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Alpha-tocopherol modulates hydrogen peroxide-induced DNA damage and telomere shortening of human skin fibroblasts derived from differently aged individuals

Makpol S, Zainuddin A, Rahim NA, Yusof YA, Ngah WZ

Planta Med, 2010 Jun;76(9):869-75.
PMID: 20112180 DOI: 10.1055/s-0029-1240812

Antioxidants such as vitamin E may act differently on skin cells depending on the age of the skin and the level of oxidative damage induced. The effects of alpha-tocopherol (ATF) on H(2)O(2)-induced DNA damage and telomere shortening of normal human skin fibroblast cells derived from young and old individual donors were determined. Fibroblasts were divided into five groups; untreated control, H(2)O(2)-induced oxidative stress, alpha-tocopherol treatment, and pre- and post-treatment with alpha-tocopherol for H(2)O(2)-induced oxidative stress. Our results showed that H(2)O(2)-induced oxidative stress increased DNA damage, shortened the telomere length and reduced the telomerase activity (p < 0.05) in fibroblasts obtained from young and old donors. Pre- and post-treatment with alpha-tocopherol protected against H(2)O(2)-induced DNA damage in fibroblasts obtained from young individuals (p = 0.005; p = 0.01, respectively). However, in fibroblasts obtained from old individuals, similar protective effects were only seen in cells pretreated with alpha-tocopherol (p = 0.05) but not in the post-treated cells. Protection against H(2)O(2)-induced telomere shortening was observed in fibroblasts obtained from both young and old donors which were pre-treated with alpha-tocopherol (p = 0.009; p = 0.008, respectively). However, similar protective effects against telomere shortening in fibroblasts obtained from both young and old donors were not observed in the post-treated fibroblasts. Protection against H(2)O(2)-induced telomerase activity loss was observed only in fibroblasts obtained from old donors which were pretreated with alpha-tocopherol (p = 0.04) but not in fibroblasts obtained from young donors. Similar protective effects against telomerase activity loss in fibroblasts obtained from both young and old donors were not observed in the post-treated fibroblasts. In conclusion, alpha-tocopherol protected against H(2)O(2)-induced telomere shortening by restoring the telomerase activity. It also modulated H(2)O(2)-induced DNA damage and this modulation was affected by donor age.

Matched MeSH terms: Telomere/drug effects*; Telomere/ultrastructure
Fulltext Assessment of Telomere Length in Archived Formalin-Fixed, Paraffinized Human Tissue Is Confounded by Chronological Age and Storage Duration

Kong PL, Looi LM, Lau TP, Cheah PL

PLoS One, 2016;11(9):e0161720.
PMID: 27598341 DOI: 10.1371/journal.pone.0161720

Telomeres shorten with physiological aging but undergo substantial restoration during cancer immortalization. Increasingly, cancer studies utilize the archive of formalin-fixed, paraffin-embedded (FFPE) tissues in diagnostic pathology departments. Conceptually, such studies would be confounded by physiological telomere attrition and loss of DNA integrity from prolonged tissue storage. Our study aimed to investigate these two confounding factors. 145 FFPE tissues of surgically-resected, non-diseased appendixes were retrieved from our pathology archive, from years 2008 to 2014. Cases from 2013 to 2014 were categorized by patient chronological age (0-20 years, 21-40 years, 41-60 years, > 60 years). Telomere lengths of age categories were depicted by telomere/chromosome 2 centromere intensity ratio (TCR) revealed by quantitative fluorescence in situ hybridization. Material from individuals aged 0-20 years from years 2013/2014, 2011/2012, 2009/2010, and 2008 were compared for storage effect. Telomere integrity was assessed by telomere fluorescence intensity (TFI). Epithelial TCRs (mean ± SD) for the respective age groups were 4.84 ± 2.08, 3.64 ± 1.21, 2.03 ± 0.37, and 1.93 ± 0.45, whereas corresponding stromal TCRs were 5.16 ± 2.55, 3.84 ± 1.36, 2.49 ± 1.20, and 2.93 ± 1.24. A trend of inverse correlation with age in both epithelial and stromal tissues is supported by r = -0.69, p < 0.001 and r = -0.42, p < 0.001 respectively. Epithelial TFIs (mean ± SD) of years 2013/2014, 2011/2012, 2009/2010 and 2008 were 852.60 ± 432.46, 353.04 ± 127.12, 209.24 ± 55.57 and 429.22 ± 188.75 respectively. Generally, TFIs reduced with storage duration (r = -0.42, p < 0.001). Our findings agree that age-related telomere attrition occurs in normal somatic tissues, and suggest that an age-based reference can be established for telomere studies on FFPE tissues. We also showed that FFPE tissues archived beyond 2 years are suboptimal for telomere analysis.

Matched MeSH terms: Telomere; Telomere Homeostasis/genetics*
Fulltext Association between telomere length and the risk of colorectal cancer: a meta-analysis of observational studies

Naing C, Aung K, Lai PK, Mak JW

BMC Cancer, 2017 01 05;17(1):24.
PMID: 28056862 DOI: 10.1186/s12885-016-2997-3

BACKGROUND: Human chromosomes are capped and stabilized by telomeres. Telomere length regulates a 'cellular mitotic clock' that defines the number of cell divisions and hence, cellular life span. This study aimed to synthesize the evidence on the association between peripheral blood leucocytes (PBL) telomere length and the risk of colorectal cancer (CRC).
METHODS: We searched relevant studies in electronic databases. When two or more observational studies reported the same outcome measures, we performed pooled analysis. All the analyses were performed on PBL using PCR. The odds ratio (OR) and its 95% confidence interval (CI) were used to assess the strength of association.
RESULTS: Seven studies (with 8 datasets) were included in this meta-analysis; 3 prospective studies, 3 retrospective studies and 1 study with a separate prospective and retrospective designs. The pooled analysis of 4 prospective studies (summary OR 1.01, 95% CI: 0.77-1.34, I (2):30%) and 4 retrospective studies (summary OR 1.65, 95% CI: 0.96-2.83, I (2):96%) showed no relationship between PBL telomere length and the CRC risk. A subgroup analysis of 2 prospective studies exclusively on females also showed no association between PBL telomere length and the CRC risk (summary OR, 1.17, 95% CI:0.72-1.91, I (2):57%).
CONCLUSION: The current analysis is insufficient to provide evidence on the relationship between PBL telomere length and the risk of CRC. Findings suggest that there may be a complex relationship between PBL telomere length and the CRC risk or discrepancy between genetics, age of patients and clinical studies. Future well powered, large prospective studies on the relationship between telomere length and the risk of CRC, and the investigations of the biologic mechanisms are recommended.

Matched MeSH terms: Telomere/pathology*
Autophagy and senescence: A new insight in selected human diseases

Rajendran P, Alzahrani AM, Hanieh HN, Kumar SA, Ben Ammar R, Rengarajan T, et al.

J Cell Physiol, 2019 12;234(12):21485-21492.
PMID: 31144309 DOI: 10.1002/jcp.28895

Senescence and autophagy play important roles in homeostasis. Cellular senescence and autophagy commonly cause several degenerative processes, including oxidative stress, DNA damage, telomere shortening, and oncogenic stress; hence, both events are known to be interrelated. Autophagy is well known for its disruptive effect on human diseases, and it is currently proposed to have a direct effect on triggering senescence and quiescence. However, it is yet to be proven whether autophagy has a positive or negative impact on senescence. It is known that elevated levels of autophagy induce cell death, whereas inadequate autophagy can trigger cellular senescence. Both have important roles in human diseases such as aging, renal degeneration, neurodegenerative disorders, and cancer. Therefore, this review aims to highlight the relevance of senescence and autophagy in selected human ailments through a summary of recent findings on the connection and effects of autophagy and senescence in these diseases.

Matched MeSH terms: Telomere/genetics; Telomere Shortening/genetics; Telomere Shortening/physiology
Fulltext Berberine Inhibits Telomerase Activity and Induces Cell Cycle Arrest and Telomere Erosion in Colorectal Cancer Cell Line, HCT 116

Samad MA, Saiman MZ, Abdul Majid N, Karsani SA, Yaacob JS

Molecules, 2021 Jan 13;26(2).
PMID: 33450878 DOI: 10.3390/molecules26020376

Colorectal cancer (CRC) is the most common cancer among males and females, which is associated with the increment of telomerase level and activity. Some plant-derived compounds are telomerase inhibitors that have the potential to decrease telomerase activity and/or level in various cancer cell lines. Unfortunately, a deeper understanding of the effects of telomerase inhibitor compound(s) on CRC cells is still lacking. Therefore, in this study, the aspects of telomerase inhibitors on a CRC cell line (HCT 116) were investigated. Screening on HCT 116 at 48 h showed that berberine (10.30 ± 0.89 µg/mL) is the most effective (lowest IC50 value) telomerase inhibitor compared to boldine (37.87 ± 3.12 µg/mL) and silymarin (>200 µg/mL). Further analyses exhibited that berberine treatment caused G0/G1 phase arrest at 48 h due to high cyclin D1 (CCND1) and low cyclin-dependent kinase 4 (CDK4) protein and mRNA levels, simultaneous downregulation of human telomerase reverse transcriptase (TERT) mRNA and human telomerase RNA component (TERC) levels, as well as a decrease in the TERT protein level and telomerase activity. The effect of berberine treatment on the cell cycle was time dependent as it resulted in a delayed cell cycle and doubling time by 2.18-fold. Telomerase activity and level was significantly decreased, and telomere erosion followed suit. In summary, our findings suggested that berberine could decrease telomerase activity and level of HCT 116, which in turn inhibits the proliferative ability of the cells.

Matched MeSH terms: Telomere/drug effects; Telomere/metabolism
Berberine and RNAi-Targeting Telomerase Reverse Transcriptase (TERT) and/or Telomerase RNA Component (TERC) Caused Oxidation in Colorectal Cancer Cell Line, HCT 116: An Integrative Approach using Molecular and Metabolomic Studies

Samad MA, Saiman MZ, Abdul Majid N, Karsani SA, Yaacob JS

Cell Biochem Biophys, 2024 Mar;82(1):153-173.
PMID: 38198024 DOI: 10.1007/s12013-023-01210-8

Colorectal cancer (CRC) is the most common cancer in both men and women and is associated with increased telomerase levels and activity. The potential downstream effects of TERT and/or TERC downregulation by berberine (a telomerase inhibitor) or RNA interference (RNAi) on various target RNAs, proteins, relative telomerase activity (RTA), relative telomere length (RTL), hydrogen peroxide concentration [H2O2], percentage of cell cycle distribution, cell size and granularity as well as cellular metabolites were explored in HCT 116 cell line. Knockdown of TERT decreased TERC. The downregulation of TERT and/or TERC caused increment of [H2O2], G0/G1 phase arrest in addition to decreased S and G2/M phases, as well as diminished cell size. RTL was later reduced as a result of TERT, TERT and/or TERC downregulation which decreased RTA. It was discovered that xanthine oxidase (XO) was significantly and positively correlated at FDR-adjusted p value

Matched MeSH terms: Telomere/metabolism
Blood Profile, Hormones, and Telomere Responses: Potential Biomarkers in Horses Exhibiting Abnormal Oral Behavior

Hanis F, Chung ELT, Kamalludin MH, Idrus Z

J Equine Vet Sci, 2022 Nov;118:104130.
PMID: 36182046 DOI: 10.1016/j.jevs.2022.104130

The high prevalence of abnormal oral behavior (AOB) in working horses has been linked to management issues and the pathophysiology of this behavior remains unclear. Therefore, this study aims to elucidate the blood profile, hormones, and telomere length responses between low and high levels of AOB among different horse working groups. A total of 207 healthy horses from various breeds were initially selected from four working groups (leisure riding, equestrian, endurance, and patrolling) and observed for the time spent on AOB. Then, six horses each with higher and lower AOB than the population means were randomly selected from each of the working groups and categorized as high and low AOB horses, respectively. Blood samples were collected for hematology, biochemistry, cortisol, ghrelin, leptin, and relative telomere length analyzes. High AOB horses notably had higher values of glucose, alanine aminotransferase (ALT), alkaline phosphatase (ALP), and creatine kinase (CK) compared to low AOB horses. High AOB horses also recorded higher plasma cortisol and ghrelin, but lower leptin concentrations. Among working groups, both endurance and patrolling horses presented the highest values in sodium, potassium, chloride, phosphate, ALT, and CK. While patrolling horses had the lowest levels of urea, ALP, and albumin levels, equestrian and leisure horses recorded the highest and lowest plasma cortisol and leptin concentrations, respectively. Finally, the telomere length of endurance and patrolling horses were significantly greater than leisure and equestrian horses. The present findings suggest that AOB horses had distinctive physiological characteristics that could be linked to improper diet and a demanding workload, while ghrelin and leptin hormones could be potential biomarkers for this behavior.

Matched MeSH terms: Telomere/genetics
Fulltext Can telomere length predict bone health? A review of current evidence

Wong SK, Ima-Nirwana S, Chin KY

Bosn J Basic Med Sci, 2020 Nov 02;20(4):423-429.
PMID: 32156247 DOI: 10.17305/bjbms.2020.4664

Telomeres are repetitive DNA sequences located at the end of chromosomes that serve as a protective barrier against chromosomal deterioration during cell division. Approximately 50-200 base pairs of nucleotides are lost per cell division, and new repetitive nucleotides are added by the enzyme telomerase, allowing telomere maintenance. Telomere shortening has been proposed as an indicator for biological aging, but its relationship with age-related osteoporosis is ambiguous. We summarize the current evidence on the relationship between telomere length and bone health in experimental and epidemiological studies, which serve as a scientific reference for the development of novel diagnostic markers of osteoporosis or novel therapeutics targeting telomere and telomerase of bone cells to treat osteoporosis.

Matched MeSH terms: Telomere/ultrastructure*; Telomere Shortening*
Chlorella vulgaris modulates hydrogen peroxide-induced DNA damage and telomere shortening of human fibroblasts derived from different aged individuals

Makpol S, Yaacob N, Zainuddin A, Yusof YA, Ngah WZ

Afr J Tradit Complement Altern Med, 2009 Jul 03;6(4):560-72.
PMID: 20606778

The objective of this study was to investigate the modulatory effect of Chlorella vulgaris on cultured fibroblast cells derived from young and old aged individuals focusing on DNA damage, telomere length and telomerase activity. Dose-response test of the algal extract on cells in both age groups revealed that optimum viability was observed at a concentration of 50 microg/ml. Results obtained showed that Chlorella vulgaris exhibited protective effects against H(2)O(2)-induced oxidative stress as shown by the reduction in damaged DNA caused by H(2)O(2) treatment (p<0.05) in Chlorella vulgaris pre- and post-treated groups (p<0.05). Pre-treatment of Chlorella vulgaris resulted in a significant decrease in DNA damage suggesting a bioprotective effect against free radical attacks. A decline in DNA damage was observed in post-treated cells which proves Chlorella vulgaris to present bioremediative properties. In cells induced with oxidative stress, telomere length decreased significantly coupled with a concomitant decline of telomerase activity (p<0.05). However, these reductions were prevented with prior and post treatment of Chlorella vulgaris. Therefore, we concluded that Chlorella vulgaris exhibited bioprotective effects especially in cells obtained from young donor but were more bioremediative for cells obtained from old donor as indicated by DNA damage, telomere shortening and reduction in telomerase activity.

Matched MeSH terms: Telomere/drug effects*; Telomere/genetics
Comparison of telomere length and telomerase activation between breast fibroadenoma and infiltrating ductal carcinoma in Malaysian women

Looi LM, Cheah PL, Ng MH, Yip CH, Mun KS, Rahman NA

Asian Pac J Cancer Prev, 2010;11(3):713-6.
PMID: 21039041

A study was initiated to explore possible differences in handling telomere attrition in the most common lignant and benign tumours of the breast in Malaysian women. Infiltrating ductal carcinoma (IDC) and fibroadenoma (FA) represented the malignant and benign prototypes respectively. 29 IDC, 28 FA and 22 benign non-lesional control (BNL) breast tissue samples were analysed for telomerase activation using a Telomerase PCR ELISA kit (Boehringer Mannheim). In addition, 23 IDC, 12 FA and 14 BNL were subjected to telomere length determination with a TeloTAGGG Telomere Length Assay Kit (Roche Diagnostic GmbH, Germany), following digestion of genomic DNA by frequently cutting restriction enzymes RsaI and HinfI. Mean telomerase activity in IDC (A450nm=0.3338), but not FA (A450nm=0.0003) was significantly raised (p<0.05) compared with BNL (A450nm=0.0031). Similarly IDC (1.2 kb), but not FA (2.2 kb), showed significant telomere shortening (p<0.05) relative to BNL (2.9 kb). The findings imply that telomere attrition and telomerase activation differ between malignant and benign tumours of the breast and may be important for targeted therapy.

Matched MeSH terms: Telomere/genetics*
Contribution of CYP2E1 polymorphism to aging in the mechanical workshop workers

Eshkoor SA, Ismail P, Rahman SA, Adon MY, Devan RV

Toxicol. Mech. Methods, 2013 May;23(4):217-22.
PMID: 23193996 DOI: 10.3109/15376516.2012.743637

Aging is attributed to both genetic and environmental factors. Occupational exposure is one of the environmental factors with potential genotoxic effects. Researchers try to determine factors involved in genetic damages at hazards exposure that could accelerate aging. Cytochrome P450 2E1 (CYP2E1) gene contributes in activation and detoxification of the environmental hazards. This polymorphism plays an important role in susceptibility of inter-individuals to DNA damage at the occupational exposure. The current study evaluated the possible influence of this gene polymorphism in aging by genomic damages through the biomarkers alterations of micronuclei (MN), comet tail length and telomere length shortening at the exposure. In this study, buccal cells were collected from the oral cavity of exposed workers and non-exposed controls. The CYP2E1 genotypes were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The wild genotype significantly affected MN frequency (p = 0.007) and relative telomere length (p = 0.047) in the older group of workers. It was concluded that the interaction of gene polymorphism and exposure enhances DNA damage and accelerates aging consequently.

Matched MeSH terms: Telomere Shortening/drug effects; Telomere Shortening/genetics
Crude protein extraction protocol for phage N15 protelomerase in vitro enzymatic assays

Chen Q, Narayanan K

Anal Biochem, 2011 Jul 1;414(1):169-71.
PMID: 21396906 DOI: 10.1016/j.ab.2011.03.006

The phage N15 protelomerase enzyme (TelN) is essential for the replication of its genome by resolution of its telRL domain, located within a telomerase occupancy site (tos), into hairpin telomeres. Isolation of TelN for in vitro processing of tos, however, is a highly complex process, requiring multiple purification steps. In this study a simplified protocol for crude total protein extraction is described that retains the tos-cleaving activity of TelN for at least 4 weeks, greatly simplifying in vitro testing of its activity. This protocol may be extended for functional analysis of other phage and bacterial proteins, particularly DNA-processing enzymes.

Matched MeSH terms: Telomere/chemistry
Deactivation of Telomerase Enzyme and Telomere Destabilization by Natural Products: a Potential Target for Cancer Green Therapy

Sasidharan S, Jothy SL, Kavitha N, Chen Y, Kanwar JR

Asian Pac J Cancer Prev, 2015;16(18):8671.
PMID: 26745135
Matched MeSH terms: Telomere/genetics; Telomere/chemistry*
Does GSTP1 polymorphism contribute to genetic damage caused by ageing and occupational exposure?

Eshkoor SA, Ismail P, Rahman SA, Moin S

Arh Hig Rada Toksikol, 2011 Dec;62(4):291-8.
PMID: 22202462 DOI: 10.2478/10004-1254-62-2011-2088

The aim of our study was to see the effects of GSTP1 polymorphism on biomarkers of ageing, including micronuclei (MN), comet tail length, and relative telomere length in automobile repair workers, who are exposed to a broad spectrum of potential mutagens. The analysis was performed on buccal cells collected from occupationally exposed and non-exposed (control) subjects. Samples were analysed using cytogenetic and molecular methods, including restriction fragment length polymorphism (RFLP), MN test, comet assay, and real-time PCR. The results confirmed the DNA damaging effects of substances used in the mechanical workshops, but did not confirm the influence of GSTP1 gene polymorphism on DNA damage. However, further studies on both occupationally exposed and control populations are needed to understand the relationship between GSTP1 polymorphism and genome damage.

Matched MeSH terms: Telomere Homeostasis
Fulltext Exploring the Causal Relationship Between Telomere Biology and Alzheimer's Disease

Kuan XY, Fauzi NSA, Ng KY, Bakhtiar A

Mol Neurobiol, 2023 Aug;60(8):4169-4183.
PMID: 37046137 DOI: 10.1007/s12035-023-03337-4

Telomeres, also known as the "protective caps" of our chromosomes, shorten with each cell cycle due to the end replication problem. This process, termed telomere attrition, is associated with many age-related disorders, such as Alzheimer's disease (AD). Despite the numerous studies conducted in this field, the role of telomere attrition in the onset of the disease remains unclear. To investigate the causal relationship between short telomeres and AD, this review aims to highlight the primary factors that regulate telomere length and maintain its integrity, with an additional outlook on the role of oxidative stress, which is commonly associated with aging and molecular damage. Although some findings thus far might be contradictory, telomere attrition likely plays a crucial role in the progression of AD due to its close association with oxidative stress. The currently available treatments for AD are only symptomatic without affecting the progression of the disease. The components of telomere biology discussed in this paper have previously been studied as an alternative treatment option for several diseases and have exhibited promising in vitro and in vivo results. Hence, this should provide a basis for future research to develop a potential therapeutic strategy for AD. (Created with BioRender.com).

Matched MeSH terms: Telomere/genetics; Telomere/metabolism; Telomere Shortening
G-quadruplex ligands as therapeutic agents against cancer, neurological disorders and viral infections

Yan MP, Wee CE, Yen KP, Stevens A, Wai LK

Future Med Chem, 2023 Nov;15(21):1987-2009.
PMID: 37933551 DOI: 10.4155/fmc-2023-0202

G-quadruplexes (G4s) within the human genome have undergone extensive molecular investigation, with a strong focus on telomeres, gene promoters and repetitive regulatory sequences. G4s play central roles in regulating essential biological processes, including telomere maintenance, replication, transcription and translation. Targeting these molecular processes with G4-binding ligands holds substantial therapeutic potential in anticancer treatments and has also shown promise in treating neurological, skeletal and muscular disorders. The presence of G4s in bacterial and viral genomes also suggests that G4-binding ligands could be a critical tool in fighting infections. This review provides an overview of the progress and applications of G4-binding ligands, their proposed mechanisms of action, challenges faced and prospects for their utilization in anticancer treatments, neurological disorders and antiviral activities.

Matched MeSH terms: Telomere
Fulltext Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma

Machiela MJ, Hofmann JN, Carreras-Torres R, Brown KM, Johansson M, Wang Z, et al.

Eur Urol, 2017 Nov;72(5):747-754.
PMID: 28797570 DOI: 10.1016/j.eururo.2017.07.015

BACKGROUND: Relative telomere length in peripheral blood leukocytes has been evaluated as a potential biomarker for renal cell carcinoma (RCC) risk in several studies, with conflicting findings.
OBJECTIVE: We performed an analysis of genetic variants associated with leukocyte telomere length to assess the relationship between telomere length and RCC risk using Mendelian randomization, an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations.
DESIGN, SETTING, AND PARTICIPANTS: Genotypes from nine telomere length-associated variants for 10 784 cases and 20 406 cancer-free controls from six genome-wide association studies (GWAS) of RCC were aggregated into a weighted genetic risk score (GRS) predictive of leukocyte telomere length.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Odds ratios (ORs) relating the GRS and RCC risk were computed in individual GWAS datasets and combined by meta-analysis.
RESULTS AND LIMITATIONS: Longer genetically inferred telomere length was associated with an increased risk of RCC (OR=2.07 per predicted kilobase increase, 95% confidence interval [CI]:=1.70-2.53, p<0.0001). As a sensitivity analysis, we excluded two telomere length variants in linkage disequilibrium (R2>0.5) with GWAS-identified RCC risk variants (rs10936599 and rs9420907) from the telomere length GRS; despite this exclusion, a statistically significant association between the GRS and RCC risk persisted (OR=1.73, 95% CI=1.36-2.21, p<0.0001). Exploratory analyses for individual histologic subtypes suggested comparable associations with the telomere length GRS for clear cell (N=5573, OR=1.93, 95% CI=1.50-2.49, p<0.0001), papillary (N=573, OR=1.96, 95% CI=1.01-3.81, p=0.046), and chromophobe RCC (N=203, OR=2.37, 95% CI=0.78-7.17, p=0.13).
CONCLUSIONS: Our investigation adds to the growing body of evidence indicating some aspect of longer telomere length is important for RCC risk.
PATIENT SUMMARY: Telomeres are segments of DNA at chromosome ends that maintain chromosomal stability. Our study investigated the relationship between genetic variants associated with telomere length and renal cell carcinoma risk. We found evidence suggesting individuals with inherited predisposition to longer telomere length are at increased risk of developing renal cell carcinoma.

Matched MeSH terms: Telomere/genetics*; Telomere/pathology; Telomere Homeostasis*
Fulltext Genetic determinants of telomere length and risk of pancreatic cancer: A PANDoRA study

Campa D, Matarazzi M, Greenhalf W, Bijlsma M, Saum KU, Pasquali C, et al.

Int J Cancer, 2019 03 15;144(6):1275-1283.
PMID: 30325019 DOI: 10.1002/ijc.31928

Telomere deregulation is a hallmark of cancer. Telomere length measured in lymphocytes (LTL) has been shown to be a risk marker for several cancers. For pancreatic ductal adenocarcinoma (PDAC) consensus is lacking whether risk is associated with long or short telomeres. Mendelian randomization approaches have shown that a score built from SNPs associated with LTL could be used as a robust risk marker. We explored this approach in a large scale study within the PANcreatic Disease ReseArch (PANDoRA) consortium. We analyzed 10 SNPs (ZNF676-rs409627, TERT-rs2736100, CTC1-rs3027234, DHX35-rs6028466, PXK-rs6772228, NAF1-rs7675998, ZNF208-rs8105767, OBFC1-rs9420907, ACYP2-rs11125529 and TERC-rs10936599) alone and combined in a LTL genetic score ("teloscore", which explains 2.2% of the telomere variability) in relation to PDAC risk in 2,374 cases and 4,326 controls. We identified several associations with PDAC risk, among which the strongest were with the TERT-rs2736100 SNP (OR = 1.54; 95%CI 1.35-1.76; p = 1.54 × 10-10 ) and a novel one with the NAF1-rs7675998 SNP (OR = 0.80; 95%CI 0.73-0.88; p = 1.87 × 10-6 , ptrend = 3.27 × 10-7 ). The association of short LTL, measured by the teloscore, with PDAC risk reached genome-wide significance (p = 2.98 × 10-9 for highest vs. lowest quintile; p = 1.82 × 10-10 as a continuous variable). In conclusion, we present a novel genome-wide candidate SNP for PDAC risk (TERT-rs2736100), a completely new signal (NAF1-rs7675998) approaching genome-wide significance and we report a strong association between the teloscore and risk of pancreatic cancer, suggesting that telomeres are a potential risk factor for pancreatic cancer.

Matched MeSH terms: Telomere/metabolism*; Telomere Shortening/genetics*
Genomic Instability and Cellular Senescence: Lessons From the Budding Yeast

Lee JW, Ong EBB

Front Cell Dev Biol, 2020;8:619126.
PMID: 33511130 DOI: 10.3389/fcell.2020.619126

Aging is a complex biological process that occurs in all living organisms. Aging is initiated by the gradual accumulation of biomolecular damage in cells leading to the loss of cellular function and ultimately death. Cellular senescence is one such pathway that leads to aging. The accumulation of nucleic acid damage and genetic alterations that activate permanent cell-cycle arrest triggers the process of senescence. Cellular senescence can result from telomere erosion and ribosomal DNA instability. In this review, we summarize the molecular mechanisms of telomere length homeostasis and ribosomal DNA stability, and describe how these mechanisms are linked to cellular senescence and longevity through lessons learned from budding yeast.

Matched MeSH terms: Telomere; Telomere Homeostasis
Fulltext Human Wharton's Jelly-Derived Mesenchymal Stem Cells Minimally Improve the Growth Kinetics and Cardiomyocyte Differentiation of Aged Murine Cardiac c-kit Cells in In Vitro without Rejuvenating Effect

Ng WH, Yong YK, Ramasamy R, Ngalim SH, Lim V, Shaharuddin B, et al.

Int J Mol Sci, 2019 Nov 06;20(22).
PMID: 31698679 DOI: 10.3390/ijms20225519

Cardiac c-kit cells show promise in regenerating an injured heart. While heart disease commonly affects elderly patients, it is unclear if autologous cardiac c-kit cells are functionally competent and applicable to these patients. This study characterised cardiac c-kit cells (CCs) from aged mice and studied the effects of human Wharton's Jelly-derived mesenchymal stem cells (MSCs) on the growth kinetics and cardiac differentiation of aged CCs in vitro. CCs were isolated from 4-week- and 18-month-old C57/BL6N mice and were directly co-cultured with MSCs or separated by transwell insert. Clonogenically expanded aged CCs showed comparable telomere length to young CCs. However, these cells showed lower Gata4, Nkx2.5, and Sox2 gene expressions, with changes of 2.4, 3767.0, and 4.9 folds, respectively. Direct co-culture of both cells increased aged CC migration, which repopulated 54.6 ± 4.4% of the gap area as compared to aged CCs with MSCs in transwell (42.9 ± 2.6%) and CCs without MSCs (44.7 ± 2.5%). Both direct and transwell co-culture improved proliferation in aged CCs by 15.0% and 16.4%, respectively, as traced using carboxyfluorescein succinimidyl ester (CFSE) for three days. These data suggest that MSCs can improve the growth kinetics of aged CCs. CCs retaining intact telomere are present in old hearts and could be obtained based on their self-renewing capability. Although these aged CCs with reduced growth kinetics are improved by MSCs via cell-cell contact, the effect is minimal.

Matched MeSH terms: Telomere Homeostasis

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