The telomerase activator TA-65 elongates short telomeres and increases health span of adult/old mice without increasing cancer incidence.
Ontology highlight
ABSTRACT:
SUBMITTER: Bernardes de Jesus B
PROVIDER: S-EPMC3627294 | biostudies-literature | 2011 Aug
REPOSITORIES: biostudies-literature
Publications
The telomerase activator TA-65 elongates short telomeres and increases health span of adult/old mice without increasing cancer incidence.
Bernardes de Jesus Bruno B Schneeberger Kerstin K Vera Elsa E Tejera Agueda A Harley Calvin B CB Blasco Maria A MA
Aging cell 20110414 4
Here, we show that a small-molecule activator of telomerase (TA-65) purified from the root of Astragalus membranaceus is capable of increasing average telomere length and decreasing the percentage of critically short telomeres and of DNA damage in haploinsufficient mouse embryonic fibroblasts (MEFs) that harbor critically short telomeres and a single copy of the telomerase RNA Terc gene (G3 Terc(+/-) MEFs). Importantly, TA-65 does not cause telomere elongation or rescue DNA damage in similarly t ...[more]
Similar Datasets
Project description:RNA polymerase II transcribes the physical ends of linear eukaryotic chromosomes into a variety of long non-coding RNA molecules including telomeric repeat-containing RNA (TERRA). Since TERRA discovery, advances have been made in the characterization of TERRA biogenesis and regulation; on the contrary its associated functions remain elusive. Most of the biological roles so far proposed for TERRA are indeed based on in vitro experiments carried out using short TERRA-like RNA oligonucleotides. In particular, it has been suggested that TERRA inhibits telomerase activity. We have exploited two alternative cellular systems to test whether TERRA and/or telomere transcription influence telomerase-mediated telomere elongation in human cancer cells. In cells lacking the two DNA methyltransferases DNMT1 and DNMT3b, TERRA transcription and steady-state levels are greatly increased while telomerase is able to elongate telomeres normally. Similarly, telomerase can efficiently elongate transgenic inducible telomeres whose transcription has been experimentally augmented. Our data challenge the current hypothesis that TERRA functions as a general inhibitor of telomerase and suggest that telomere length homeostasis is maintained independently of TERRA and telomere transcription.
| S-EPMC3338753 | biostudies-literature
Project description:Telomeres at the termini of human chromosomes are shortened with each round of cell division due to the "end replication problem" as well as oxidative stress. During carcinogenesis, cells acquire or retain mechanisms to maintain telomeres to avoid initiation of cellular senescence or apoptosis and halting cell division by critically short telomeres. The unique reverse transcriptase enzyme complex, telomerase, catalyzes the maintenance of telomeres but most human somatic cells do not have sufficient telomerase activity to prevent telomere shortening. Tissues with high and prolonged replicative potential demonstrate adequate cellular telomerase activity to prevent telomere erosion, and high telomerase activity appears to be a critical feature of most (80-90%) epithelial cancers, including endometrial cancer. Endometrial cancers regress in response to progesterone which is frequently used to treat advanced endometrial cancer. Endometrial telomerase is inhibited by progestogens and deciphering telomere and telomerase biology in endometrial cancer is therefore important, as targeting telomerase (a downstream target of progestogens) in endometrial cancer may provide novel and more effective therapeutic avenues. This review aims to examine the available evidence for the role and importance of telomere and telomerase biology in endometrial cancer.
| S-EPMC6533802 | biostudies-literature
Project description:Telomeres are protein-DNA complexes that protect chromosome ends from illicit ligation and resection. Telomerase is a ribonucleoprotein enzyme that synthesizes telomeric DNA to counter telomere shortening. Human telomeres are composed of complexes between telomeric DNA and a six-protein complex known as shelterin. The shelterin proteins TRF1 and TRF2 provide the binding affinity and specificity for double-stranded telomeric DNA, while the POT1-TPP1 shelterin subcomplex coats the single-stranded telomeric G-rich overhang that is characteristic of all our chromosome ends. By capping chromosome ends, shelterin protects telomeric DNA from unwanted degradation and end-to-end fusion events. Structures of the human shelterin proteins reveal a network of constitutive and context-specific interactions. The shelterin protein-DNA structures reveal the basis for both the high affinity and DNA sequence specificity of these interactions, and explain how shelterin efficiently protects chromosome ends from genome instability. Several protein-protein interactions, many provided by the shelterin component TIN2, are critical for upholding the end-protection function of shelterin. A survey of these protein-protein interfaces within shelterin reveals a series of "domain-peptide" interactions that allow for efficient binding and adaptability towards new functions. While the modular nature of shelterin has facilitated its part-by-part structural characterization, the interdependence of subunits within telomerase has made its structural solution more challenging. However, the exploitation of several homologs in combination with recent advancements in cryo-EM capabilities has led to an exponential increase in our knowledge of the structural biology underlying telomerase function. Telomerase homologs from a wide range of eukaryotes show a typical retroviral reverse transcriptase-like protein core reinforced with elements that deliver telomerase-specific functions including recruitment to telomeres and high telomere-repeat addition processivity. In addition to providing the template for reverse transcription, the RNA component of telomerase provides a scaffold for the catalytic and accessory protein subunits, defines the limits of the telomeric repeat sequence, and plays a critical role in RNP assembly, stability, and trafficking. While a high-resolution definition of the human telomerase structure is only beginning to emerge, the quick pace of technical progress forecasts imminent breakthroughs in this area. Here, we review the structural biology surrounding telomeres and telomerase to provide a molecular description of mammalian chromosome end protection and end replication.
| S-EPMC6986361 | biostudies-literature
Project description:ABSTRACT MAGWIRE, MICHAEL MAHLON. Mutations Increasing Drosophila melanogaster Life Span. (Under the direction of Trudy F. C. Mackay.) Better living conditions and advances in medicine have made it possible for humans to live considerably longer than before. This has uncovered many health problems associated with age. By identifying genes involved in the limitation of life span, we may better understand the processes that lead to aging. In model organisms, we can use mutagenesis to discover mutations that increase life span, and hence infer that the wild-type allele limits life span by some means. We have assessed longevity in a collection of 1332 co-isogenic gene-trap P-element insertion lines and determined changes in life span of each insert line relative to the corresponding control line. Significant lines were determined via two different methods of analysis: A 95% confidence interval was established based on deviations of the mutant life spans from the controls and Dunnett’s two tailed t-tests were used to examine differences between mutant and control in each individual block. Based on the 95% confidence interval, 139 inserts displayed an increase in life span and 194 inserts a decrease. Using Dunnett’s, 70 lines increased in life span, while 270 decreased in life span. An additional 48 increased longevity lines were close enough to meeting Dunnett’s criteria to be considered for additional investigation. Combining these two analyses, we chose 83 inserts associated with increased life span for a secondary screen using an additional twelve replicates. 58 of these lines remained significant. We have determined the P-element insertion site for 50 of these lines. Starvation resistance, chill coma recovery time and climbing activity were measured on the lines remaining significant after the the secondary screen to identify pleiotropic effects. A positive correlation was found for males between life span and starvation resistance as well as between life span and chill coma recovery. Females only displayed a correlation between life span and chill coma recovery, which was negative. None of the lines indicated increased fitness for all phenotypes, indicating there may be some type of trade-off. There also appears to be a lot of pleiotropic variation depending on background and sex. Ten of the lines, all with the same parental background, were chosen for a half-diallel cross to identify epistasis between the mutants. There were substantial epistatic interactions between all ten lines. Furthermore, males and females displayed vastly different patterns of epistasis, again indicating major differences in life span regulation between the sexes. Finally, a subset of seven of the lines used in the epistatic study, in addition to the corresponding parental control, were chosen for microarray analysis to look for possible pathways and novel genes involved in increasing life span. 1,996 probe sets were significant at a false discovery rate q-value threshold of q < 0.0001. Tukeys tests were carried out for these probe sets to determine how each of the seven mutant backgrounds differed compared to the control and each other. In addition, each mutant background was compared individually with the control to identify any changes in expression. Gene ontologies were determined for each of the lines to identify over-represented biological functions which would indicate possible longevity pathways. Dozens of pathways were suggested, including several novel pathways. Keywords: Genetic (P-element insertion) modification and comparison to control line
2008-08-01 | GSE8775 | GEO
Project description:TA-65 is a dietary supplement based on an improved formulation of a small molecule telomerase activator that was discovered in a systematic screening of natural product extracts from traditional Chinese medicines. This study summarizes the findings on telomere length (TL) changes from a randomized, double blind, placebo controlled study of TA-65 over a 1 year period. The study was conducted on 117 relatively healthy cytomegalovirus-positive subjects aged 53-87 years old. Subjects taking the low dose of TA-65 (250?U) significantly increased TL over the 12 months period (530?±?180?bp; p?=?0.005), whereas subjects in the placebo group significantly lost TL (290?±?100?bp; p?=?0.01). The high dose of TA-65 (1000?U) showed a trend of improvements in TL compared with that of the placebo group; however, the improvements did not reach statistical significance. TL changes in the low-dose group were similar for both median and 20th percentile TLs. The findings suggest that TA-65 can lengthen telomeres in a statistically and possibly clinically significant manner.
| S-EPMC5178008 | biostudies-other
Project description:BackgroundThe increase in average life expectancy increases the risk of illness and frailty in the elderly, especially in the cognitive arena. This study has the objective to estimate the prevalence and incidence of cognitive impairment, in a representative sample of 65 to 85 years old followed for a mean period of 6-years.MethodsSubjects aged 65-85 years (n = 586) were screened at baseline (1999-2004) to estimate the prevalence of cognitive impairment using the Mini-Mental State Examination. A total of 287 individuals with a normal MMSE at baseline were reassessed after 6.2 mean years (± 4.30 years) to evaluate the incidence of cognitive impairment, defined as scoring below the age and education-adjusted MMSE cut-off points adapted for the Portuguese population. We did not exclude Dementia.ResultsThe baseline prevalence of cognitive impairment was 15.5% (95% CI: 12.7-18.7). Higher in women (18.9%; 95% CI: 14.9-23.3), that in men (10.4%; 95% CI: 6.7-15.1). Increased with age and was highest for participants without any schooling. The overall incidence rate was 26.97 per 1000 person-years; higher in women (33.8 per 1000 person-years) than in men (18.0 per 1000 person-years). Higher for the oldest participants and those with no schooling. Taking the standard European population, we estimated a prevalence of 16.5% and an incidence of 34.4 per 1000 person-years.ConclusionThe prevalence of cognitive impairment in Portugal is within the estimated interval for the European population, and the incidence is lower than for the majority of the European countries. Women, senior and elders without education have a higher risk of cognitive impairment. In our sample, neither employment nor marital status has a significant effect on cognitive impairment.
| S-EPMC7667782 | biostudies-literature
Project description:A major goal in aging research is to improve health during aging. In the case of mice, genetic manipulations that shorten or lengthen telomeres result, respectively, in decreased or increased longevity. Based on this, we have tested the effects of a telomerase gene therapy in adult (1 year of age) and old (2 years of age) mice. Treatment of 1- and 2-year old mice with an adeno associated virus (AAV) of wide tropism expressing mouse TERT had remarkable beneficial effects on health and fitness, including insulin sensitivity, osteoporosis, neuromuscular coordination and several molecular biomarkers of aging. Importantly, telomerase-treated mice did not develop more cancer than their control littermates, suggesting that the known tumorigenic activity of telomerase is severely decreased when expressed in adult or old organisms using AAV vectors. Finally, telomerase-treated mice, both at 1-year and at 2-year of age, had an increase in median lifespan of 24 and 13%, respectively. These beneficial effects were not observed with a catalytically inactive TERT, demonstrating that they require telomerase activity. Together, these results constitute a proof-of-principle of a role of TERT in delaying physiological aging and extending longevity in normal mice through a telomerase-based treatment, and demonstrate the feasibility of anti-aging gene therapy.
| S-EPMC3494070 | biostudies-literature
Project description:Telomeres maintain genomic integrity in normal cells, and their progressive shortening during successive cell divisions induces chromosomal instability. In the large majority of cancer cells, telomere length is maintained by telomerase. Thus, telomere length and telomerase activity are crucial for cancer initiation and the survival of tumors. Several pathways that regulate telomere length have been identified, and genome-scale studies have helped in mapping genes that are involved in telomere length control. Additionally, genomic screening for recurrent human telomerase gene hTERT promoter mutations and mutations in genes involved in the alternative lengthening of telomeres pathway, such as ATRX and DAXX, has elucidated how these genomic changes contribute to the activation of telomere maintenance mechanisms in cancer cells. Attempts have also been made to develop telomere length- and telomerase-based diagnostic tools and anticancer therapeutics. Recent efforts have revealed key aspects of telomerase assembly, intracellular trafficking and recruitment to telomeres for completing DNA synthesis, which may provide novel targets for the development of anticancer agents. Here, we summarize telomere organization and function and its role in oncogenesis. We also highlight genomic mutations that lead to reactivation of telomerase, and mechanisms of telomerase reconstitution and trafficking that shed light on its function in cancer initiation and tumor development. Additionally, recent advances in the clinical development of telomerase inhibitors, as well as potential novel targets, will be summarized.
| S-EPMC4915101 | biostudies-literature
Project description:Telomeres, the ends of linear eukaryotic chromosomes, are characterized by the presence of multiple repeats of a short DNA sequence. This telomeric DNA is protected from illicit repair by telomere-associated proteins, which in mammals form the shelterin complex. Replicative polymerases are unable to synthesize DNA at the extreme ends of chromosomes, but in unicellular eukaryotes such as yeast and in mammalian germ cells and stem cells, telomere length is maintained by a ribonucleoprotein enzyme known as telomerase. Recent work has provided insights into the mechanisms of telomerase recruitment to telomeres, highlighting the contribution of telomere-associated proteins, including TPP1 in humans, Ccq1 in Schizosaccharomyces pombe and Cdc13 and Ku70-Ku80 in Saccharomyces cerevisiae.
| S-EPMC3805138 | biostudies-literature
Project description:Research investigating telomere lengths and telomerase expression in vertebrates has progressively become important due to the association of these two biological endpoints with cellular aging and cancer in humans. Studies that rely upon the traditional use of laboratory mice have been faced with limitations largely due to inbred mice possessing large telomeres and ubiquitous expression of telomerase. Recently, a number of small fish species have been shown to provide potentially informative models for examining the role of telomeres and telomerase within intact vertebrate animals. Xiphophorus fishes represent a new world live-bearing genus that has not previously been assessed for telomere length or telomerase expression. To add to the knowledge base of telomere and telomerase biology in vertebrates we assessed telomere length and telomerase expression among several species of Xiphophorus. The telomere lengths in several organs (gill, brain, eyes, testis, ovary and liver) in three species (Xiphophorus hellerii, Xiphophorus maculatus, Xiphophorus couchianus) and also in F(1) interspecies hybrids were approximately 2-6 kb. This size was consistent within the same organs of the same species, as well as between species and F(1) hybrids. Despite possessing relatively short telomere lengths compared to humans, the consistency of size among Xiphophorus species and organs may allow experimental detection of telomere shortening. The relative expression of telomerase reverse transcriptase (TERT) was determined by quantitative real-time PCR. Expression levels of TERT was measured in seven organs (ovary, testis, liver, gill, brain, heart, skin) from X. maculatus, X. hellerii and in control and ultraviolet light (UVB) exposed skin samples from X. maculatus, X. hellerii, and F(1) interspecies hybrids. TERT gene expression was significantly higher in ovary and testis, while all other organs showed low relative TERT expression. Detectable increases in TERT expression were found in skin samples upon UVB exposure. Our findings suggest that Xiphophorus may serve as a suitable model for future studies investigating the association of telomere length and telomerase expression in regard to aging and disease.
| S-EPMC3208803 | biostudies-literature