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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/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
Fulltext Is There an Interconnection between Epithelial-Mesenchymal Transition (EMT) and Telomere Shortening in Aging?

Imran SAM, Yazid MD, Idrus RBH, Maarof M, Nordin A, Razali RA, et al.

Int J Mol Sci, 2021 Apr 09;22(8).
PMID: 33918710 DOI: 10.3390/ijms22083888

Epithelial-Mesenchymal Transition (EMT) was first discovered during the transition of cells from the primitive streak during embryogenesis in chicks. It was later discovered that EMT holds greater potential in areas other than the early development of cells and tissues since it also plays a vital role in wound healing and cancer development. EMT can be classified into three types based on physiological functions. EMT type 3, which involves neoplastic development and metastasis, has been the most thoroughly explored. As EMT is often found in cancer stem cells, most research has focused on its association with other factors involving cancer progression, including telomeres. However, as telomeres are also mainly involved in aging, any possible interaction between the two would be worth noting, especially as telomere dysfunction also contributes to cancer and other age-related diseases. Ascertaining the balance between degeneration and cancer development is crucial in cell biology, in which telomeres function as a key regulator between the two extremes. The essential roles that EMT and telomere protection have in aging reveal a potential mutual interaction that has not yet been explored, and which could be used in disease therapy. In this review, the known functions of EMT and telomeres in aging are discussed and their potential interaction in age-related diseases is highlighted.

Matched MeSH terms: Telomere/metabolism
Telomerase: is it the future diagnostic and prognostic tool in human cancer?

Mabruk MJ, O'Flatharta C

Expert Rev Mol Diagn, 2005 Nov;5(6):907-16.
PMID: 16255632

A number of methods exist to detect levels of telomerase activity and the presence of telomerase subunits in a variety of tissues. As telomerase activation seems to be an important step in tumorigenesis, accurate detection of the presence and activity of the enzyme and its subunits is vital. The original method of detecting telomerase activity was developed by Kim and coworkers in 1994, and was termed the telomeric repeat amplification protocol. This assay led to a staggering increase in the number of telomerase-associated publications in scientific journals (85 publications from 1974-1994, 5063 publications from 1994-2004). A number of methods have been described to detect telomeres and to measure their length, with the standard measurement of telomere length performed using a modification of the Southern blot protocol. RNA in situ hybridization can be performed to detect levels of the RNA component of telomerase, and standard in situ hybridization and immunohistochemistry can be applied to examine expression levels and localization of the catalytic subunit of the enzyme. Reverse transcriptase PCR has also been applied to assess expression levels of the telomerase components in various tissues. This review provides a synopsis of telomeres, telomerase, telomerase and cancer, and finally, methods for the detection of telomerase in cancer.

Matched MeSH terms: Telomere/metabolism
Effects of HSV-G47Δ Oncolytic Virus on Telomerase and Telomere Length Alterations in Glioblastoma Multiforme Cancer Stem Cells Under Hypoxia and Normoxia Conditions

Vazifehmand R, Ali DS, Homaie FM, Jalalvand FM, Othman Z, Deming C, et al.

Curr Cancer Drug Targets, 2024;24(12):1262-1274.
PMID: 38357955 DOI: 10.2174/0115680096274769240115165344

BACKGROUND: Due to the existence of tumor stem cells with tumorigenicity properties and resistance patterns, treatment of glioblastoma is not easy. Hypoxia is a major concern in glioblastoma therapy. Telomerase activity and telomere length alterations have been known to play a critical role in glioblastoma progression and invasion.
OBJECTIVE: This study aimed to investigate the effects of HSV-G47Δ oncolytic virus on telomerase and telomere length alterations in U251GBMCSCs (U251-Glioblastoma cancer stem cells) under hypoxia and normoxia conditions.
METHODS: U251-CSCs were exposed to the HSV-G47Δ virus in optimized MOI (Multiplicity of infection= 1/14 hours). An absolute telomere length and gene expression of telomerase subunits were determined using an absolute human telomere length quantification PCR assay. Furthermore, a bioinformatics pathway analysis was carried out to evaluate physical and genetic interactions between dysregulated genes with other potential genes and pathways.
RESULTS: Data revealed that U251CSCs had longer telomeres when exposed to HSV-G47Δ in normoxic conditions but had significantly shorter telomeres in hypoxic conditions. Furthermore, hTERC, DKC1, and TEP1 genes were significantly dysregulated in hypoxic and normoxic microenvironments. The analysis revealed that the expression of TERF2 was significantly reduced in both microenvironments, and two critical genes from the MRN complex, MER11 and RAD50, were significantly upregulated in normoxic conditions. RAD50 showed a significant downregulation pattern in the hypoxic niche. Our results suggested that repair complex in the telomeric structure could be targeted by HSV-G47Δ in both microenvironments.
CONCLUSION: In the glioblastoma treatment strategy, telomerase and telomere complex could be potential targets for HSV-G47Δ in both microenvironments.

Matched MeSH terms: Telomere/metabolism
Fulltext gamma-Tocotrienol prevents oxidative stress-induced telomere shortening in human fibroblasts derived from different aged individuals

Makpol S, Abidin AZ, Sairin K, Mazlan M, Top GM, Ngah WZ

Oxid Med Cell Longev, 2010 Jan-Feb;3(1):35-43.
PMID: 20716926 DOI: 10.4161/oxim.3.1.9940

The effects of palm gamma-tocotrienol (GGT) on oxidative stress-induced cellular ageing was investigated in normal human skin fibroblast cell lines derived from different age groups; young (21-year-old, YF), middle (40-year-old, MF) and old (68-year-old, OF). Fibroblast cells were treated with gamma-tocotrienol for 24 hours before or after incubation with IC50 dose of H2O2 for 2 hours. Changes in cell viability, telomere length and telomerase activity were assessed using the MTS assay (Promega, USA), Southern blot analysis and telomere repeat amplification protocol respectively. Results showed that treatment with different concentrations of gamma-tocotrienol increased fibroblasts viability with optimum dose of 80 microM for YF and 40 microM for both MF and OF. At higher concentrations, gamma-tocotrienol treatment caused marked decrease in cell viability with IC50 value of 200 microM (YF), 300 microM (MF) and 100 microM (OF). Exposure to H2O2 decreased cell viability in dose dependent manner, shortened telomere length and reduced telomerase activity in all age groups. The IC50 of H2O2 was found to be; YF (700 microM), MF (400 microM) and OF (100 microM). Results showed that viability increased significantly (p < 0.05) when cells were treated with 80 microM and 40 microM gamma-tocotrienol prior or after H2O2-induced oxidative stress in all age groups. In YF and OF, pretreatment with gamma-tocotrienol prevented shortening of telomere length and reduction in telomerase activity. In MF, telomerase activity increased while no changes in telomere length was observed. However, post-treatment of gamma-tocotrienol did not exert any significant effects on telomere length and telomerase activity. Thus, these data suggest that gamma-tocotrienol protects against oxidative stress-induced cellular ageing by modulating the telomere length possibly via telomerase.

Matched MeSH terms: Telomere/metabolism*
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*
Fulltext Tocotrienol-rich fraction prevents cell cycle arrest and elongates telomere length in senescent human diploid fibroblasts

Makpol S, Durani LW, Chua KH, Mohd Yusof YA, Ngah WZ

J Biomed Biotechnol, 2011;2011:506171.
PMID: 21541185 DOI: 10.1155/2011/506171

This study determined the molecular mechanisms of tocotrienol-rich fraction (TRF) in preventing cellular senescence of human diploid fibroblasts (HDFs). Primary culture of HDFs at various passages were incubated with 0.5 mg/mL TRF for 24 h. Telomere shortening with decreased telomerase activity was observed in senescent HDFs while the levels of damaged DNA and number of cells in G(0)/G(1) phase were increased and S phase cells were decreased. Incubation with TRF reversed the morphology of senescent HDFs to resemble that of young cells with decreased activity of SA-β-gal, damaged DNA, and cells in G(0)/G(1) phase while cells in the S phase were increased. Elongated telomere length and restoration of telomerase activity were observed in TRF-treated senescent HDFs. These findings confirmed the ability of tocotrienol-rich fraction in preventing HDFs cellular ageing by restoring telomere length and telomerase activity, reducing damaged DNA, and reversing cell cycle arrest associated with senescence.

Matched MeSH terms: Telomere/metabolism*
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/metabolism
Zinc supplementation influences genomic stability biomarkers, antioxidant activity, and zinc transporter genes in an elderly Australian population with low zinc status

Sharif R, Thomas P, Zalewski P, Fenech M

Mol Nutr Food Res, 2015 Jun;59(6):1200-12.
PMID: 25755079 DOI: 10.1002/mnfr.201400784

An increased intake of Zinc (Zn) may reduce the risk of degenerative diseases but may prove to be toxic if taken in excess. This study aimed to investigate whether zinc carnosine supplement can improve Zn status, genome stability events, and Zn transporter gene expression in an elderly (65-85 years) South Australian cohort with low plasma Zn levels.

Matched MeSH terms: Telomere/metabolism