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Understanding Telomeres: Composition, Benefits, and Practical Uses

Telomere

Keywords: telomeric repeat, exercise, d3, nutrition, telomere, telomerase, tert, htr, dyskerin, cancer, telomeres, shelterin complex, end replication, telomere maintenance mechanisms, TERT promoter mutations, telomere length heritability, genetic variants, cancer-risk, aging, biobehavior, nursing research, oxidative stress, psychological stress, telomere, Telomeres length, oxidative damage, breast cancer, Aging syndromes, Aging process, autophagy, Astragalus membranaceus, Astragalus membranaceus extracts, autophagy dysregulation-associated diseases, Astragalus polysaccharide, preparation, chemical composition, pharmacological action, immune regulation, anti-aging, anti-tumor, regulation of blood glucose, Whole ingredients extract, Chemical integrity, Immunomodulation, Astragali Radix, Astragalus membranaceus, aging, neurodegenerative disease, cancer, immnoregulation, Astragalus membranaceus extract, macrophage, heparanase, migration, immune response mediator, immune response, Telomerase, telomeres, senescence, cancer, immortalization, peripheral blood leukocytes, serum lipids concentrations, telomere length, DNA damage response, flavanoid, polyphenol, telomere, telomeric position effect, telomere-induced foci, aging, anti-aging, antioxidants, laser, peeling, fillers, botulinum toxin, hormone replacement therapy, cell regulators, prevention, carnosine, complexation, dermo-cosmetic formulation, topical delivery, telomerase, DNA damage responses, G-quadruplex, guanine-rich oligonucleotides (GROs), telomere homolog oligonucleotides (T-oligos), s

Summary of Abstracts:

Expression of Telomeric Repeat–Containing RNA Decreases in Sarcopenia and Increases after Exercise and Nutrition Intervention Sarcopenia is defined as aging-related loss of muscle mass and function. Telomere length in chromosomes shortens with age and is modulated by telomeric repeat-containing RNA (TERRA). This study aimed to explore the impact of aging and sarcopenia on telomere length and TERRA expression, and changes following strengthening exercise and nutrition intervention (supplement of branched-chain amino acids, calcium and vitamin D3) for 12 weeks in the sarcopenic population. Sarcopenia is associated with a decrease in TERRA expression in leukocytes. Rebound TERRA expression (returning to the level similar to the non-sarcopenic controls) was observed in the sarcopenic group after exercise and nutrition intervention. Future studies are warranted to examine the potential of TERRA as a biomarker for sarcopenia and its subsequent responses to intervention.

Prolonged Glucocorticoid Exposure Does Not Accelerate Telomere Shortening in Cultured Human Fibroblasts While our findings await extension in other cell types and biological contexts, they indicate that the in vivo association of psychosocial stress with telomere shortening is unlikely to be mediated by a direct and universal glucocorticoid effect on telomere length.

Updated Understanding of Cancer as a Metabolic and Telomere-Driven Disease, and Proposal for Complex Personalized Treatment, a Hypothesis In this review, we propose a holistic approach to understanding cancer as a metabolic disease. Our search for relevant studies in medical databases concludes that cancer cells do not evolve directly from normal healthy cells. We hypothesize that aberrant DNA damage accumulates over time—avoiding the natural DNA controls that otherwise repair or replace the rapidly replicating cells. DNA damage starts to accumulate in non-replicating cells, leading to senescence and aging. DNA damage is linked with genetic and epigenetic factors, but the development of cancer is favored by telomerase activity. Evidence indicates that telomere length is affected by chronic inflammations, alterations of mitochondrial DNA, and various environmental factors. Emotional stress also influences telomere length. Chronic inflammation can cause oxidative DNA damage. Oxidative stress, in turn, can trigger mitochondrial changes, which ultimately alter nuclear gene expression. This vicious cycle has led several scientists to view cancer as a metabolic disease. We have proposed complex personalized treatments that seek to correct multiple changes simultaneously using a psychological approach to reduce chronic stress, immune checkpoint therapy with reduced doses of chemo and radiotherapy, minimal surgical intervention, if any, and mitochondrial metabolic reprogramming protocols supplemented by intermittent fasting and personalized dietary plans without interfering with the other therapies.

The Role of microRNAs in Organismal and Skin Aging The aging process starts directly after birth and lasts for the entire lifespan; it manifests itself with a decline in an organism’s ability to adapt and is linked to the development of age-related diseases that eventually lead to premature death. This review aims to explore how microRNAs (miRNAs) are involved in skin functioning and aging. Recent evidence has suggested that miRNAs regulate all aspects of cutaneous biogenesis, functionality, and aging.

Telomeres and Telomerase in the Development of Liver Cancer Liver cancer is one of the most common cancer types worldwide and the fourth leading cause of cancer-related death. Liver carcinoma is distinguished by a high heterogeneity in pathogenesis, histopathology and biological behavior. Dysregulated signaling pathways and various gene mutations are frequent in hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), which represent the two most common types of liver tumors. Both tumor types are characterized by telomere shortening and reactivation of telomerase during carcinogenesis. Continuous cell proliferation, e.g., by oncogenic mutations, can cause extensive telomere shortening in the absence of sufficient telomerase activity, leading to dysfunctional telomeres and genome instability by breakage–fusion–bridge cycles, which induce senescence or apoptosis as a tumor suppressor mechanism. Telomerase reactivation is required to stabilize telomere functionality and for tumor cell survival, representing a genetic risk factor for the development of liver cirrhosis and liver carcinoma. Therefore, telomeres and telomerase could be useful targets in hepatocarcinogenesis. Here, we review similarities and differences between HCC and iCCA in telomere biology.

Effect of Sechium edule var. nigrum spinosum (Chayote) on Telomerase Levels and Antioxidant Capacity in Older Adults with Metabolic Syndrome Patients with metabolic syndrome (MetS) have a redox imbalance, due to a decay in antioxidant capacity. Oxidative stress (OxS) is considered an important modulator of telomere shortening and telomerase activity. One of the fruits that has been associated with an antioxidant effect is Sechium edule and although its properties are well established, there is only one exploratory study evaluating its effectiveness in patients with MetS. The present investigation is a much more robust and controlled study, including a placebo group. Hence, we determined the effect of consumption of the dried fruit powder (500 mg, three times per day) for three months. We measured effects on telomerase levels, antioxidant capacity, and markers for OxS. The study was performed in a sample of 75 older adults: placebo group (n = 30) and experimental group (n = 45) with the diagnosis of MetS according to the National Adult Treatment Panel of the National Cholesterol Program III (NCEP/ATP III) criteria. All markers were measured before and after three months of treatment. There was a statistically significant decrease in lipoperoxides and protein carbonylation with an increased superoxide dismutase (SOD), as well as sustained levels of telomerase in patients who consumed Sechium edule. Our findings suggest that consumption of this fruit has a hypoglycemic, hypotensive, and antioxidant effect, without altering telomerase levels, which could suggest better protection against telomere shortening.

Telomeres and telomerase Telomeres are the protective DNA-protein complexes found at the ends of eukaryotic chromosomes. Telomeric DNA consists of tandem repeats of a simple, often G-rich, sequence specified by the action of telomerase, and complete replication of telomeric DNA requires telomerase. Telomerase is a specialized cellular ribonucleoprotein reverse transcriptase. By copying a short template sequence within its intrinsic RNA moiety, telomerase synthesizes the telomeric DNA strand running 5' to 3' towards the distal end of the chromosome, thus extending it. Fusion of a telomere, either with another telomere or with a broken DNA end, generally constitutes a catastrophic event for genomic stability. Telomerase acts to prevent such fusions.

Telomere structure and telomerase in health and disease Telomerase is the enzyme responsible for maintenance of the length of telomeres by addition of guanine-rich repetitive sequences. Telomerase activity is exhibited in gametes and stem and tumor cells. In human somatic cells, proliferation potential is strictly limited and senescence follows approximately 50–70 cell divisions. In most tumor cells, on the contrary, replication potential is unlimited. The key role in this process of the system of the telomere length maintenance with involvement of telomerase is still poorly studied. Although telomerase therapeutics are not approved yet for clinical use, we can assume that based on the promising in vitro and in vivo results and successful clinical trials, it can be predicted that telomerase therapeutics will be utilized soon in the combat against malignancies and degenerative diseases.

Telomeres and Telomere Length: A General Overview Telomeres are highly conserved tandem nucleotide repeats that include proximal double-stranded and distal single-stranded regions that in complex with shelterin proteins afford protection at chromosomal ends to maintain genomic integrity. Due to the inherent limitations of DNA replication and telomerase suppression in most somatic cells, telomeres undergo age-dependent incremental attrition. Short or dysfunctional telomeres are recognized as DNA double-stranded breaks, triggering cells to undergo replicative senescence. Telomere shortening, therefore, acts as a counting mechanism that drives replicative senescence by limiting the mitotic potential of cells. Telomere length, a complex hereditary trait, is associated with aging and age-related diseases. In addition to genetic factors, environmental factors also influence telomere length during growth and development. Telomeres hold potential as biomarkers that reflect the genetic predisposition together with the impact of environmental conditions and as targets for anti-cancer therapies.

Telomeres and telomerase in ageing and cancer Telomeres lie at the ends of human chromosomes and contain long tandem repeats of a simple nucleotide sequence. Because DNA replication cannot proceed to the very end of chromosomes, copies of these repeats are lost at each cell division. If the telomeres shorten below a critical length, the cells will eventually die as a result of genomic instability. Aging cells usually avoid death by entering senescence before the critical telomere length is reached. Malignantly transformed, immortal cells overcome senescence but they must still avoid the final, critical shortening of telomeres to survive.

Human Telomerase and Its Regulation The telomere is a special functional complex at the end of linear eukaryotic chromosomes, consisting of tandem repeat DNA sequences and associated proteins. It is essential for maintaining the integrity and stability of linear eukaryotic genomes. Telomere length regulation and maintenance contribute to normal human cellular aging and human diseases. The synthesis of telomeres is mainly achieved by the cellular reverse transcriptase telomerase, an RNA-dependent DNA polymerase that adds telomeric DNA to telomeres. Expression of telomerase is usually required for cell immortalization and long-term tumor growth. In humans, telomerase activity is tightly regulated during development and oncogenesis. The modulation of telomerase activity may therefore have important implications in antiaging and anticancer therapy. This review describes the currently known components of the telomerase complex and attempts to provide an update on the molecular mechanisms of human telomerase regulation.

An Integrative Review of Factors Associated with Telomere Length and Implications for Biobehavioral Research Although telomere shortening occurs as a natural part of aging, there is now a robust body of research that suggests that there is a relationship between psychosocial, environmental, and behavioral factors and changes in telomere length. These factors need to be considered when integrating telomere measurement in biobehavioral research studies. Multiple factors have been shown to affect telomere length. To advance understanding of the role of telomere length in health and disease risk, it will be important to further elucidate the mechanisms that contribute to telomere shortening.

Telomere length, oxidative damage, antioxidants and breast cancer risk Telomeres play a critical role in maintaining the integrity and stability of the genome, and are susceptible to oxidative damage after telomere shortening to a critical length. In the present study, we explored the role of white blood cell (WBC) DNA telomere length on breast cancer risk. A moderate increase in breast cancer risk was observed among women with the shortest telomeres (Q4) and lower dietary and supplemental intake of β-carotene, vitamin C or E intake (OR (95%CI)=1.48 (1.08–2.03), 1.39 (1.01–1.92) and 1.57 (1.14–2.18), respectively), although the trend test exhibited statistical significance only within the lower vitamin E intake subgroup (P trend =0.01). These results provided the strongest evidence to date that breast cancer risk may be affected by telomere length among pre-menopausal women or women with low dietary intake of antioxidants or antioxidant supplements.

Significance of Telomere and Telomerase Biology and Their Relationship with Aging Process Telomeres, found at eukaryotic chromosome ends, are made up of tandem DNA repeats(TTAGGG repeats). Telomere is heterochromatic domain and protect the chromosome end from rearrangement, end to end fusion and degradation. In most cells, the number of telomeric repeats is reduced with each cell cycle division. If telomeres are ever completely lost, the exposed chromosome ends are recognized as damaged DNA, activating a DNA damage response that can eventually lead to senescence or apoptosis. Telomerase - the enzyme that maintains telomere length in cells - counteracts telomere erosion and provides some somatic cells an unlimited proliferative potential in vitro.full Investigation of the association between telomere and telomerase can make useful contribution to prevention from human aging , aging syndromes and age related diseases.

The Effects of Astragalus membranaceus Active Extracts on Autophagy-Related Diseases Autophagy is an evolutionarily conserved ‘self-eating’ process that maintains cellular, tissue, and organismal homeostasis. New studies on autophagy, mediated by subsets of autophagy proteins, are emerging in many physiological and pathological processes. Astragalus membranaceus (AM), also named Huangqi, is one of the fundamental herbs in traditional Chinese medicine and its extracts have been proved to possess many biological activities related to autophagy, including anti-oxidation, anti-inflammation, anticancer, anti-photoaging, and improvement of cardiomyocyte function. Evidence suggests that AM extracts can have therapeutic potential in autophagy dysregulation-associated diseases because of their biological positive effects.

A Review of the Pharmacological Action of Astragalus Polysaccharide Astragalus membranaceus (A. membranaceus) is a type of traditional Chinese medicine with a long history of clinical application. It is used in the improvement and treatment of various diseases as medicine and food to invigorate the spleen and replenish qi. The main components of A. membranaceus are Astragalus polysaccharide (APS), flavonoids compounds, saponins compounds, alkaloids, etc. APS is the most important natural active component in A. membranaceus, and possesses multiple pharmacological properties. At present, APS possess the huge potential to develop a drug improving or treating different diseases. In this review, we reveal the potential approaches of pre-treating and preparation on APS as much as possible and the study on content of APS and its chemical composition including different monosaccharides. More importantly, this paper summarize pharmacological actions on immune regulation, such as enhancing the immune organ index, promoting the proliferation of immune cells, stimulating the release of cytokines, and affecting the secretion of immunoglobulin and conduction of immune signals; anti-aging; anti-tumor by enhancing immunity, inducing apoptosis of tumor cells and inhibiting the proliferation and transfer of tumor cells; antiviral effects; regulation of blood glucose such as type I diabetes mellitus, type II diabetes mellitus and diabetic complications; lipid-lowering; anti-fibrosis; antimicrobial activities and anti-radiation. It provided theoretical basis for the further research such as its structure and mechanism of action, and clinical application of APS.

Immunomodulatory effects of a new whole ingredients extract from Astragalus: a combined evaluation on chemistry and pharmacology Water extract (WAE) and ultrafine powder (UFP) are two types of commonly used supplements in preparing various pharmaceutical products and functional foods. However, the correlations of the chemical compositions with the traditional functions between WAE and the herb itself, as well as the potential problems of safety for UFP have been more and more concerned by many doctors and customers. Conclusion: WIE maximally retained the chemical integrity of astragalus, and presented better therapeutic effectiveness than UFP and WAE. It can be further developed as new strategy for reasonable use of medicinal/edible herb-derived supplement (extract) for pharmaceutical and healthcare applications.

Anti-Aging Implications of Astragalus Membranaceus (Huangqi): A Well-Known Chinese Tonic Owing to a dramatic increase in average life expectancy and the Family Planning program of the 1970s - 1990s, China is rapidly becoming an aging society. Therefore, the investigation of healthspan-extending drugs becomes more urgent. Astragalus membranaceus (Huangqi) is a major medicinal herb that has been commonly used in many herbal formulations in the practice of traditional Chinese medicine (TCM) to treat a wide variety of diseases and body disorders, or marketed as life-prolonging extracts for human use in China, for more than 2000 years. The major components of Astragalus membranaceus are polysaccharides, flavonoids, and saponins. Pharmacological research indicates that the extract component of Astragalus membranaceus can increase telomerase activity, and has antioxidant, anti-inflammatory, immunoregulatory, anticancer, hypolipidemic, antihyperglycemic, hepatoprotective, expectorant, and diuretic effects. A proprietary extract of the dried root of Astragalus membranaceus, called TA-65, was associated with a significant age-reversal effect in the immune system. Our review focuses on the function and the underlying mechanisms of Astragalus membranaceus in lifespan extension, anti-vascular aging, anti-brain aging, and anti-cancer effects, based on experimental and clinical studies.

Astragalus membranaceus Extract Activates Immune Response in Macrophages via Heparanase Astragalus membranaceus (AM), a traditional Chinese medicinal herb, has immunoregulatory properties in many diseases. We investigated the effects and mechanism of Astragalus membranaceus extract (AME) in the macrophage migration and immune response mediator release. The viability of Ana-1 macrophages treated with AME was evaluated by the MTT method. The secretion and mRNA levels of IL-1β and TNF-α were measured by ELISA and RT-PCR, respectively. Macrophage migration was assayed by transwell assay. The activity of heparanase (HPA) was determined by a heparin-degrading enzyme assay. Our results didn’t show any toxicity of AME in macrophages. AME increased the activity of HPA, cell migration, mRNA levels and secretion of IL-1β and TNF-α in macrophages. Pretreatment with anti-HPA antibody reduced cell migration, secretion of IL-1β and TNF-α did not change the mRNA levels of IL-1β and TNF-α significantly in AME-treated macrophages. This suggests that AME may increase the release of immune response mediator and cell migration via HPA to activate immune response in macrophages.

Telomerase and the aging process The level of telomerase activity is important in determining telomere length in aging cells and tissues. Here evidence on the importance of telomerase activity is reviewed with respect to aging rates of mammalian species and the health and life span of individuals within a species. The significance of telomerase reactivation for both cancer development and for immortalizing cells for therapeutic processes is assessed.

The polygenic nature of telomere length and the anti-ageing properties of lithium Telomere length is a promising biomarker for age-related disease and a potential anti-ageing drug target. Here, we study the genetic architecture of telomere length and the repositioning potential of lithium as an anti-ageing medication. Lithium may be catalysing the activity of endogenous mechanisms that promote telomere lengthening, whereby its efficacy eventually becomes limited by each individual’s inherent telomere maintenance capabilities. Our work indicates a potential use of polygenic risk scoring for the prediction of adult telomere length and consequently lithium’s anti-ageing efficacy.

Serum Level of Total Lipids and Telomere Length in the Male Population: A Cross-Sectional Study Telomeres contain TTAGGG (T; Thymine, A; Adenine and G; Guanine) repetitive sequences and are placed at the end of human chromosomes. Telomere dysfunction is implicated in some age-related and chronic diseases, but its association with total serum lipids and obesity is unknown. Our research suggests that the inverse relationship was found between TL and weight, BMI, age, and TSL which were associated with obesity. High serum lipids concentration may be associated with systemic inflammation and atherosclerosis and may lead to oxidative stress, resulting in telomere shortening.

Walnut phenolic extracts reduce telomere length and telomerase activity in a colon cancer stem cell model Telomeres are located at the chromosomal ends and progressively shortened during each cell cycle. Telomerase, which is regulated by hTERT and c-MYC, maintains telomeric DNA sequences. Especially, telomerase is active in cancer and stem cells to maintain telomere length for replicative immortality. Recently we reported that walnut phenolic extract (WPE) can reduce cell viability in a colon cancer stem cell (CSC) model. We, therefore, investigated the effect of WPE on telomere maintenance in the same model. CONCLUSION In the present cell culture model, WPE reduced telomere maintenance, which may provide a mechanistic link to the effect of walnuts on the viability of colon CSCs.

Acacetin and Chrysin, Two Polyphenolic Compounds, Alleviate Telomeric Position Effect in Human Cells We took advantage of the ability of human telomeres to silence neighboring genes (telomere position effect or TPE) to design a high-throughput screening assay for drugs altering telomeres. We identified, for the first time, that two dietary flavones, acacetin and chrysin, are able to specifically alleviate TPE in human cells. We further investigated their influence on telomere integrity and showed that both drugs drastically deprotect telomeres against DNA damage response. However, telomere deprotection triggered by shelterin dysfunction does not affect TPE, indicating that acacetin and chrysin target several functions of telomeres. These results show that TPE-based screening assays represent valuable methods to discover new compounds targeting telomeres.

Skin anti-aging strategies Skin aging is a complex biological process influenced by combination of endogenous or intrinsic (genetics, cellular metabolism, hormone and metabolic processes) and exogenous or extrinsic (chronic light exposure, pollution, ionizing radiation, chemicals, toxins) factors.1 These factors lead together to cumulative structural and physiological alterations and progressive changes in each skin layer as well as changes in skin appearance, especially, on the sun-exposed skin areas.2-12 In contrast to thin and atrophic, finely wrinkled and dry intrinsically aged skin, premature photoaged skin typically shows a thickened epidermis, mottled discoloration, deep wrinkles, laxity, dullness and roughness.13-18 Gradual loss of skin elasticity leads to the phenomenon of sagging.19 Slowing of the epidermal turnover rate and cell cycle lengthening coincides with a slower wound healing and less effective desquamation in older adults. nThree primary structural components of the dermis, collagen, elastin and GAGs have been the subjects of the majority of anti-aging research and efforts for aesthetic-anti-aging strategies pertaining to the skin, from ”anti-wrinkle creams” to various filling agents. While natural aging is genetically determined, extrinsic aging can be prevented. Aesthetic dermatology should contribute to “healthy aging” not only in cosmetic means by trying to erase time vestiges in skin but by also playing a significant part in prevention, regeneration, and delaying of skin aging combining knowledge of possible local and systemic therapy, instrumental devices and invasive procedures, filling the lack of scientific investigations and becoming one of the important focuses of the aging research.

Evaluation of the Transepidermal Penetration of a Carnosine Complex in Gel Formulation by 3D Skin Models Carnosine has several physiological roles, from intracellular pH buffering to antioxidant activities, which all depend on bioavailability. This study was conducted in a human skin 3D model and focuses on the effects of the topical delivery of carnosine, from a dermo-cosmetic gel, through the stratum corneum in the presence of a magnesium ion as a complexing agent. To evaluate possible enhancement for small peptide delivery to the skin from simple cosmetic formulations, we discovered that complexation was able to improve the delivery of carnosine into human skin 3D models by application in gel formulation. The concentrations of carnosine released in the underlying media and those that remained in the reconstructed human epidermis (RHE) tissues after 24 and 48 h exposure were measured. Moreover, the influence of magnesium ions was also evaluated comparing the same formulation with and without the salt. The results obtained in this study support hypothesis that magnesium can influence the delivery of small peptides and that the gel formulation based on the carnosine-magnesium complex allows for superior delivery of carnosine in the lower skin layer at a concentration up to 60% more than carnosine alone.

Treating Cancer by Targeting Telomeres and Telomerase Telomerase is expressed in more than 85% of cancer cells. Tumor cells with metastatic potential may have a high telomerase activity, allowing cells to escape from the inhibition of cell proliferation due to shortened telomeres. Human telomerase primarily consists of two main components: hTERT, a catalytic subunit, and hTR, an RNA template whose sequence is complimentary to the telomeric 5′-dTTAGGG-3′ repeat. In humans, telomerase activity is typically restricted to renewing tissues, such as germ cells and stem cells, and is generally absent in normal cells. The loss of telomeres is an important tumor suppressor mechanism that is commonly absent in transformed malignant cells, and hence, T-oligos have garnered significant interest as a novel strategy to combat cancer. However, little is known about their mechanism of action. In this review, we discuss the current understanding of how T-oligos exert their antiproliferative effects in cancer cells and their role in inhibition of telomerase. We also discuss the current understanding of telomerase in cancer and various therapeutic targets related to the telomeres and telomerase.

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