BACKGROUND Hepatocellular carcinoma(HCC)is the most common primary liver cancer,with high mortality at advanced stages.Loco-regional treatment including:Radiofrequency(RF)or transarterial chemoembolization(TACE)is dec...BACKGROUND Hepatocellular carcinoma(HCC)is the most common primary liver cancer,with high mortality at advanced stages.Loco-regional treatment including:Radiofrequency(RF)or transarterial chemoembolization(TACE)is decided according to the size,and the site of the tumor,according to practice guidelines.Alpha fetoprotein(AFP),the most used biomarker in the guidelines,although specific,lacks sensitivity.New biomarkers are needed to understand the underlying pathophysiology,and to be used in clinical practice.AIM To study the effect of loco-regional treatment on telomere length,as a diagnostic and short-term(3 months)prognostic marker.METHODS This is a prospective cohort study,and includes 60 patients visiting Ain Shams University Hospitals.The patients were divided into 2 groups:30 patients with liver cirrhosis(group 1)and 30 HCC patients undergoing RF or TACE(group 2).Laboratory investigations for all patients included:Telomere length in peripheral leukocytes by polymerase chain reaction,AFP,and liver function.In the HCC group,the aforementioned laboratory investigations with abdominal triphasic computed tomography with contrast were performed at baseline,and after 3 months.RESULTS With regard to age,Child-Pugh and Model for End-Stage Liver Disease scores,there was no statistically significant correlation with telomere length.However,there was a correlation between telomere length and age,and both scores before and after 3 months of treatment among HCC patients.On dividing the HCC group according to tumor size with a cutoff of 5 cm,and performing the Mann-Whitney test we found that at baseline telomere length was significantly lower among cases with tumor size≥5 cm than in those with tumor size<5 cm(30 patients;P=0.03).In addition,we found a positive Spearman's rank correlation between telomere length and tumor size in the≥5 cm only group(28 samples from the before and after intervention data;P=0.025).CONCLUSION Telomere length in leukocytes is a potential marker in HCC tumor prognosis.Further research using telomerase activity and telomerase reverse transcriptase promoter gene mutation in a larger cohort is recommended.展开更多
Telomeres have been a subject of genetic research since the 1930s. They play a crucial role in cancer biology, as they influence both cellular senescence and genomic stability. In cancer cells, dysfunctional telomeres...Telomeres have been a subject of genetic research since the 1930s. They play a crucial role in cancer biology, as they influence both cellular senescence and genomic stability. In cancer cells, dysfunctional telomeres can lead to chromosomal fusions and, through deregulation of telomerase, allow replication of mutated chromosomes that might otherwise lead to apoptosis. Research is now focused on improving telomere-based cancer cell detection and developing potential therapies that inhibit telomerase activity in cancerous cells. Telomere research is crucial in understanding the molecular mechanisms influencing tumor growth and invasiveness because of the central role played by telomeres in various cancer types. Several telomerase inhibitors and immunotherapy treatments are in pre-clinical or clinical development. Research on the role of telomeres in oncogenesis has made significant strides, but obstacles remain, including a lack of high-resolution structural understanding, inadequate preclinical models, and concern over potential side effects. Even so, the current path of telomere research holds promise.展开更多
Telomeres are protective structures at the ends of eukaryotic chromosomes. The loss of telomeres through cell division and oxidative stress is related to cellular aging, organismal growth and disease. In this way, tel...Telomeres are protective structures at the ends of eukaryotic chromosomes. The loss of telomeres through cell division and oxidative stress is related to cellular aging, organismal growth and disease. In this way, telomeres link molecular and cellular mechanisms with organismal processes, and may explain variation in a number of important life-history traits. Here, we discuss how telomere biology relates to the study of physiological ecology and life history evolution. We emphasize current knowledge on how telomeres may relate to growth, survival and lifespan in natural populations. We finish by examining interest- ing new connections between telomeres and the glucocorticoid stress response. Glucocorticoids are often employed as indices of physiological condition, and there is evidence that the glucocorticoid stress response is adaptive. We suggest that one way that glucocorticoids impact organismal survival is through elevated oxidative stress and telomere loss. Future work needs to establish and explore the link between the glucocorticoid stress response and telomere shortening in natural populations. If a link is found, it provides an explanatory mechanism by which environmental perturbation impacts life history trajectories [Current Zoology 56 （6）： 714-727, 2010].展开更多
It has been well documented that Tel1 positively regulates telomere-end resection by promoting Mre11-Rad50-Xrs2（MRX） activity, while Rif2 negatively regulates telomere-end resection by inhibiting MRX activity. At un...It has been well documented that Tel1 positively regulates telomere-end resection by promoting Mre11-Rad50-Xrs2（MRX） activity, while Rif2 negatively regulates telomere-end resection by inhibiting MRX activity. At uncapped telomeres, whether Tel1 or Rif2 plays any role remains largely unknown. In this work, we examined the roles of Tel1 and Rif2 at uncapped telomeres in yku70△ and/or cdc13-1 mutant cells cultured at non-permissive temperature. We found that deletion of TEL1 exacerbates the temperature sensitivity of both yku70△ and cdc13-1 cells. Further epistasis analysis indicated that MRX and Tel1 function in the same pathway in telomere protection. Consistently, TEL1 deletion increases accumulation of Exo1-dependent telomeric single-stranded DNA（ssDNA） at uncapped telomeres, which stimulates checkpoint-dependent cell cycle arrest. Moreover, TEL1 deletion in yku70△ cells facilitates Rad51-dependent Y0 recombination. In contrast, RIF2 deletion in yku70△ cells decreases the accumulation of telomeric ssDNA after 8 h of incubation at the non-permissive temperature of 37℃ and suppresses the temperature sensitivity of yku70△ cells, likely due to the increase of Mre11 association at telomeres.Collectively, our findings indicate that Tel1 and Rif2 regulate telomere protection at uncapped telomeres via their roles in balancing MRX activity in telomere resection.展开更多
BACKGROUND Dyskeratosis congenita is a rare disease characterized by bone marrow failure and a clinical triad of oral leukoplakia,nail dystrophy,and abnormal skin pigmentation.The genetics of dyskeratosis congenita in...BACKGROUND Dyskeratosis congenita is a rare disease characterized by bone marrow failure and a clinical triad of oral leukoplakia,nail dystrophy,and abnormal skin pigmentation.The genetics of dyskeratosis congenita include mutations in genes involved in telomere maintenance,including TINF2.CASE SUMMARY Here,we report a female patient who presented thrombocytopenia,anemia,reticulate hyperpigmentation,dystrophy in fingernails and toenails,and leukoplakia on the tongue.A histopathological study of the skin showed dyskeratocytes;however,a bone marrow biopsy revealed normal cell morphology.The patient was diagnosed with dyskeratosis congenita,but her family history did not reveal significant antecedents.Whole-exome sequencing showed a novel heterozygous punctual mutation in exon 6 from the TINF2 gene,namely,NM_001099274.1:-c.854delp.(Val285-Alafs*32).An analysis of telomere length showed short telomeres relative to the patient’s age.CONCLUSION The disease in this patient was caused by a germline novel mutation of TINF2 in one of her parents.展开更多
We have read with interest the article “Telomere length regulates TERRA levels through increased trimethylation of telomeric H3K9 and HP1α” by Arnoult and colleagues [1]. This study focuses on human telomeric chrom...We have read with interest the article “Telomere length regulates TERRA levels through increased trimethylation of telomeric H3K9 and HP1α” by Arnoult and colleagues [1]. This study focuses on human telomeric chromatin structure using different techniques like Chromatin Immunoprecipitation (ChIP), cytolocalization or RT-qPCR. However, it has been performed without taking into consideration the presence of Interstitial Telomeric Sequences (ITSs) in the human genome. Some of the conclusions of the article are undoubtedly clear but there are others that might be explained in alternative ways, considering the existence of ITSs. Following, we mention some comments that arise from this interesting article.展开更多
Colorectal cancer(CRC)is the third most common cancer worldwide and,despite improved treatments,is still an important cause of cancer-related deaths.CRC encompasses a complex of diseases arising from a multistep proce...Colorectal cancer(CRC)is the third most common cancer worldwide and,despite improved treatments,is still an important cause of cancer-related deaths.CRC encompasses a complex of diseases arising from a multistep process of genetic and epigenetic events.Besides heterogeneity in the molecular and biological features of CRC,chromosomal instability is a hallmark of cancer and cancer cells may also circumvent replicative senescence and acquire the ability to sustain unlimited proliferation.Telomere/telomerase interplay is an important mechanism involved in both genomic stability and cellular replicative potential,and its dysfunction plays a key role in the oncogenetic process.The erosion of telomeres,mainly because of cell proliferation,may be accelerated by specific alterations in the genes involved in CRC,such as APC and MSH2.Although there is general agreement that the shortening of telomeres plays a role in the early steps of CRC carcinogenesis by promoting chromosomal instability,the prognostic role of telomere length in CRC is still under debate.The activation of telomerase reverse transcriptase(TERT),the catalytic component of the telomerase complex,allows cancer cells to grow indefinitely by maintaining the length of the telomeres,thus favouring tumour formation/progression.Several studies indicate that TERT increases with disease progression,and most studies suggest that telomerase is a useful prognostic factor.Plasma TERT mRNA may also be a promising marker for the minimally invasive monitoring of disease progression and response to therapy.展开更多
The use of tree shrews as experimental animals for biomedical research is a new practice.Several recent studies suggest that tree shrews are suitable for studying cancers,including breast cancer,glioblastoma,lung canc...The use of tree shrews as experimental animals for biomedical research is a new practice.Several recent studies suggest that tree shrews are suitable for studying cancers,including breast cancer,glioblastoma,lung cancer,and hepatocellular carcinoma.However,the telomeres and the telomerase of tree shrews have not been studied to date.Here,we characterize telomeres and telomerase in tree shrews.The telomere length of tree shrews is approximately 23 kb,which is longer than that of primates and shorter than that of mice,and it is extended in breast tumor tissues according to Southern blot and flow-fluorescence in situ hybridization(FISH)analyses.Tree shrew spleen,bone marrow,testis,ovary,and uterus show high telomerase activities,which are increased in breast tumor tissues by telomeric repeat amplification protocol assays.The telomere length becomes shorter,and telomerase activity decreases with age.The tree shrew TERT and TERC are more highly similar to primates than to rodents.These findings lay a solid foundation for using tree shrews to study aging and cancers.展开更多
Telomere, the nucleoprotein structure at the end of eukaryotic linear chromosomes is indispensable for maintaining the genome stability. Telomeric DNA loss is apparent with each cell division, which marks an endpoint ...Telomere, the nucleoprotein structure at the end of eukaryotic linear chromosomes is indispensable for maintaining the genome stability. Telomeric DNA loss is apparent with each cell division, which marks an endpoint to the indefinite replication of the cell by causing replicative senescence that may lead to the programmed cell death. The loss of telomere is normal in cell division and as such after 20 - 40 divisions, telomere becomes too short to facilitate the capping function. Telomere uncapping or chromosomal free end causes a potential threat to the genomic stability and thus leads to the accumulation of chromosomal abnormalities that have been known to play a role in aging and cancer. Telomerase, the ribonucleoprotein complex, and its accessory proteins are required to maintain the telomere sequence. Telomerase plays a key role in maintaining the length of telomere by adding G-rich repeat sequences. Its activity has been found to be quite high in the gametes, stem cells and most importantly tumor cells. Almost 85% of tumor cells compensate for telomere loss aided by telomerase-associated protein complex and shelter in complex or telosome. However, 5% - 10% of the cells undergo telomerase-independent mechanism. This review presents the molecular view of the telomere and telomerase along with its associated complex structures. It also discusses its contrasting role in causing cellular senescence and promoting tumorigenesis.展开更多
Dear Editor,The completeness and accuracy of genome assemblies are crucial for ensuring the reliability of downstream analyses,including functional and evolutionary studies.With the advent of third-generation sequenci...Dear Editor,The completeness and accuracy of genome assemblies are crucial for ensuring the reliability of downstream analyses,including functional and evolutionary studies.With the advent of third-generation sequencing,the assembly of telomere-totelomere(T2T)genomes has become possible.展开更多
A consistent association has been observed between leukocyte telomere length(LTL)and atherosclerosis,but the mechanisms underlying these associations are still not well understood.Premature biology aging was evident i...A consistent association has been observed between leukocyte telomere length(LTL)and atherosclerosis,but the mechanisms underlying these associations are still not well understood.Premature biology aging was evident in atherosclerotic plaques,characterized by reduced cell proliferation,irreversible growth arrest and apoptosis,and telomere attrition.As atherosclerosis is a state of chronic low-grade inflammation and increased oxidative stress,shortened LTL in patients with atherosclerosis might stem from the two sources,one is an accelerated rate in hematopoietic stem cells(HSCs)replication to replace leukocytes consumed in the inflammatory process,and another is the increase in the loss of telomere repeats per replication.Thus,diminished HSC reserves at birth and age-dependent telomere attrition afterward are mirrored in shortened LTL during the adulthood.In addition,the inter-individual variation of LTL in the general population can be partly explained by genetic factors regulating telomere maintenance and the rate of HSCs replication.Atherosclerosis is an aging-related disease,and practically all humans develop atherosclerosis if they live long enough.Here we overview the potential roles of LTL dynamics in the imbalance between injurious oxidative stress/inflammation and endothelial repair during the pathogenesis of age-related atherosclerosis,and discuss the possibility that preventing accelerated cellular senescence is a potential target in prevention of atherosclerosis.展开更多
Functional telomeres protect chromosome ends and play important roles in stem cell maintenance and differentiation. Short telomeres negatively impact germ cell development and can contribute to age-associated infertil...Functional telomeres protect chromosome ends and play important roles in stem cell maintenance and differentiation. Short telomeres negatively impact germ cell development and can contribute to age-associated infertility. Moreover, telomere syndrome resulting from mutations of telomerase or telomere-associated genes exhibits short telomeres and reduced fertility. It remains elusive whether and how telomere lengths affect germ cell specification. We report that functional telomere is required for the coordinated germ cell and somatic cell fate decisions. Using telomerase gene Terc deficient mice as a model, we show that short telomeres restrain germ cell specification of epiblast cells but promote differentiation towards somatic lineage. Short telomeres increase chromatin accessibility to elevate TGFβ and MAPK/ERK signaling for somatic cell differentiation. Notably,elevated Fst expression in TGFβ pathway represses the BMP4-pSmad signaling pathway, thus reducing germ cell formation. Reelongation of telomeres by targeted knock-in of Terc restores normal chromatin accessibility to suppress TGFβ and MAPK signaling, thereby facilitating germ cell formation. Taken together, our data reveal that functional telomeres are required for germ cell specification by repressing TGFβ and MAPK signaling.展开更多
The significant role of telomeres in cells has attracted much attention since they were discovered.Fluorescence imaging is an effective method to study subcellular structures like telomeres.However,the diffraction lim...The significant role of telomeres in cells has attracted much attention since they were discovered.Fluorescence imaging is an effective method to study subcellular structures like telomeres.However,the diffraction limit of traditional optical microscope hampers further investigation on them.Recent progress on superresolution fluorescence microscopy has broken this limit.In this work,we used stimulated emission depletion(STED) microscope to observe fluorescence-labeled telomeres in interphase cell nuclei.The results showed that the size of fluorescent puncta representing telomeres under the STED microscope was much smaller than that under the confocal microscope.Two adjacent telomeres were clearly separated via STED imaging,which could hardly be discriminated by confocal microscopy due to the diffraction limit.We conclude that STED microscope is a more powerful tool that enable us to obtain detailed information about telomeres.展开更多
Telomeres are specialized structures at the ends of linear chromosomes that protect genome stability.The telomeric repeat-containing RNA(TERRA)that is transcribed from subtelomeric regions can invade into double-stran...Telomeres are specialized structures at the ends of linear chromosomes that protect genome stability.The telomeric repeat-containing RNA(TERRA)that is transcribed from subtelomeric regions can invade into double-stranded DNA regions and form RNA:DNA hybrid-containing structure called R-loop.In tumor cells,R-loop formation is closely linked to gene expression and the alternative lengthening of telomeres(ALT)pathway.Dysregulated R-loops can cause stalled replication forks and telomere instability.However,how R-loops are recognized and regulated,particularly at telomeres,is not well understood.We discovered that ILF3 selectively associates with telomeric R-loops and safeguards telomeres from abnormal homologous recombination.Knocking out ILF3 results in excessive R-loops at telomeres and triggers telomeric DNA damage responses.In addition,ILF3 deficiency disrupts telomere homeostasis and causes abnormalities in the ALT pathway.Using the proximity-dependent biotin identification(BioID)technology,we mapped the ILF3 interactome and discovered that ILF3 could interact with several DNA/RNA helicases,including DHX9.Importantly,ILF3 may aid in the resolution of telomeric R-loops through its interaction with DHX9.Our findings suggest that ILF3 may function as a reader of telomeric R-loops,helping to prevent abnormal homologous recombination and maintain telomere homeostasis.展开更多
Aging,as an inherent stage of life processes,has always been a core research focus in life sciences.Current studies confirm that the accumulation of intracellular molecular damage is a key driver of aging.As protectiv...Aging,as an inherent stage of life processes,has always been a core research focus in life sciences.Current studies confirm that the accumulation of intracellular molecular damage is a key driver of aging.As protective structures at chromosome ends,telomeres exhibit direct correlations between their length and stability and cellular aging processes,disease risks,and lifespan.This article systematically reviews the structural functions of telomeres and their relationship with aging,with particular emphasis on telomere rejuvenation strategies based on electromagnetic radiation techniques.Key experimental approaches include Gavich's mitotic radiation,Composite Wave Resonator(CWRT),and modern telomere length intervention trials.By synthesizing the latest domestic and international research findings,this paper analyzes the feasibility and limitations of these technologies while exploring their potential applications in anti-aging research,providing theoretical references for future studies.展开更多
This article is based on a recent bibliometric analysis of research progress on liver aging.The liver is notable for its extraordinary ability to rejuvenate,thereby safeguarding and maintaining the organism’s integri...This article is based on a recent bibliometric analysis of research progress on liver aging.The liver is notable for its extraordinary ability to rejuvenate,thereby safeguarding and maintaining the organism’s integrity.With advancing age,there is a noteworthy reduction in both the liver’s size and blood circulation.Furthermore,the wide range of physiological alterations driven on by aging may foster the development of illnesses.Previous studies indicate that liver aging is linked to impaired lipid metabolism and abnormal gene expression associated with chronic inflammation.Factors such as mitochondrial dysfunction and telomere shortening accumulate,which may result in increased hepatic steatosis,which impacts liver regeneration,metabolism,and other functions.Knowing the structural and functional changes could help elderly adults delay liver aging.Increasing public awareness of anti-aging interventions is essential.Besides the use of dietary supplements,alterations in lifestyle,including changes in dietary habits and physical exercise routines,are the most efficacious means to decelerate the aging process of the liver.This article highlights recent advances in the mechanism research of liver aging and summarizes the promising intervention options to delay liver aging for preventing related diseases.展开更多
Amborella trichopoda(Amborellaceae;hereafter simply Amborella)(Fig.1A)is a shrub endemic to New Caledonia in the Southwest Pacific that represents the sole sister species of all other extant angiosperms(Qiu et al.,199...Amborella trichopoda(Amborellaceae;hereafter simply Amborella)(Fig.1A)is a shrub endemic to New Caledonia in the Southwest Pacific that represents the sole sister species of all other extant angiosperms(Qiu et al.,1999;One Thousand Plant Transcriptomes Initiative,2019).Due to its unique phylogenetic status,it holds tremendous interest for botanists.The nuclear and mitochondrial genomes of Amborella were first published in 2013,providing valuable resources for studies on genome and gene family evolution,phylogenomics,and flower development,despite the fact that the assembly is heavily fragmented(Amborella Genome Project,2013;Rice et al.,2013).In 2024,a haplotype-resolved Amborella genome assembly was published,showing significant improvement in quality and completeness(Carey et al.,2024).展开更多
Background:Evidence regarding the effectiveness of prenatal nutritional supplements has mainly considered anthropometric pregnancy outcomes.The effect on markers of health and disease,such as offspring telomere length...Background:Evidence regarding the effectiveness of prenatal nutritional supplements has mainly considered anthropometric pregnancy outcomes.The effect on markers of health and disease,such as offspring telomere length(TL)and mitochondrial DNA content(mtDNAc)is unknown.Objectives:We assessed the efficacy of maternal multiple micronutrient(MMN)-fortified balanced-energy protein(BEP)and iron-folic acid(IFA)supplementation on newborn TL as a secondary outcome and mtDNAc as a non-declared outcome.Design:We conducted a randomized controlled trial in rural Burkina Faso,among pregnant females(15-40 years old)enrolled at<21 weeks of gestation.Mothers received either MMN-fortified BEP and IFA(intervention)or IFA only(control)throughout pregnancy.Whole arterial blood samples were collected from the umbilical cord of 104 control and 90 intervention group infants,respectively.Average relative TL and mtDNAc were measured using quantitative polymerase chain reaction.Linear regression models were fitted to assess TL and mtDNAc differences across trial arms.Results:We found that a combined daily MMN-fortified BEP supplement and IFA tablet did not affect newborn TL[β=-0.010(95%CI:-0.057,0.036);P=0.662]or mtDNAc[β=0.065(95%CI:-0.203,0.073);P=0.354],as compared to an IFA tablet alone.These findings were confirmed(P>0.05)by adjusting the regression models for potential prognostic factors of study outcomes at enrollment.Exploratory analyses indicated higher,but non-significantly different mtDNAc among children born either small-for-gestational age,low birthweight,or preterm.Conclusion:Newborns from mothers who received daily nutritional supplements across gestation did not have different relative TL or mtDNAc.展开更多
Objective Telomere length is a key aging biomarker,but its sex-specific impact on individualized life expectancy remains uncertain.This study explores sex differences in leukocyte telomere length(LTL)and individualize...Objective Telomere length is a key aging biomarker,but its sex-specific impact on individualized life expectancy remains uncertain.This study explores sex differences in leukocyte telomere length(LTL)and individualized expected years of life lost(YLL).Methods A prospective cohort of 445,399 participants(203,731 males and 241,668 females)from the UK Biobank was analyzed.LTL values were log-transformed,and YLL was calculated using life tables.Multiple linear regression was applied to examine sex-specific associations.Results In males,each standard deviation(S.D.)increase in LTL was linked to a 0.965-year decrease in YLL(95%CI:–1.025,–0.900;P<0.001).In females,longer LTL was related to a 0.102-year increase in YLL(95%CI:0.057,0.146;P<0.001).Among postmenopausal females,LTL showed a protective effect similar to that in males(0.387-year decrease,95%CI:−0.446,–0.328;P<0.001),while premenopausal females exhibited a detrimental association(0.705-year increase,95%CI:0.625,0.785;P<0.001).Comparable trends were observed across major aging-related diseases,pointing to a consistent biological pattern.Conclusion The influence of LTL on life expectancy varies significantly by sex,with protective associations seen in males and postmenopausal females.This suggests hormonal involvement in telomere dynamics.The results support integrating sex-specific perspectives into aging and telomere research and clinical practice.展开更多
文摘BACKGROUND Hepatocellular carcinoma(HCC)is the most common primary liver cancer,with high mortality at advanced stages.Loco-regional treatment including:Radiofrequency(RF)or transarterial chemoembolization(TACE)is decided according to the size,and the site of the tumor,according to practice guidelines.Alpha fetoprotein(AFP),the most used biomarker in the guidelines,although specific,lacks sensitivity.New biomarkers are needed to understand the underlying pathophysiology,and to be used in clinical practice.AIM To study the effect of loco-regional treatment on telomere length,as a diagnostic and short-term(3 months)prognostic marker.METHODS This is a prospective cohort study,and includes 60 patients visiting Ain Shams University Hospitals.The patients were divided into 2 groups:30 patients with liver cirrhosis(group 1)and 30 HCC patients undergoing RF or TACE(group 2).Laboratory investigations for all patients included:Telomere length in peripheral leukocytes by polymerase chain reaction,AFP,and liver function.In the HCC group,the aforementioned laboratory investigations with abdominal triphasic computed tomography with contrast were performed at baseline,and after 3 months.RESULTS With regard to age,Child-Pugh and Model for End-Stage Liver Disease scores,there was no statistically significant correlation with telomere length.However,there was a correlation between telomere length and age,and both scores before and after 3 months of treatment among HCC patients.On dividing the HCC group according to tumor size with a cutoff of 5 cm,and performing the Mann-Whitney test we found that at baseline telomere length was significantly lower among cases with tumor size≥5 cm than in those with tumor size<5 cm(30 patients;P=0.03).In addition,we found a positive Spearman's rank correlation between telomere length and tumor size in the≥5 cm only group(28 samples from the before and after intervention data;P=0.025).CONCLUSION Telomere length in leukocytes is a potential marker in HCC tumor prognosis.Further research using telomerase activity and telomerase reverse transcriptase promoter gene mutation in a larger cohort is recommended.
文摘Telomeres have been a subject of genetic research since the 1930s. They play a crucial role in cancer biology, as they influence both cellular senescence and genomic stability. In cancer cells, dysfunctional telomeres can lead to chromosomal fusions and, through deregulation of telomerase, allow replication of mutated chromosomes that might otherwise lead to apoptosis. Research is now focused on improving telomere-based cancer cell detection and developing potential therapies that inhibit telomerase activity in cancerous cells. Telomere research is crucial in understanding the molecular mechanisms influencing tumor growth and invasiveness because of the central role played by telomeres in various cancer types. Several telomerase inhibitors and immunotherapy treatments are in pre-clinical or clinical development. Research on the role of telomeres in oncogenesis has made significant strides, but obstacles remain, including a lack of high-resolution structural understanding, inadequate preclinical models, and concern over potential side effects. Even so, the current path of telomere research holds promise.
文摘Telomeres are protective structures at the ends of eukaryotic chromosomes. The loss of telomeres through cell division and oxidative stress is related to cellular aging, organismal growth and disease. In this way, telomeres link molecular and cellular mechanisms with organismal processes, and may explain variation in a number of important life-history traits. Here, we discuss how telomere biology relates to the study of physiological ecology and life history evolution. We emphasize current knowledge on how telomeres may relate to growth, survival and lifespan in natural populations. We finish by examining interest- ing new connections between telomeres and the glucocorticoid stress response. Glucocorticoids are often employed as indices of physiological condition, and there is evidence that the glucocorticoid stress response is adaptive. We suggest that one way that glucocorticoids impact organismal survival is through elevated oxidative stress and telomere loss. Future work needs to establish and explore the link between the glucocorticoid stress response and telomere shortening in natural populations. If a link is found, it provides an explanatory mechanism by which environmental perturbation impacts life history trajectories [Current Zoology 56 （6）： 714-727, 2010].
基金the support of SA-SIBS scholarship programsupported by the grants from the Ministry of Science and Technology (2016YFA0500701)+2 种基金the National Natural Science Foundation of China (Nos.31230040, 31461143003 and 31521061) to J.-Q.Z.the China Postdoctoral Science Foundation (2015M571611 and 2016T90386)the National Natural Science Foundation of China (No.31500658) to Z.W.
文摘It has been well documented that Tel1 positively regulates telomere-end resection by promoting Mre11-Rad50-Xrs2（MRX） activity, while Rif2 negatively regulates telomere-end resection by inhibiting MRX activity. At uncapped telomeres, whether Tel1 or Rif2 plays any role remains largely unknown. In this work, we examined the roles of Tel1 and Rif2 at uncapped telomeres in yku70△ and/or cdc13-1 mutant cells cultured at non-permissive temperature. We found that deletion of TEL1 exacerbates the temperature sensitivity of both yku70△ and cdc13-1 cells. Further epistasis analysis indicated that MRX and Tel1 function in the same pathway in telomere protection. Consistently, TEL1 deletion increases accumulation of Exo1-dependent telomeric single-stranded DNA（ssDNA） at uncapped telomeres, which stimulates checkpoint-dependent cell cycle arrest. Moreover, TEL1 deletion in yku70△ cells facilitates Rad51-dependent Y0 recombination. In contrast, RIF2 deletion in yku70△ cells decreases the accumulation of telomeric ssDNA after 8 h of incubation at the non-permissive temperature of 37℃ and suppresses the temperature sensitivity of yku70△ cells, likely due to the increase of Mre11 association at telomeres.Collectively, our findings indicate that Tel1 and Rif2 regulate telomere protection at uncapped telomeres via their roles in balancing MRX activity in telomere resection.
文摘BACKGROUND Dyskeratosis congenita is a rare disease characterized by bone marrow failure and a clinical triad of oral leukoplakia,nail dystrophy,and abnormal skin pigmentation.The genetics of dyskeratosis congenita include mutations in genes involved in telomere maintenance,including TINF2.CASE SUMMARY Here,we report a female patient who presented thrombocytopenia,anemia,reticulate hyperpigmentation,dystrophy in fingernails and toenails,and leukoplakia on the tongue.A histopathological study of the skin showed dyskeratocytes;however,a bone marrow biopsy revealed normal cell morphology.The patient was diagnosed with dyskeratosis congenita,but her family history did not reveal significant antecedents.Whole-exome sequencing showed a novel heterozygous punctual mutation in exon 6 from the TINF2 gene,namely,NM_001099274.1:-c.854delp.(Val285-Alafs*32).An analysis of telomere length showed short telomeres relative to the patient’s age.CONCLUSION The disease in this patient was caused by a germline novel mutation of TINF2 in one of her parents.
文摘We have read with interest the article “Telomere length regulates TERRA levels through increased trimethylation of telomeric H3K9 and HP1α” by Arnoult and colleagues [1]. This study focuses on human telomeric chromatin structure using different techniques like Chromatin Immunoprecipitation (ChIP), cytolocalization or RT-qPCR. However, it has been performed without taking into consideration the presence of Interstitial Telomeric Sequences (ITSs) in the human genome. Some of the conclusions of the article are undoubtedly clear but there are others that might be explained in alternative ways, considering the existence of ITSs. Following, we mention some comments that arise from this interesting article.
基金Supported by A grant from Cariparo,Project"Tumour mi-croenvironment and tumour spread in gastrointestinal cancers",2013/2014,No.6421 to Rampazzo E
文摘Colorectal cancer(CRC)is the third most common cancer worldwide and,despite improved treatments,is still an important cause of cancer-related deaths.CRC encompasses a complex of diseases arising from a multistep process of genetic and epigenetic events.Besides heterogeneity in the molecular and biological features of CRC,chromosomal instability is a hallmark of cancer and cancer cells may also circumvent replicative senescence and acquire the ability to sustain unlimited proliferation.Telomere/telomerase interplay is an important mechanism involved in both genomic stability and cellular replicative potential,and its dysfunction plays a key role in the oncogenetic process.The erosion of telomeres,mainly because of cell proliferation,may be accelerated by specific alterations in the genes involved in CRC,such as APC and MSH2.Although there is general agreement that the shortening of telomeres plays a role in the early steps of CRC carcinogenesis by promoting chromosomal instability,the prognostic role of telomere length in CRC is still under debate.The activation of telomerase reverse transcriptase(TERT),the catalytic component of the telomerase complex,allows cancer cells to grow indefinitely by maintaining the length of the telomeres,thus favouring tumour formation/progression.Several studies indicate that TERT increases with disease progression,and most studies suggest that telomerase is a useful prognostic factor.Plasma TERT mRNA may also be a promising marker for the minimally invasive monitoring of disease progression and response to therapy.
基金supported by the National Key Research and Development Program of China(2018YFC2000400,2020YFA0112300 to C.Chen)National Natural Science Foundation of China(81830087,31771516 to C.Chen)+1 种基金project of Innovative Research Team of Yunnan Province(2019HC005)CAS“light of West China”Program(xbzg-zdsys-201909)。
文摘The use of tree shrews as experimental animals for biomedical research is a new practice.Several recent studies suggest that tree shrews are suitable for studying cancers,including breast cancer,glioblastoma,lung cancer,and hepatocellular carcinoma.However,the telomeres and the telomerase of tree shrews have not been studied to date.Here,we characterize telomeres and telomerase in tree shrews.The telomere length of tree shrews is approximately 23 kb,which is longer than that of primates and shorter than that of mice,and it is extended in breast tumor tissues according to Southern blot and flow-fluorescence in situ hybridization(FISH)analyses.Tree shrew spleen,bone marrow,testis,ovary,and uterus show high telomerase activities,which are increased in breast tumor tissues by telomeric repeat amplification protocol assays.The telomere length becomes shorter,and telomerase activity decreases with age.The tree shrew TERT and TERC are more highly similar to primates than to rodents.These findings lay a solid foundation for using tree shrews to study aging and cancers.
文摘Telomere, the nucleoprotein structure at the end of eukaryotic linear chromosomes is indispensable for maintaining the genome stability. Telomeric DNA loss is apparent with each cell division, which marks an endpoint to the indefinite replication of the cell by causing replicative senescence that may lead to the programmed cell death. The loss of telomere is normal in cell division and as such after 20 - 40 divisions, telomere becomes too short to facilitate the capping function. Telomere uncapping or chromosomal free end causes a potential threat to the genomic stability and thus leads to the accumulation of chromosomal abnormalities that have been known to play a role in aging and cancer. Telomerase, the ribonucleoprotein complex, and its accessory proteins are required to maintain the telomere sequence. Telomerase plays a key role in maintaining the length of telomere by adding G-rich repeat sequences. Its activity has been found to be quite high in the gametes, stem cells and most importantly tumor cells. Almost 85% of tumor cells compensate for telomere loss aided by telomerase-associated protein complex and shelter in complex or telosome. However, 5% - 10% of the cells undergo telomerase-independent mechanism. This review presents the molecular view of the telomere and telomerase along with its associated complex structures. It also discusses its contrasting role in causing cellular senescence and promoting tumorigenesis.
基金supported by the National Natural Science Foundation of China(NSFC)(no.32300475)the Science and Technology Talent Special Project of Guangxi(Gui Ke AD23026320)+1 种基金funding from the State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources(SKLCUSA-b202307)the Starting Research Grant for High-level Talents from Guangxi University to L.X.
文摘Dear Editor,The completeness and accuracy of genome assemblies are crucial for ensuring the reliability of downstream analyses,including functional and evolutionary studies.With the advent of third-generation sequencing,the assembly of telomere-totelomere(T2T)genomes has become possible.
文摘A consistent association has been observed between leukocyte telomere length(LTL)and atherosclerosis,but the mechanisms underlying these associations are still not well understood.Premature biology aging was evident in atherosclerotic plaques,characterized by reduced cell proliferation,irreversible growth arrest and apoptosis,and telomere attrition.As atherosclerosis is a state of chronic low-grade inflammation and increased oxidative stress,shortened LTL in patients with atherosclerosis might stem from the two sources,one is an accelerated rate in hematopoietic stem cells(HSCs)replication to replace leukocytes consumed in the inflammatory process,and another is the increase in the loss of telomere repeats per replication.Thus,diminished HSC reserves at birth and age-dependent telomere attrition afterward are mirrored in shortened LTL during the adulthood.In addition,the inter-individual variation of LTL in the general population can be partly explained by genetic factors regulating telomere maintenance and the rate of HSCs replication.Atherosclerosis is an aging-related disease,and practically all humans develop atherosclerosis if they live long enough.Here we overview the potential roles of LTL dynamics in the imbalance between injurious oxidative stress/inflammation and endothelial repair during the pathogenesis of age-related atherosclerosis,and discuss the possibility that preventing accelerated cellular senescence is a potential target in prevention of atherosclerosis.
基金supported by China National Key R&D Program(2018YFA0107002,2018YFC1003004)the National Natural Science Foundation of China(32030033,31430052)。
文摘Functional telomeres protect chromosome ends and play important roles in stem cell maintenance and differentiation. Short telomeres negatively impact germ cell development and can contribute to age-associated infertility. Moreover, telomere syndrome resulting from mutations of telomerase or telomere-associated genes exhibits short telomeres and reduced fertility. It remains elusive whether and how telomere lengths affect germ cell specification. We report that functional telomere is required for the coordinated germ cell and somatic cell fate decisions. Using telomerase gene Terc deficient mice as a model, we show that short telomeres restrain germ cell specification of epiblast cells but promote differentiation towards somatic lineage. Short telomeres increase chromatin accessibility to elevate TGFβ and MAPK/ERK signaling for somatic cell differentiation. Notably,elevated Fst expression in TGFβ pathway represses the BMP4-pSmad signaling pathway, thus reducing germ cell formation. Reelongation of telomeres by targeted knock-in of Terc restores normal chromatin accessibility to suppress TGFβ and MAPK signaling, thereby facilitating germ cell formation. Taken together, our data reveal that functional telomeres are required for germ cell specification by repressing TGFβ and MAPK signaling.
基金supported by the National Natural Science Foundation of China(61378062,21227804,21390414,61475181)the National Basic ResearchProgram of China(2012CB825805)the Shanghai Municipal Commission for Science and Technology(14ZR1448000)
文摘The significant role of telomeres in cells has attracted much attention since they were discovered.Fluorescence imaging is an effective method to study subcellular structures like telomeres.However,the diffraction limit of traditional optical microscope hampers further investigation on them.Recent progress on superresolution fluorescence microscopy has broken this limit.In this work,we used stimulated emission depletion(STED) microscope to observe fluorescence-labeled telomeres in interphase cell nuclei.The results showed that the size of fluorescent puncta representing telomeres under the STED microscope was much smaller than that under the confocal microscope.Two adjacent telomeres were clearly separated via STED imaging,which could hardly be discriminated by confocal microscopy due to the diffraction limit.We conclude that STED microscope is a more powerful tool that enable us to obtain detailed information about telomeres.
基金National Natural Science Foundation(Grant Nos.82271598,81871109,82071587,31930058,32330023 and 32170757)National Key Research and Development Program of China(2018YFA0107003)Guang Dong Basic and Applied Basic Research Foundation(2020A1515010462).
文摘Telomeres are specialized structures at the ends of linear chromosomes that protect genome stability.The telomeric repeat-containing RNA(TERRA)that is transcribed from subtelomeric regions can invade into double-stranded DNA regions and form RNA:DNA hybrid-containing structure called R-loop.In tumor cells,R-loop formation is closely linked to gene expression and the alternative lengthening of telomeres(ALT)pathway.Dysregulated R-loops can cause stalled replication forks and telomere instability.However,how R-loops are recognized and regulated,particularly at telomeres,is not well understood.We discovered that ILF3 selectively associates with telomeric R-loops and safeguards telomeres from abnormal homologous recombination.Knocking out ILF3 results in excessive R-loops at telomeres and triggers telomeric DNA damage responses.In addition,ILF3 deficiency disrupts telomere homeostasis and causes abnormalities in the ALT pathway.Using the proximity-dependent biotin identification(BioID)technology,we mapped the ILF3 interactome and discovered that ILF3 could interact with several DNA/RNA helicases,including DHX9.Importantly,ILF3 may aid in the resolution of telomeric R-loops through its interaction with DHX9.Our findings suggest that ILF3 may function as a reader of telomeric R-loops,helping to prevent abnormal homologous recombination and maintain telomere homeostasis.
文摘Aging,as an inherent stage of life processes,has always been a core research focus in life sciences.Current studies confirm that the accumulation of intracellular molecular damage is a key driver of aging.As protective structures at chromosome ends,telomeres exhibit direct correlations between their length and stability and cellular aging processes,disease risks,and lifespan.This article systematically reviews the structural functions of telomeres and their relationship with aging,with particular emphasis on telomere rejuvenation strategies based on electromagnetic radiation techniques.Key experimental approaches include Gavich's mitotic radiation,Composite Wave Resonator(CWRT),and modern telomere length intervention trials.By synthesizing the latest domestic and international research findings,this paper analyzes the feasibility and limitations of these technologies while exploring their potential applications in anti-aging research,providing theoretical references for future studies.
基金Supported by the National Natural Science Foundation of China,No.82104525Open Foundation of Key Laboratory of Tropical Plant Resource Chemistry of Hainan Province,No.rdzw2024s01.
文摘This article is based on a recent bibliometric analysis of research progress on liver aging.The liver is notable for its extraordinary ability to rejuvenate,thereby safeguarding and maintaining the organism’s integrity.With advancing age,there is a noteworthy reduction in both the liver’s size and blood circulation.Furthermore,the wide range of physiological alterations driven on by aging may foster the development of illnesses.Previous studies indicate that liver aging is linked to impaired lipid metabolism and abnormal gene expression associated with chronic inflammation.Factors such as mitochondrial dysfunction and telomere shortening accumulate,which may result in increased hepatic steatosis,which impacts liver regeneration,metabolism,and other functions.Knowing the structural and functional changes could help elderly adults delay liver aging.Increasing public awareness of anti-aging interventions is essential.Besides the use of dietary supplements,alterations in lifestyle,including changes in dietary habits and physical exercise routines,are the most efficacious means to decelerate the aging process of the liver.This article highlights recent advances in the mechanism research of liver aging and summarizes the promising intervention options to delay liver aging for preventing related diseases.
基金supported by the National Natural Science Foundation of China(32270217,31970205,31770211)Metasequoia funding of Nanjing Forestry University to YY。
文摘Amborella trichopoda(Amborellaceae;hereafter simply Amborella)(Fig.1A)is a shrub endemic to New Caledonia in the Southwest Pacific that represents the sole sister species of all other extant angiosperms(Qiu et al.,1999;One Thousand Plant Transcriptomes Initiative,2019).Due to its unique phylogenetic status,it holds tremendous interest for botanists.The nuclear and mitochondrial genomes of Amborella were first published in 2013,providing valuable resources for studies on genome and gene family evolution,phylogenomics,and flower development,despite the fact that the assembly is heavily fragmented(Amborella Genome Project,2013;Rice et al.,2013).In 2024,a haplotype-resolved Amborella genome assembly was published,showing significant improvement in quality and completeness(Carey et al.,2024).
基金supported by the Bill&Melinda Gates Foundation(OPP1175213)supported by the Research Foundation Flanders(12X9620N and 12X9623N)the European Research Council(ERC)under the European Union’s Horizon 2020 research and innovation program(946192,HUMYCO)。
文摘Background:Evidence regarding the effectiveness of prenatal nutritional supplements has mainly considered anthropometric pregnancy outcomes.The effect on markers of health and disease,such as offspring telomere length(TL)and mitochondrial DNA content(mtDNAc)is unknown.Objectives:We assessed the efficacy of maternal multiple micronutrient(MMN)-fortified balanced-energy protein(BEP)and iron-folic acid(IFA)supplementation on newborn TL as a secondary outcome and mtDNAc as a non-declared outcome.Design:We conducted a randomized controlled trial in rural Burkina Faso,among pregnant females(15-40 years old)enrolled at<21 weeks of gestation.Mothers received either MMN-fortified BEP and IFA(intervention)or IFA only(control)throughout pregnancy.Whole arterial blood samples were collected from the umbilical cord of 104 control and 90 intervention group infants,respectively.Average relative TL and mtDNAc were measured using quantitative polymerase chain reaction.Linear regression models were fitted to assess TL and mtDNAc differences across trial arms.Results:We found that a combined daily MMN-fortified BEP supplement and IFA tablet did not affect newborn TL[β=-0.010(95%CI:-0.057,0.036);P=0.662]or mtDNAc[β=0.065(95%CI:-0.203,0.073);P=0.354],as compared to an IFA tablet alone.These findings were confirmed(P>0.05)by adjusting the regression models for potential prognostic factors of study outcomes at enrollment.Exploratory analyses indicated higher,but non-significantly different mtDNAc among children born either small-for-gestational age,low birthweight,or preterm.Conclusion:Newborns from mothers who received daily nutritional supplements across gestation did not have different relative TL or mtDNAc.
基金supported by the National Natural Science Foundation of China(82192903,82192904)the National Science and Technology Major Projects of China(2023ZD0510103)。
文摘Objective Telomere length is a key aging biomarker,but its sex-specific impact on individualized life expectancy remains uncertain.This study explores sex differences in leukocyte telomere length(LTL)and individualized expected years of life lost(YLL).Methods A prospective cohort of 445,399 participants(203,731 males and 241,668 females)from the UK Biobank was analyzed.LTL values were log-transformed,and YLL was calculated using life tables.Multiple linear regression was applied to examine sex-specific associations.Results In males,each standard deviation(S.D.)increase in LTL was linked to a 0.965-year decrease in YLL(95%CI:–1.025,–0.900;P<0.001).In females,longer LTL was related to a 0.102-year increase in YLL(95%CI:0.057,0.146;P<0.001).Among postmenopausal females,LTL showed a protective effect similar to that in males(0.387-year decrease,95%CI:−0.446,–0.328;P<0.001),while premenopausal females exhibited a detrimental association(0.705-year increase,95%CI:0.625,0.785;P<0.001).Comparable trends were observed across major aging-related diseases,pointing to a consistent biological pattern.Conclusion The influence of LTL on life expectancy varies significantly by sex,with protective associations seen in males and postmenopausal females.This suggests hormonal involvement in telomere dynamics.The results support integrating sex-specific perspectives into aging and telomere research and clinical practice.
