM, conf=0.88)

  cites [68] Stanley, S. E. et al. Telomerase mutations in smokers with severe emphysema. J. Clin. Invest. 125, 563–570 (2015). sourceExperimental — accuracy not yet measured

In the paper

“In both models, danazol or AAV-mediated Tert expression improved haematopoiesis85,86.”

What the sources say

• Supported

  For this source, the relevant part of the sentence is AAV-mediated Tert expression, not danazol. The Discussion reports enhanced colony formation by bone marrow cells after AAV9-Tert treatment, and the results section reports significantly less loss of marrow cellularity in treated mice with aplastic anemia. Page numbers are not provided in our copy’s passages. (LLM, conf=0.92)

  cites [85] Bär, C. et al. Telomerase gene therapy rescues telomere length, bone marrow aplasia, and survival in mice with aplastic anemia. Blood 127, 1770–1779 (2016). source
• Partly supported

  The Results report that testosterone treatment improved survival in a mouse model of aplastic anemia, and the Discussion says androgen therapy delayed disease. But this paper did not test danazol or AAV-mediated Tert expression: the Discussion mentions danazol only as the subject of ongoing clinical investigations. (LLM, conf=0.88)

  cites [86] Bär, C., Huber, N., Beier, F. & Blasco, M. A. Therapeutic effect of androgen therapy in a mouse model of aplastic anemia produced by short telomeres. Haematologica 100, 1267–1274 (2015). sourceExperimental — accuracy not yet measured

In the paper

“cardiac ischaemia–reperfusion injury (IRI), which is associated with massive induction of oxidative stress, promotes TAF formation and senescence”

What the sources say

• Supported

  The Results section (‘Myocardial infarction with reperfusion induces senescence in multiple cardiac lineages,’ Figure 1) reports increased telomere-associated DNA damage foci (TAF) and senescence markers after cardiac ischemia–reperfusion in mice. It also reports increased staining for an oxidative-stress marker after injury. (LLM, conf=0.93)

  cites [106] Dookun, E. et al. Clearance of senescent cells during cardiac ischemia–reperfusion injury improves recovery. Aging Cell 19, e13249 (2020). source

In the paper

“their clearance increased bone strength130”

What the sources say

• Partly supported

  The 'Causal role of senescent cells in mediating age-related bone loss' section reports that treatment reduced senescent osteocytes and that eliminating senescent cells improved bone strength in old mice. But the treatment eliminated senescent cells systemically and locally, not osteocytes specifically, so the paper does not establish that clearing senescent osteocytes caused the strength increase. (LLM, conf=0.87)

  cites [130] Farr, J. N. & Khosla, S. Cellular senescence in bone. Bone 121, 121–133 (2019). sourceExperimental — accuracy not yet measured

In the paper

“patients with osteoarthritis have leukocytes with shorter telomeres than age-matched individuals123,124”

What the sources say

• ?Not checked — no full text of the sourcecites [123] Poonpet, T. et al. Association between leukocyte telomere length and angiogenic cytokines in knee osteoarthritis. Int. J. Rheum. Dis. 21, 118–125 (2018). source
• Partly supported

  The Discussion reports that, after adjustment for age and other factors, leucocyte telomere length was 178 bp shorter in subjects with hand osteoarthritis than in those without it. The claim extends this finding to osteoarthritis patients generally, whereas the study examined radiographic hand osteoarthritis and says its predominantly female sample does not permit extrapolation to men. (LLM, conf=0.85)

  cites [124] Zhai, G. et al. Reduction of leucocyte telomere length in radiographic hand osteoarthritis: a population-based study. Ann. Rheum. Dis. 65, 1444–1448 (2006). sourceExperimental — accuracy not yet measured

In the paper

“AAV-mediated Tert expression in adult mice improved their survival following myocardial infarction112.”

What the sources say

• Supported

  The Results section, “Telomerase gene therapy reduces mortality after MI,” reports that adult mice given AAV9-Tert three weeks before artery ligation had greater post-infarction survival than mice given an empty vector (over 74% versus 57%). This directly supports the claim, with the timing of treatment specified. (LLM, conf=0.95)

  cites [112] Bär, C. et al. Telomerase expression confers cardioprotection in the adult mouse heart after acute myocardial infarction. Nat. Commun. 5, 5863 (2014). source

In the paper

“treatment with a senolytic agent improved cardiac function106”

What the sources say

• Supported

  The Abstract states that treatment with the senolytic drug navitoclax after cardiac ischemia–reperfusion improved left ventricular function. The Introduction specifies that this was shown in young adult mice. (LLM, conf=0.94)

  cites [106] Dookun, E. et al. Clearance of senescent cells during cardiac ischemia–reperfusion injury improves recovery. Aging Cell 19, e13249 (2020). source

In the paper

“This observation confirms a role for cellular senescence in heart disease and hints at the negligible contribution of telomere length to cardiomyocyte senescence36.”

What the sources say

• Supported

  The Discussion states that the authors’ data suggest telomere length is not a limiting factor in cardiomyocyte senescence. The Introduction likewise reports that age-related damage foci increase independently of telomere length. This supports the citing sentence’s hedged claim. (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

“clearance of senescent cells reduced TAF-positive cells in the medial layer of the aorta from aged and hypercholesterolaemic mice46”

What the sources say

• Supported

  The Abstract states that senolytic treatment significantly reduced TAF-positive cells in the aortic medial layer of both aged and hypercholesterolemic mice. The hypercholesterolemia results also report reduced senescent cell burden in medial vessel segments, but not in established intimal plaques. (LLM, conf=0.95)

  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). source

In the paper

“with TAFs being associated with impaired osteoblast differentiation132,133”

What the sources say

• Supported

  The Results report that osteoblast differentiation was negatively correlated with the percentage of mouse mesenchymal progenitor cells containing dysfunctional telomeres. The paper calls the measured telomeric damage foci TIFs rather than TAFs, but its assay describes them as telomere-colocalized damage foci (page unavailable). (LLM, conf=0.90)

  cites [132] Wang, H. et al. Impairment of osteoblast differentiation due to proliferation-independent telomere dysfunction in mouse models of accelerated aging. Aging Cell 11, 704–713 (2012). source
• Partly supported

  The Introduction links telomere dysfunction in the mouse models to declines in osteoblast differentiation, and the Discussion reports dysfunctional osteoblast differentiation in those models. Neither passage identifies or measures telomere-associated foci (TAFs), so the specific association with TAFs is not established by this paper. (LLM, conf=0.82)

  cites [133] Brennan, T. A. et al. Mouse models of telomere dysfunction phenocopy skeletal changes found in human age-related osteoporosis. Dis. Model. Mech. 7, 583–592 (2014). sourceExperimental — accuracy not yet measured

In the paper

“In CKD, senescence markers were observed in tubular epithelial cells, podocytes, interstitial and mesangial cells136”

What the sources say

• Supported

  The “Sources of Senescence in CKD” section (page not supplied) explicitly says senescence is observed in tubular epithelial cells (TECs), podocytes, interstitial cells, and mesangial cells. The “Cellular Senescence” section also describes senescence markers observed in CKD patients. (LLM, conf=0.93)

  cites [136] Schroth, J., Thiemermann, C. & Henson, S. M. Senescence and the aging immune system as major drivers of chronic kidney disease. Front. Cell Dev. Biol. 8, 564461 (2020). source

In the paper

“mouse models of increased oxidative stress and mitochondrial dysfunction show early onset of age-dependent telomere dysfunction36”

What the sources say

• Supported

  The Results section, “Mitochondrial ROS drive TAF in mouse cardiomyocytes in vivo” (page unavailable), reports increased telomere-associated damage in mouse models with elevated mitochondrial ROS or mitochondrial dysfunction. The Animals and procedures section (page unavailable) identifies models tested at 6 and 12 months, supporting the description of early onset relative to the age-related increase observed in cardiomyocytes. (LLM, conf=0.87)

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

In the paper

“telomere length inversely correlates with chronic severe pain125”

What the sources say

• Partly supported

  The Abstract Results and §4.1 report shorter telomeres in the high chronic knee-pain severity group than in the no- or low-severity group, with a significant severity dose response. The study concerns knee osteoarthritis pain; the unqualified claim extends that finding to chronic severe pain generally. (LLM, conf=0.84)

  cites [125] Sibille, K. T. et al. Accelerated aging in adults with knee osteoarthritis pain: consideration for frequency, intensity, time, and total pain sites. Pain Rep. 2, e591 (2017). sourceExperimental — accuracy not yet measured

In the paper

“This observation confirms a role for cellular senescence in heart disease and hints at the negligible contribution of telomere length to cardiomyocyte senescence36.”

What the sources say

• Supported

  The Abstract reports that clearing senescent cells in mice alleviates features of cardiac ageing, including myocardial hypertrophy and fibrosis. The Discussion concludes that cardiomyocyte senescence contributes to age-related cardiac dysfunction, supporting the broad claim about heart disease. (LLM, conf=0.90)

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

In the paper

“Length-independent telomere damage may result from oxidative damage”

What the sources say

• Supported

  The Results section reports that H2O2 increased telomere-associated damage foci in adult cardiomyocytes and found no evidence that stressors specifically targeted the shortest telomeres. The Discussion also identifies oxidative stress as a contributor to telomere-associated damage in cardiomyocytes. Page numbers were not provided in our copy. (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

In the paper

“During physiological ageing in humans and mice, TAFs occur independently from telomere length in post-mitotic cardiomyocytes.”

What the sources say

• Supported

  The Introduction states that persistent telomere-associated DNA damage foci increase with age in human and mouse cardiomyocytes independently of telomere length or DNA replication. The Results section, “Length-independent telomere damage in aged cardiomyocytes in vivo,” reports increased telomere-associated foci in both human and mouse hearts. Page numbers were not provided in our copy. (LLM, conf=0.94)

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

In the paper

“late-generation telomerase-deficient mice recapitulate several features of osteoporosis, such as decreased bone volume, diminished osteoblast number and function, and increased porosity”

What the sources say

• Partly supported

  The Introduction reports low bone mass in older telomerase-deficient mice, and the Results report reduced osteoblast differentiation in fourth-generation Terc−/− mice compared with first-generation mice. The paper does not report increased bone porosity or a diminished in-vivo osteoblast count in late-generation mice; its cell-count measures concern mesenchymal progenitors and osteoblast-forming colonies. (LLM, conf=0.87)

  cites [132] Wang, H. et al. Impairment of osteoblast differentiation due to proliferation-independent telomere dysfunction in mouse models of accelerated aging. Aging Cell 11, 704–713 (2012). sourceExperimental — accuracy not yet measured
• Partly supported

  The Animals section identifies the Terc−/− mice as fourth-generation (G4). The Results and Discussion report decreased bone volume, increased cortical porosity, and impaired osteoblast function. But the Results say osteoblast number decreased with age across all genotypes, and the Discussion says numbers in aged mice were comparable across genotypes; the claimed decrease in osteoblast number relative to controls is not supported. (LLM, conf=0.92)

  cites [133] Brennan, T. A. et al. Mouse models of telomere dysfunction phenocopy skeletal changes found in human age-related osteoporosis. Dis. Model. Mech. 7, 583–592 (2014). sourceExperimental — accuracy not yet measured

In the paper

“Short telomeres were also observed in a large independent cohort, with the severity of hypertrophic cardiomyopathy correlating with the telomere length of leukocyte telomeres109.”

What the sources say

• Partly supported

  The Results report that leukocyte telomere length was negatively associated with severity in the obstructive HCM (HOCM) subgroup. The Discussion specifies that this severity finding came from 56 patients; it does not establish the correlation across HCM generally, and the authors call for larger validation cohorts. Page numbers are not available in our copy. (LLM, conf=0.88)

  cites [109] Chatterjee, S. et al. Leukocyte telomere length correlates with hypertrophic cardiomyopathy severity. Sci. Rep. 8, 11227 (2018). sourceExperimental — accuracy not yet measured

In the paper

“A causal role of short and dysfunctional telomeres in cardiac diseases has been established in mice110.”

What the sources say

• Partly supported

  Section 4.6 (page unavailable) reports that late-generation TERC-deficient mice with shortened telomeres develop severe ventricular failure, supporting a role in mouse cardiac disease. But the paper describes these findings as suggestive, while Section 3.3 says definite proof of a causal role in heart failure has not been generated. The claim overstates the certainty of the evidence. (LLM, conf=0.86)

  cites [110] Wong, L. S. et al. Telomere biology in cardiovascular disease: the TERC–/– mouse as a model for heart failure and ageing. Cardiovasc. Res. 81, 244–252 (2009). sourceExperimental — accuracy not yet measured

In the paper

“their accumulation was associated with disease progression135”

What the sources say

• Supported

  The Stress-induced premature ageing section reports that kidney levels of the senescence marker p16 and SASP factors increased with CKD progression in a mouse model. It also reports more pronounced p16 expression and SA-β-gal staining in patients with heavy proteinuria than in those with micro-albuminuria. (LLM, conf=0.90)

  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

“treatment with a senolytic therapy mitigated age-dependent disc degeneration122”

What the sources say

• Supported

  The Discussion reports that dasatinib plus quercetin targeted senescence in mouse discs and may mitigate age-dependent disc degeneration. The Abstract reports lower incidences of degeneration in mice whose treatment began at 6 or 14 months. The claim is supported in that mouse-treatment context. (LLM, conf=0.92)

  cites [122] Novais, E. J. et al. Long-term treatment with senolytic drugs dasatinib and quercetin ameliorates age-dependent intervertebral disc degeneration in mice. Nat. Commun. 12, 5213 (2021). source

In the paper

“Senescent osteocytes that express p16 at high levels have been associated with age-related bone loss in mice”

What the sources say

• Supported

  The “Do old osteocytes become senescent?” section reports increased p16Ink4a expression and senescence features in osteocytes from old mice. The “Causal role of senescent cells in mediating age-related bone loss” section reports that increased p16Ink4a in mouse bone coincided with age-related bone loss. Together, these support the stated association, without establishing that senescent osteocytes themselves caused the loss. (LLM, conf=0.87)

  cites [130] Farr, J. N. & Khosla, S. Cellular senescence in bone. Bone 121, 121–133 (2019). source

In the paper

“Patients with genetic forms of hypertrophic or dilated cardiomyopathy, conditions that affect 1 in 500–2,500 people worldwide, have cardiomyocytes with shorter telomeres than age-matched individuals107,108.”

What the sources say

• Partly supported

  The Abstract describes a comparison between older patients with an age-related dilated myopathy and individuals of similar age with normal ventricular function. “Length of Telomeres in Senescent Myocytes” reports significantly shorter myocyte telomeres in the diseased hearts. The paper does not establish this finding for genetic hypertrophic or dilated cardiomyopathy, and the cited passages do not support the prevalence figure. (LLM, conf=0.88)

  cites [107] Chimenti, C. et al. Senescence and death of primitive cells and myocytes lead to premature cardiac aging and heart failure. Circ. Res. 93, 604–613 (2003). sourceExperimental — accuracy not yet measured
• Supported

  The Results report that cardiomyocyte telomere levels in genetic HCM and DCM hearts were significantly lower than in age- and sex-matched healthy controls—by an average of 25% and 40%, respectively. The paper also states that genetic cardiomyopathy affects 1 in 500–2,500 people worldwide. (LLM, conf=0.95)

  cites [108] Chang, A. C. Y. et al. Telomere shortening is a hallmark of genetic cardiomyopathies. Proc. Natl Acad. Sci. USA 115, 9276–9281 (2018). source

In the paper

“Chondrocytes, the cells that constitute the articular cartilage, show several senescence markers, including DDR activation, in osteoarthritis119,120.”

What the sources say

• Supported

  The ‘Senescence in OA chondrocytes & cartilage’ section explicitly says that, compared with chondrocytes from normal cartilage, OA chondrocytes express several senescence-associated markers, including activated DNA damage response (DDR). The ‘Senescence in osteoarthritis pathology’ section identifies chondrocytes as the cells present in articular cartilage. (LLM, conf=0.95)

  cites [119] McCulloch, K., Litherland, G. J. & Rai, T. S. Cellular senescence in osteoarthritis pathology. Aging Cell 16, 210–218 (2017). source
• Partly supported

  The ‘Cellular senescence and OA’ section reports senescent signatures in chondrocytes derived from osteoarthritic cartilage, and the ‘Extracellular vesicles’ section reports more senescent chondrocytes in OA cartilage than in healthy cartilage. However, the paper does not identify DDR activation as a marker observed in those chondrocytes; its discussion of DNA damage as a senescence trigger does not establish that specific point. (LLM, conf=0.85)

  cites [120] Coryell, P. R., Diekman, B. O. & Loeser, R. F. Mechanisms and therapeutic implications of cellular senescence in osteoarthritis. Nat. Rev. Rheumatol. 17, 47–57 (2021). sourceExperimental — accuracy not yet measured

In the paper

“Telomere dysfunction induced by VSMC-specific expression of mutant TRF2 is sufficient to increase atherosclerosis116,117.”

What the sources say

• ?Not checked — no full text of the sourcecites [116] Wang, J. et al. Vascular smooth muscle cell senescence promotes atherosclerosis and features of plaque vulnerability. Circulation 132, 1909–1919 (2015). source
• Partly supported

  The Results section (‘VSMC-specific TRF2T188A promotes neointima formation’; page unavailable) says that VSMC senescence was previously shown to promote atherogenesis in mice and identifies the VSMC-specific TRF2T188A model. This paper’s own experiment, however, found increased neointima formation after carotid injury, not increased atherosclerosis; it does not establish the claimed sufficiency for atherosclerosis. (LLM, conf=0.84)

  cites [117] Uryga, A. K. et al. Telomere damage promotes vascular smooth muscle cell senescence and immune cell recruitment after vessel injury. Commun. Biol. https://doi.org/10.1038/s42003-021-02123-z (2021). sourceExperimental — accuracy not yet measured

In the paper

“removal of senescent cells reduced the development of post-traumatic and naturally occurring osteoarthritis in mouse models121”

What the sources say

• Supported

  The main text reports that clearing senescent cells reduced cartilage erosion and pain after surgically induced osteoarthritis in mice (Fig. 1e–h). It also reports reduced age-related cartilage degeneration in mice with naturally occurring disease (Fig. 3a–c). Page numbers were not provided in our copy. (LLM, conf=0.94)

  cites [121] Jeon, O. H. et al. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat. Med. 23, 775–781 (2017). source

In the paper

“which indicates that senescence has an important role in age-associated cognitive impairment.”

What the sources say

• Partly supported

  The Discussion (page not provided) says the mouse data support a role for senescence in age-dependent cognitive decline. But the authors describe its contribution as speculative and say further cognitive testing is needed; the unqualified claim that senescence has an important role is stronger than their conclusion. (LLM, conf=0.84)

  cites [152] Ogrodnik, M. et al. Whole-body senescent cell clearance alleviates age-related brain inflammation and cognitive impairment in mice. Aging Cell 20, e13296 (2021). sourceExperimental — accuracy not yet measured

In the paper

“Although there is no clear evidence of telomere length changes in patients with Parkinson’s disease170”

What the sources say

• Supported

  The Results section reports no significant difference in telomere length between Parkinson’s disease patients and controls across eight studies. The Discussion likewise says there was no consistent, significant evidence of shorter telomeres in patient samples. (LLM, conf=0.93)

  cites [170] Forero, D. A. et al. Telomere length in Parkinson’s disease: a meta-analysis. Exp. Gerontol. 75, 53–55 (2016). source

In the paper

“Senescent astrocytes have been detected in postmortem brain samples from patients with Parkinson’s disease168”

What the sources say

• Supported

  The Introduction reports increased senescence markers, particularly in astrocytes, in postmortem tissue from Parkinson’s disease patients. The Results section on the substantia nigra further reports a senescence-associated marker in astrocytes from those tissues. Page numbers were not provided. (LLM, conf=0.93)

  cites [168] Chinta, S. J. et al. Cellular senescence is induced by the environmental neurotoxin paraquat and contributes to neuropathology linked to Parkinson’s disease. Cell Rep. 22, 930–940 (2018). source

In the paper

“Clearance of senescent cells in aged mice significantly improved cognitive function152”

What the sources say

• Supported

  The Abstract states that both senescent-cell clearance approaches significantly improved cognitive function in aged mice. The Results section, ‘Clearance of senescent cells alleviates age-associated cognitive impairment,’ likewise concludes that whole-body clearance alleviated cognitive impairment. (LLM, conf=0.94)

  cites [152] Ogrodnik, M. et al. Whole-body senescent cell clearance alleviates age-related brain inflammation and cognitive impairment in mice. Aging Cell 20, e13296 (2021). source

In the paper

“telomere shortening is linked to complications of kidney transplantation144”

What the sources say

• Supported

  The Discussion reports that post-transplant complications—delayed graft function, acute rejection and chronic allograft dysfunction—significantly affected telomere shortening. The Conclusions likewise link these complications with telomere length and graft ageing. (LLM, conf=0.94)

  cites [144] Domański, L. et al. Effect of delayed graft function, acute rejection and chronic allograft dysfunction on kidney allograft telomere length in patients after transplantation: a prospective cohort study. BMC Nephrol. 16, 23 (2015). source

In the paper

“Across patients with amyloid pathology, leukocyte telomere length positively correlated with better cognition and memory”

What the sources say

• Partly supported

  The Results (Table 2; page not provided) report that longer telomeres were associated with better global cognition across all amyloid-positive participants. The positive association with memory was found in the amyloid-positive mild cognitive impairment subgroup, not across all amyloid-positive participants. (LLM, conf=0.88)

  cites [163] Koh, S. H. et al. Telomere shortening reflecting physical aging is associated with cognitive decline and dementia conversion in mild cognitive impairment due to Alzheimer’s disease. Aging (Albany NY) 12, 4407–4423 (2020). sourceExperimental — accuracy not yet measured

In the paper

“which indicates that senescence contributes to these pathological alterations147”

What the sources say

• Supported

  The section ‘Renal epithial cell senescence and glomerulosclerosis’ reports that clearing senescent cells in aged mice markedly reduced glomerulosclerosis and attenuated age-related increases in blood urea nitrogen. These findings support the attributed conclusion that senescence contributes to both alterations. (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

“A study of a large cohort of patients with CKD revealed that telomere length measured in peripheral blood was a strong independent predictor of all-cause mortality142.”

What the sources say

• Supported

  The Abstract reports that relative telomere length was measured in peripheral blood in 4,955 patients with CKD and explicitly calls it a strong, independent predictor of all-cause mortality. The Conclusions likewise report an independent association between shorter leukocyte telomere length and all-cause mortality during four years of follow-up. (LLM, conf=0.95)

  cites [142] Fazzini, F. et al. Results from the German Chronic Kidney Disease (GCKD) study support association of relative telomere length with mortality in a large cohort of patients with moderate chronic kidney disease. Kidney Int. 98, 488–497 (2020). source

In the paper

“late-generation telomerase-deficient mice recapitulate Alzheimer’s disease phenotypes164”

What the sources say

• Partly supported

  The Results report increased phosphorylated tau in old G3 Tert-/- mice, identify tau pathology as associated with Alzheimer’s disease, and report poorer memory performance in G4 Tert-/- mice. But the Discussion describes these findings as signs of brain aging and neurodegeneration, and discusses Alzheimer’s disease models separately; it does not establish that these mice recapitulate Alzheimer’s disease phenotypes broadly. The indexed passages provide section labels but no page numbers. (LLM, conf=0.86)

  cites [164] Whittemore, K. et al. Telomerase gene therapy ameliorates the effects of neurodegeneration associated to short telomeres in mice. Aging (Albany NY) 11, 2916–2948 (2019). sourceExperimental — accuracy not yet measured

In the paper

“in a large population study, telomere shortening was associated with an increased risk for CKD progression in individuals who actively smoke and in patients with diabetes mellitus143”

What the sources say

• Supported

  The Discussion states that shorter relative telomere length was significantly associated with CKD progression in active smokers and patients with diabetes mellitus. The study comprised two prospective cohorts totaling 1,055 patients with CKD, supporting the description of a large study. (LLM, conf=0.94)

  cites [143] Raschenberger, J. et al. Association of relative telomere length with progression of chronic kidney disease in two cohorts: effect modification by smoking and diabetes. Sci. Rep. 5, 11887 (2015). source

In the paper

“TAFs increase with age in hippocampal neurons in baboons19 and mice151”

What the sources say

• Supported

  The Results section reports that persistent DNA-damage-response foci accumulate with age in hippocampal neurons from baboons and examines their localization at telomeres. This source is cited for the baboon portion of the sentence; the mouse portion has a separate citation. No page number is available in our copy. (LLM, conf=0.90)

  cites [19] Fumagalli, M. et al. Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nat. Cell Biol. 14, 355–365 (2012). source
• Supported

  The Results section reports that telomere-associated DNA damage foci (TAF) increased significantly with age in the mice studied. The Telomere ImmunoFISH methods identify the measured neurons as hippocampal neurons. This source supports the mice portion of the citing sentence; the baboon portion has a separate citation. (LLM, conf=0.93)

  cites [151] Fielder, E. et al. Anti-inflammatory treatment rescues memory deficits during aging in nfkb1−/− mice. Aging Cell 19, e13188 (2020). source

In the paper

“Age-dependent TAF increases in the brain also correlate with chronic inflammation151 and obesity37”

What the sources say

• Supported

  Citation 151 is attached to chronic inflammation; obesity has a separate citation. The Results section ('Chronic inflammation is associated with increased senescent cell burden,' page not provided) reports that neuronal TAF increased with age, were elevated in the chronically inflamed nfkb1−/− mice, and fell after ibuprofen treatment. (LLM, conf=0.92)

  cites [151] Fielder, E. et al. Anti-inflammatory treatment rescues memory deficits during aging in nfkb1−/− mice. Aging Cell 19, e13188 (2020). 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

In the paper

“Genetic clearance of senescent cells or senolytic treatment in tauopathy mouse models mitigated cognitive decline and neurode-generation158,159”

What the sources say

• Partly supported

  The paper’s main text (page not specified) reports that genetic clearance in PS19 tauopathy mice prevented neurodegeneration and mitigated memory loss. Its senolytic ABT263 experiment reports reduced tau phosphorylation, but does not report that treatment mitigated cognitive decline or neurodegeneration. (LLM, conf=0.90)

  cites [158] Bussian, T. J. et al. Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature 562, 578–582 (2018). sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction and Results (pages not available in our copy) report that dasatinib and quercetin reduced tau pathology, brain atrophy, and neuron loss in tau-transgenic mice. They do not report that treatment mitigated cognitive decline. The paper describes genetically reducing neurofibrillary tangles, not genetically clearing senescent cells in these mice. (LLM, conf=0.90)

  cites [159] Musi, N. et al. Tau protein aggregation is associated with cellular senescence in the brain. Aging Cell 17, e12840 (2018). sourceExperimental — accuracy not yet measured

In the paper

“treatment of an Alzheimer’s disease mouse model with a senolytic agent improved memory and learning ability160”

What the sources say

• Supported

  The Results (Fig. 5e–f; page not provided) report that senolytic-treated APP/PS1 Alzheimer’s disease mice performed better in the Y maze and showed faster learning and better memory retention in the water maze. (LLM, conf=0.94)

  cites [160] Zhang, P. et al. Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model. Nat. Neurosci. 22, 719–728 (2019). source

In the paper

“AAV-mediated Tert expression ameliorated memory impairment164”

What the sources say

• Partly supported

  The Results section, “AAV9-Tert gene therapy has beneficial effects on memory” (page unavailable), reports better Barnes maze performance after AAV9-Tert treatment than after AAV9-null treatment. But the treated mice were wild-type or telomerase-deficient mice with short telomeres, not an Alzheimer’s disease mouse model. The printed citing sentence omits that Alzheimer’s qualifier; it is the additional qualifier in the supplied claim that is unsupported. (LLM, conf=0.88)

  cites [164] Whittemore, K. et al. Telomerase gene therapy ameliorates the effects of neurodegeneration associated to short telomeres in mice. Aging (Albany NY) 11, 2916–2948 (2019). sourceExperimental — accuracy not yet measured

In the paper

“Telomerase appears to have a protective role against tau pathological hyperphosphorylation in neurons from patients165”

What the sources say

• Partly supported

  In “TERT and tau in AD brain,” the authors report that TERT and pathological tau were mutually exclusive in patients’ hippocampal neurons. They say this could mean TERT-expressing neurons are protected, but could also mean TERT is lost after tau pathology develops. The paper therefore supports a possible protective role, not protection specifically against tau hyperphosphorylation in patient neurons. (LLM, conf=0.87)

  cites [165] Spilsbury, A., Miwa, S., Attems, J. & Saretzki, G. The role of telomerase protein TERT in Alzheimer’s disease and in tau-related pathology in vitro. J. Neurosci. 35, 1659–1674 (2015). sourceExperimental — accuracy not yet measured

In the paper

“cognitive decline over 2 years was steeper in patients with the lowest quartile of telomere length”

What the sources say

• Partly supported

  The Results (“Influence of telomere length on clinical outcomes over time”) report worse two-year cognitive outcomes in the lowest versus highest telomere-length quartile, but specifically among participants with mild cognitive impairment and amyloid pathology (MCI A+). The claim’s broader wording, “patients with amyloid pathology,” does not preserve that restriction. (LLM, conf=0.84)

  cites [163] Koh, S. H. et al. Telomere shortening reflecting physical aging is associated with cognitive decline and dementia conversion in mild cognitive impairment due to Alzheimer’s disease. Aging (Albany NY) 12, 4407–4423 (2020). sourceExperimental — accuracy not yet measured

In the paper

“Telomere length predicts long-term kidney allograft function”

What the sources say

• Supported

  The Conclusions explicitly state that telomere length measured in peri-transplant biopsy specimens predicts long-term kidney allograft function. The claim is a concise paraphrase of that statement. (LLM, conf=0.95)

  cites [144] Domański, L. et al. Effect of delayed graft function, acute rejection and chronic allograft dysfunction on kidney allograft telomere length in patients after transplantation: a prospective cohort study. BMC Nephrol. 16, 23 (2015). source

In the paper

“and against amyloid-β-induced cell death in embryonic mouse hippocampal neurons in vitro166”

What the sources say

• Supported

  The Abstract reports that suppressing telomerase’s catalytic subunit, TERT, in cultured embryonic mouse hippocampal neurons significantly increased their vulnerability to amyloid-β-induced cell death. The Discussion likewise reports greater amyloid-β-induced apoptosis when TERT levels were reduced, supporting the cautious claim that telomerase appears protective in this in vitro setting. (LLM, conf=0.93)

  cites [166] Zhu, H., Fu, W. & Mattson, M. P. The catalytic subunit of telomerase protects neurons against amyloid β-peptide-induced apoptosis. J. Neurochem. 75, 117–124 (2000). source

In the paper

“Single-cell RNA sequencing of the hippocampus of aged mice revealed an increased p16 level with age, which was stronger in microglia and oligodendrocyte progenitor cells152.”

What the sources say

• Supported

  The Results section reports that single-cell RNA sequencing of young and old mouse hippocampi found an age-related increase in p16Ink4a-positive cells, most prominently in microglia and oligodendrocyte progenitor cells. The measured increase was in the number of p16-positive cells, rather than necessarily the p16 level within each cell. (LLM, conf=0.93)

  cites [152] Ogrodnik, M. et al. Whole-body senescent cell clearance alleviates age-related brain inflammation and cognitive impairment in mice. Aging Cell 20, e13296 (2021). source

In the paper

“which suggests that cellular senescence has a causative effect in this pathology”

What the sources say

• Supported

  The paper’s opening summary states a causal link between senescent-cell accumulation and neuronal loss in a mouse model of tau-dependent disease. Its discussion reports that clearing senescent cells before disease onset reduced tau pathology and other aspects of disease progression. This supports the citing sentence’s hedged causal interpretation. (LLM, conf=0.93)

  cites [158] Bussian, T. J. et al. Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature 562, 578–582 (2018). source
• Supported

  The Discussion (page unavailable) says the findings suggest cellular senescence may be an underlying pathogenic process in tauopathies. It also reports that targeting senescent cells reduced NFT-associated pathology and interrupted a neurodegenerative cascade, supporting the citing sentence’s hedged causal interpretation. (LLM, conf=0.90)

  cites [159] Musi, N. et al. Tau protein aggregation is associated with cellular senescence in the brain. Aging Cell 17, e12840 (2018). source

In the paper

“mice with critically short telomeres recapitulate some features of the disease, including poor performance in neuromuscular coordination tests164”

What the sources say

• Supported

  The Results section, “Behavioral defects associated to shorter telomeres in the brain of telomerase-deficient mice” (page unavailable), reports that mice with shorter telomeres performed worse than age-matched controls on rotarod and tightrope tests, which measure neuromuscular coordination and balance. The paper also discusses Parkinson’s disease models, so the claim’s limited wording—“some features”—is consistent with the reported motor impairment. (LLM, conf=0.88)

  cites [164] Whittemore, K. et al. Telomerase gene therapy ameliorates the effects of neurodegeneration associated to short telomeres in mice. Aging (Albany NY) 11, 2916–2948 (2019). source

In the paper

“which suggests a causal role for telomere dysfunction in this process”

What the sources say

• Supported

  The Results report increased senescence-associated markers in brain neurons of mice with dysfunctional telomeres, with those changes reversed by loss of p21. The Abstract describes the finding as a senescence-like phenotype in postmitotic neurons, supporting the citing sentence’s cautious suggestion of a causal role. (LLM, conf=0.88)

  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). source

In the paper

“Multiple senescence markers were detected in retinal tissues of AMD animal models and in patients with AMD173.”

What the sources say

• Partly supported

  The section ‘Senescence occurs in a variety of retinal cells’ (page unavailable) reports multiple senescence-characteristic genes—p16INK4A, p21CIP1, p53 and BMP4—in RPE cells from human aging or AMD donor eyes. The section ‘Cell senescence is an important driver for age-related diseases including AMD’ describes retinal transcriptome changes in a rat model with AMD-like pathology, but does not establish that multiple senescence markers were detected in retinal tissues of AMD animal models. (LLM, conf=0.84)

  cites [173] Lee, K. S., Lin, S., Copland, D. A., Dick, A. D. & Liu, J. Cellular senescence in the aging retina and developments of senotherapies for age-related macular degeneration. J. Neuroinflammation 18, 32 (2021). sourceExperimental — accuracy not yet measured

In the paper

“Increased levels of γH2AX and phosphorylated ATM in glomeruli are associated with clinicopathological parameters in patients with IgA nephropathy”

What the sources say

• Supported

  The Results section reports that glomeruli from patients with IgA nephropathy had more γH2AX-positive and pATM-positive cells than controls. It also reports that counts for both markers correlated with one-year eGFR decline, a clinical parameter; γH2AX-positive podocytes were associated with podocytopathic features. Page numbers are unavailable in our copy. (LLM, conf=0.93)

  cites [138] Hayashi, K. et al. Association of glomerular DNA damage and DNA methylation with one-year eGFR decline in IgA nephropathy. Sci. Rep. 10, 237 (2020). source

In the paper

“who also have a greater chance of developing dementia163”

What the sources say

• Partly supported

  The Results (Figure 3 and Table 4) show a significantly greater probability of dementia conversion for the lowest versus highest telomere-length quartile, but specifically among participants with mild cognitive impairment and amyloid pathology (MCI A+). The claim omits the MCI restriction and thus extends the finding to patients with amyloid pathology generally. (LLM, conf=0.86)

  cites [163] Koh, S. H. et al. Telomere shortening reflecting physical aging is associated with cognitive decline and dementia conversion in mild cognitive impairment due to Alzheimer’s disease. Aging (Albany NY) 12, 4407–4423 (2020). sourceExperimental — accuracy not yet measured

In the paper

“Small-molecule inhibitors of PAPD5, a non-canonical poly(A) polymerase that destabilizes TERC RNA, have been shown to rescue TERC levels in induced pluripotent stem cells from patients with dyskeratosis congenita190.”

What the sources say

• Supported

  The Introduction states that pharmacologic PAPD5 inhibition increases TERC in iPSCs from dyskeratosis congenita patients. The Results section on DKC1-mutant cells specifically reports that small-molecule inhibitor treatment enhanced TERC levels in patient iPSCs. Page numbers are not supplied in our copy. (LLM, conf=0.94)

  cites [190] Nagpal, N. et al. Small-molecule PAPD5 inhibitors restore telomerase activity in patient stem cells. Cell Stem Cell 26, 896–909.e8 (2020). source

In the paper

“Similar observations have been made in zebrafish and killifish186,187.”

What the sources say

• Partly supported

  The Results section (‘Telomerase-deficient zebrafish can be bred for only one generation’; page unavailable) reports reduced offspring survival and developmental defects associated with shorter telomeres. The paper also reports premature infertility, but the passages found do not establish a decreased fertilization rate. This source studies zebrafish, not killifish; the citing sentence carries a second citation for that species. (LLM, conf=0.82)

  cites [186] Anchelin, M. et al. Premature aging in telomerase-deficient zebrafish. Dis. Model. Mech. 6, 1101–1112 (2013). sourceExperimental — accuracy not yet measured
• Supported

  The Results section on germline defects reports that TERT-deficient killifish males fertilized 9% of eggs versus 81% for controls. The Results section on genetic anticipation reports that second-generation TERT-deficient embryos had shorter telomeres, developmental abnormalities, and died before hatching. The Discussion also reports premature infertility in TERT-deficient zebrafish; the source supports the observation, though the fertilization and embryo findings in killifish were measured in different generations. (LLM, conf=0.90)

  cites [187] Harel, I. et al. A platform for rapid exploration of aging and diseases in a naturally short-lived vertebrate. Cell 160, 1013–1026 (2015). source

In the paper

“and to improve health span and lifespan in a progeria animal model199”

What the sources say

• Supported

  The Introduction states that telomeric ASOs improve tissue homeostasis and extend healthspan and lifespan in a transgenic HGPS mouse model. The Results report improved skin homeostasis and significantly longer survival with anti-teloG ASO. Page numbers are not provided in the supplied passages. (LLM, conf=0.95)

  cites [199] Aguado, J. et al. Inhibition of DNA damage response at telomeres improves the detrimental phenotypes of Hutchinson–Gilford progeria syndrome. Nat. Commun. 10, 4990 (2019). source

In the paper

“Women undergoing in vitro fertilization tend to have shorter leukocyte telomere length than healthy individuals177”

What the sources say

• Supported

  The Results report significantly shorter telomeres in women undergoing IVF than in healthy controls (mean T/S ratio 1.15 versus 1.53; p=0.029). The Abstract identifies the measured cells as lymphocytes, a type of leukocyte. This was a small exploratory study of 20 IVF patients and 10 controls. (LLM, conf=0.93)

  cites [177] Czamanski-Cohen, J. et al. Cell-free DNA and telomere length among women undergoing in vitro fertilization treatment. J. Assist. Reprod. Genet. 32, 1697–1703 (2015). source

In the paper

“The discovery that DDR activation depends on noncoding RNAs, such as damage-induced long non-coding RNAs (dilncRNA) and DNA damage-response RNAs (DDRNA), generated at exposed DNA ends, including dysfunctional telomeres, make such RNAs attractive targets for potential therapeutic interventions196.”

What the sources say

• Supported

  The section on damage-induced transcription at DNA breaks says dilncRNAs are transcribed from DNA ends and that their interaction with DDRNAs is fundamental to fully activate the DDR. The section on other noncoding telomeric transcripts reports the same RNA pathway at dysfunctional telomeres, where telomeric DDRNAs are essential for full DDR signaling. (LLM, conf=0.92)

  cites [196] Michelini, F. et al. From “cellular” RNA to “smart” RNA: multiple roles of RNA in genome stability and beyond. Chem. Rev. 118, 4365–4403 (2018). source

In the paper

“Short telomeres have been associated with poor sperm quality in males with normozoosperm183”

What the sources say

• Supported

  The Introduction (p. 2) identifies the study population as men with normozoospermia. The Discussion (p. 3) reports a positive correlation between sperm telomere length and progressive motility and vitality, supporting the association between shorter telomeres and poorer sperm quality. It does not establish causation, which the claim does not assert. (LLM, conf=0.92)

  cites [183] Rocca, M. S. et al. Sperm telomere length as a parameter of sperm quality in normozoospermic men. Hum. Reprod. 31, 1158–1163 (2016). source

In the paper

“in vitro studies indicate that telomerase expression is not able to prevent the accumulation of persistent double-strand breaks at telomeres after exogenous genotoxic insults19,20”

What the sources say

• Supported

  The Results section on exogenous DNA damage reports persistent DNA-damage-response foci after irradiation even in telomerase-expressing BJ hTERT cells. The Results section on telomeric localization finds that persistent foci accumulate at telomeres after irradiation and also occur there after bleomycin treatment. The paper uses these foci as evidence of unrepaired DNA damage, supporting the citing sentence’s qualified conclusion. (LLM, conf=0.86)

  cites [19] Fumagalli, M. et al. Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation. Nat. Cell Biol. 14, 355–365 (2012). source
• Partly supported

  The Results (TAF are persistent in stress-induced senescence; page unavailable) report that telomerase overexpression did not significantly reduce telomere-associated DNA damage foci after irradiation. The Discussion (page unavailable) says the authors could not establish the exact position of a DNA double-strand break, so the claim overstates the evidence by calling the persistent foci double-strand breaks at telomeres. (LLM, conf=0.88)

  cites [20] Hewitt, G. et al. Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence. Nat. Commun. 3, 708–708 (2012). sourceExperimental — accuracy not yet measured

In the paper

“a double-blinded study of a small number of patients with early AMD showed that treatment with a telomerase activator significantly improved macular function176”

What the sources say

• Supported

  The Methods describe 38 participants in a double-blinded trial of oral TA-65 versus placebo, and the Background identifies the patients as having early AMD. The Discussion reports that TA-65 significantly improved macular function compared with controls. The indexed passages provide section labels but no page numbers. (LLM, conf=0.94)

  cites [176] Dow, C. T. & Harley, C. B. Evaluation of an oral telomerase activator for early age-related macular degeneration—a pilot study. Clin. Ophthalmol. 10, 243–249 (2016). source

In the paper

“Short telomeres in human oocytes and polar bodies, which are extruded after meiotic divisions, are associated with aneuploidy in oocytes and early-stage embryos”

What the sources say

• Supported

  The Abstract reports significantly less telomere DNA in aneuploid polar bodies than in euploid polar bodies from sibling oocytes, and likewise in aneuploid embryonic cells at the cleavage stage. It interprets the polar-body finding as indicating that oocytes with telomere DNA deficiency are prone to aneuploidy. The association was not significant at the later blastocyst stage, which is consistent with the claim’s early-stage qualification; page numbers are not provided in our copy. (LLM, conf=0.92)

  cites [180] Treff, N. R., Su, J., Taylor, D. & Scott, R. T. Jr. Telomere DNA deficiency is associated with development of human embryonic aneuploidy. PLoS Genet. 7, e1002161 (2011). source

In the paper

“Therapeutic benefits have been observed for AAV-mediated delivery of TERT in animal models of aplastic anaemia, IPF and Alzheimer’s disease164,191.”

What the sources say

• Partly supported

  The Introduction reports therapeutic effects of AAV9-mediated telomerase activation in mouse models of aplastic anaemia and pulmonary fibrosis (IPF). The Discussion reports benefits in aging and telomerase-deficient mice, but says testing an Alzheimer’s disease model is for future study; this source therefore does not support the Alzheimer’s-model part of the claim. The indexed passages provide section labels but no page numbers. (LLM, conf=0.91)

  cites [164] Whittemore, K. et al. Telomerase gene therapy ameliorates the effects of neurodegeneration associated to short telomeres in mice. Aging (Albany NY) 11, 2916–2948 (2019). sourceExperimental — accuracy not yet measured
• Partly supported

  The section “Therapeutic strategies in the treatment of telomere syndromes” reports that AAV9-Tert rescued aplastic anemia and mouse survival, and says that investigation of its use for pulmonary fibrosis had positive results so far, although those results were unpublished. It reports reduced cognitive decline in Tert-treated adult mice, but does not identify an Alzheimer’s disease animal model or a therapeutic benefit in one. The claim therefore overstates the pulmonary-fibrosis evidence and is unsupported as to Alzheimer’s disease. (LLM, conf=0.88)

  cites [191] Martinez, P. & Blasco, M. A. Telomere-driven diseases and telomere-targeting therapies. J. Cell Biol. 216, 875–887 (2017). sourceExperimental — accuracy not yet measured

In the paper

“Although efficacy has been observed in cardiomyocytes194,195”

What the sources say

• Partly supported

  The “Gene Therapy With Telomere and Telomerase for CVDs” section (page not available) reports improved ventricular function and smaller infarct scars after TERT gene therapy in a mouse model. It does not establish efficacy specifically in cardiomyocytes, as the claim states. (LLM, conf=0.84)

  cites [194] Yeh, J. K., Lin, M. H. & Wang, C. Y. Telomeres as therapeutic targets in heart disease. JACC Basic Transl. Sci. 4, 855–865 (2019). sourceExperimental — accuracy not yet measured
• Supported

  The Results section, “TERT therapy ameliorates doxorubicin toxicity in human cardiomyocytes” (page not provided), reports that AAV6-hTERT delivery increased TERT expression and significantly rescued human iPSC-derived cardiomyocytes from doxorubicin-induced apoptosis. This supports the attributed observation of efficacy in cardiomyocytes. (LLM, conf=0.94)

  cites [195] Chatterjee, S. et al. Telomerase therapy attenuates cardiotoxic effects of doxorubicin. Mol. Ther. 29, 1395–1410 (2021). source

In the paper

“patients with polycystic ovary syndrome with low telomerase activity and short telomeres in granulosa cells, which support oocyte maturation, show an earlier onset of infertility178”

What the sources say

• Supported

  The Conclusions state that PCOS patients with lower granulosa-cell telomerase activity and shorter telomeres had an earlier onset of infertility symptoms. The IVF treatment section confirms that all enrolled patients underwent IVF. (LLM, conf=0.94)

  cites [178] Li, Y. et al. Telomere length is short in PCOS and oral contraceptive does not affect the telomerase activity in granulosa cells of patients with PCOS. J. Assist. Reprod. Genet. 34, 849–859 (2017). source