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Association of Marine Omega-3 Fatty Acid Levels With Telomeric Aging in Patients With Coronary Heart Disease
Abstract
Increased dietary intake of marine omega-3 fatty acids is associated with prolonged survival in patients with coronary heart disease. However, the mechanisms underlying this protective effect are poorly understood.
To investigate the association of omega-3 fatty acid blood levels with temporal changes in telomere length, an emerging marker of biological age.
Prospective cohort study of 608 ambulatory outpatients in California with stable coronary artery disease recruited from the Heart and Soul Study between September 2000 and December 2002 and followed up to January 2009 (median, 6.0 years; range, 5.0-8.1 years).
We measured leukocyte telomere length at baseline and again after 5 years of follow-up. Multivariable linear and logistic regression models were used to investigate the association of baseline levels of omega-3 fatty acids (docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]) with subsequent change in telomere length.
Individuals in the lowest quartile of DHA+EPA experienced the fastest rate of telomere shortening (0.13 telomere-to-single-copy gene ratio [T/S] units over 5 years; 95% confidence interval [CI], 0.09-0.17), whereas those in the highest quartile experienced the slowest rate of telomere shortening (0.05 T/S units over 5 years; 95% CI, 0.02-0.08; P < .001 for linear trend across quartiles). Levels of DHA+EPA were associated with less telomere shortening before (unadjusted beta coefficient x 10(-3) = 0.06; 95% CI, 0.02-0.10) and after (adjusted beta coefficient x 10(-3) = 0.05; 95% CI, 0.01-0.08) sequential adjustment for established risk factors and potential confounders. Each 1-SD increase in DHA+EPA levels was associated with a 32% reduction in the odds of telomere shortening (adjusted odds ratio, 0.68; 95% CI, 0.47-0.98).
Among this cohort of patients with coronary artery disease, there was an inverse relationship between baseline blood levels of marine omega-3 fatty acids and the rate of telomere shortening over 5 years.
... The cornerstone of studies on the impact of omega-3 fatty acids on telomere length was the work of Farzaneh-Far et al. [47]. They examined cohort studies of more than 600 patients with coronary artery disease (CAD), which showed strong evidence for an association between omega-3 fatty acid consumption and telomere length, and more precisely, an inverse relationship between the baseline blood levels of omega-3 fatty acids (DHA and EPA) and changes in leukocyte telomere length over five years. ...
... They found no significant association between omega-3 fatty acid intake and telomere length. The two newest cross-sectional studies, published by Chinese groups, are in line with the work of Farzaneh-Far et al. [47]. Chang et al. [49] examined 711 patients with nested CAD and 638 CAD-free controls. ...
... A number of factors, such as ROS, nitric oxide, stress, hormones, growth factors, inflammation, socioeconomic status, lifestyle, and diet, have been suggested as putative telomere length modulators [89,97,98]. Thus, the pioneering work by Farzaneh-Far et al. [47]-indicating for the first time that among patients with stable CAD, there was an inverse relationship between the baseline blood levels of marine omega-3 fatty acids and the rate of telomere shortening over 5 years-contributed to the in-depth study of the role of omega-3 fatty acids and their effects on the aging of telomeres. Although the measurements were limited to the telomere length in leukocytes and did not necessarily reflect the telomere trajectory in other cellular compartments, such as the myocardium, endothelium, or atherosclerotic plaque, they showed that patients receiving omega-3 fatty acids had lower levels of C-reactive protein (CRP), low-density lipoprotein cholesterol (LDL-C), and IL-6, clearly demonstrating the anti-inflammatory role of DHA and EPA in coronary heart disease. ...
Telomeres are complexes consisting of tandem repeat DNA combined with associated proteins that play a key role in protecting the ends of chromosomes and maintaining genome stability. They are considered a biological clock, as they shorten in parallel with aging. Furthermore, short telomeres are associated with several age-related diseases. However, the variability in telomere shortening independent of chronological age suggests that it is a modifiable factor. In fact, it is regulated inter alia by genetic damage, cell division, aging, oxidative stress, and inflammation. A key question remains: how can we prevent accelerated telomere attrition and subsequent premature replicative senescence? A number of studies have explored the possible impact of omega-3 fatty acids on telomere shortening. This review summarizes published cross-sectional studies, randomized controlled trials, and rodent studies investigating the role of omega-3 fatty acids in telomere biology. It also covers a broad overview of the mechanism, currently favored in the field, that explains the impact of omega-3 fatty acids on telomeres—the food compound’s ability to modulate oxidative stress and inflammation. Although the results of the studies performed to date are not consistent, the vast majority indicate a beneficial effect of omega-3 fatty acids on telomere length.
... Although omega 3 supplementation seems to show benefit towards reducing inflammation [37][38][39], the level of omega 6 could mask the anti-inflammatory activity of omega 3 [27,29]. While some studies show a positive association between omega 3 and LTL [40][41][42], others have shown null findings [43,44]. Thus, omega 6:omega 3 ratio (omega 6:3 ratio) may be more informative than omega 3 levels alone. ...
... While the evidence linking the omega 6:3 ratio and LTL is limited [44], there is mixed evidence on the associations between omega 3 and LTL [40][41][42][43]. One of the randomized controlled trials reported no association between omega 3 and LTL and an inverse association between the omega 6:3 ratio and LTL [44]. ...
... One of the randomized controlled trials reported no association between omega 3 and LTL and an inverse association between the omega 6:3 ratio and LTL [44]. Other studies have shown a positive association between omega 3 and LTL in people living with cardiovascular diseases [40,42] and cognitive impairment [41]. Importantly, LTL is a downstream measure of biological and psychosocial stress influenced by the cellular inflammatory milieu. ...
Elevated inflammatory cytokines and chronic pain are associated with shorter leukocyte telomere length (LTL), a measure of cellular aging. Micronutrients, such as 25-hydroxyvitamin D (vitamin D) and omega 3, have anti-inflammatory properties. Little is known regarding the relationships between vitamin D, omega 6:3 ratio, LTL, inflammation, and chronic pain. We investigate associations between vitamin D, omega 6:3 ratio, LTL, and C-reactive protein (CRP) in people living with/without chronic pain overall and stratified by chronic pain status. A cross-sectional analysis of 402 individuals (63% women, 79.5% with chronic pain) was completed. Demographic and health information was collected. Chronic pain was assessed as pain experienced for at least three months. LTL was measured in genomic DNA isolated from blood leukocytes, and micronutrients and CRP were measured in serum samples. Data were analyzed with general linear regression. Although an association between the continuous micronutrients and LTL was not observed, a positive association between omega 6:3 ratio and CRP was detected. In individuals with chronic pain, based on clinical categories, significant associations between vitamin D, omega 6:3 ratio, and CRP were observed. Findings highlight the complex relationships between anti-inflammatory micronutrients, inflammation, cellular aging, and chronic pain.
... Presumably, it has been hypothesised that the intake of omega-3 PUFA from fish consumption might promote the maintenance of TL through its anti-inflammatory properties. Although the relationship between fish consumption and TL remains unclear, there seems to be evidence that supports the protective action of marine omega-3 PUFA against telomere attrition [14,[51][52][53][54][55]. ...
... Aside from the foods or food groups, other dietary intake factors that were positively associated with TL in the young population found in this review were PUFA and TAC [67]. According to available evidence, the positive effect of PUFA on TL was mainly due to the intake of omega-3 PUFA [14,[51][52][53][54][55]. Although PUFA may play a role in regulating gene expression implicated in metabolic alterations and chronic diseases [68], the association between omega-3 PUFA and TL cannot be firmly stated, let alone the influence of omega-6 PUFA or the role of overall PUFA intake concerning TL. ...
Environmental factors such as diet can affect telomere length (TL) dynamics. However, the role that children’s and adolescents’ diets play in maintaining TL is not well understood. Thus, we conducted a systematic review to examine the association between the intake of nutrients, foods, food groups, and/or dietary patterns and TL in childhood and adolescence. Following the PRISMA guidelines, we searched MEDLINE via PubMed, Embase, and Cochrane databases and additional registers and methods. The five selected studies were cross-sectional and conducted in children and adolescents aged 2 to 18 years. The main results suggest that a higher consumption of fish, nuts and seeds, fruits and vegetables, green leafy and cruciferous vegetables, olives, legumes, polyunsaturated fatty acids, and an antioxidant-rich diet might positively affect TL. On the contrary, a higher intake of dairy products, simple sugar, sugar-sweetened beverages, cereals, especially white bread, and a diet high in glycaemic load were factors associated with TL shortening. To our knowledge, this is the first systematic review examining the impact of dietary intake factors on TL in childhood and adolescence. Although limited, these results are consistent with previous studies in different adult populations. Further research is needed to ascertain potential nutritional determinants of TL in childhood and adolescence.
... This prompted a more detailed analysis of the literature, as no studies on the association between RLTL and LHON disease have been published to date. In the literature, an association between a genetically determined longer telomere length and an increased risk of certain oncological processes was observed [41], with lower stress levels, physical activity, a high-quality diet (e.g., with free ω-3 fatty acids, intake of some antioxidants, and low consumption of processed red meat), and adequate sleep associated with longer telomeres [42,43]. Studies of ocular structures showed that telomeres were longer in people with uveitis than in healthy controls (in cases of chronic inflammation) [17]. ...
... Another important question in the study was whether treatment with idebenone, a synthetic coenzyme Q10 analogue, could affect RLTL. In the literature, idebenone was reported to act as an antioxidant and inhibit the formation of excess ROS, and the use of some antioxidants was associated with longer telomeres [41,42]. Therefore, in this study, we wanted to determine whether there was a statistically significant difference in the RLTL of LHON patients who received blood before treatment with idebenone compared with other LHON patients treated with idebenone, but no statistically significant difference was found. ...
Background and Objectives: To evaluate the association of relative leukocyte telomere length (RLTL) and telomerase complex regulatory markers with Leber’s hereditary optic neuropathy (LHON). Material and Methods: A case-control study was performed in patients with LHON (≥18 years) and healthy subjects. The diagnosis of LHON was based on a genetic blood test (next-generation sequencing with Illumina MiSeq, computer analysis: BWA2.1 Illumina BaseSpace, Alamut, and mtDNA Variant analyzer 1000 were performed) and diagnostic criteria approved by the LHON disease protocol. Statistical analysis was performed using the standard statistical software package, IBM SPSS Statistics 27. Statistically significant results were considered when p < 0.05. Results: Significantly longer RLTL was observed in LHON patients than in healthy controls (p < 0.001). RLTL was significantly longer in women and men with LOHN than in healthy women and men in the control group (p < 0.001 and p = 0.003, respectively). In the elderly group (>32 years), RLTL was statistically significantly longer in LHON patients compared with healthy subjects (p < 0.001). The GG genotype of the TERC rs12696304 polymorphism was found to be statistically significantly higher in the LHON group (p = 0.041), and the C allele in the TERC rs12696304 polymorphism was found to be statistically significantly less common in the LHON group (p < 0.001). The RLTL of LHON patients was found to be statistically significantly longer in the TERC rs12696304 polymorphism in all tested genotypes (CC, p = 0.005; CG, p = 0.008; GG, p = 0.025), TEP1 rs1760904 polymorphism in the GA genotype (p < 0.001), and TEP1 gene rs1713418 in the AA and AG genotypes (p = 0.011 and p < 0.001, respectively). Conclusions: The RLTL in LHON patients was found to be longer than in healthy subjects regardless of treatment with idebenone. The TERC rs12696304 polymorphism, of all studied polymorphisms, was the most significantly associated with changes in LHON and telomere length.
... Age, sex, paternal age at birth and ethnicity are associated with LTL, but also account only for a small proportion of the inter-individual variation in LTL 7,10-14 . Even after taking these factors into account, several biological, behavioral and environmental characteristics correlate with, and potentially modify, LTL, including oxidative stress, inflammation, obesity, smoking, physical activity and dietary intake [15][16][17][18] . It remains uncertain, however, whether they are correlates or causative determinants. ...
... Compared to white Europeans, mean LTL was longer in people of Black, Chinese and mixed ancestries (Extended Data Fig. 9). Adjusting for traits that have previously been associated with LTL and that differ by ethnicity 14,16,18,[31][32][33][34][35] (Supplementary Table 1) had minimal effect on the observed ethnic differences in LTL (Extended Data Fig. 9). Within each ethnic group, we observed similar relationships of shorter LTL with older age and male sex ( Table 4) to those reported overall, with somewhat steeper associations with age in Black participants (Table 4 and Extended Data Fig. 10). ...
Leukocyte telomere length (LTL) is a proposed marker of biological age. Here we report the measurement and initial characterization of LTL in 474,074 participants in UK Biobank. We confirm that older age and male sex associate with shorter LTL, with women on average ~7 years younger in ‘biological age’ than men. Compared to white Europeans, LTL is markedly longer in African and Chinese ancestries. Older paternal age at birth is associated with longer individual LTL. Higher white cell count is associated with shorter LTL, but proportions of white cell subtypes show weaker associations. Age, ethnicity, sex and white cell count explain ~5.5% of LTL variance. Using paired samples from 1,351 participants taken ~5 years apart, we estimate the within-individual variability in LTL and provide a correction factor for this. This resource provides opportunities to investigate determinants and biomedical consequences of variation in LTL. The authors measured blood cell telomere length in 474,074 participants of UK Biobank providing a major resource for assessing the role of this proposed marker of biological age in human health and disease.
... It has been reported that TL in the offspring is positively related to folate, vitamin D, and caffeine concentrations in maternal diet (24), but negatively related to maternal saturated fat intake during pregnancy and prepregnancy BMI (25,26). In addition, n-3 polyunsaturated fatty acids (n-3 PUFAs) may be a factor that prevents telomere shortening in cell division, for which they have anti-inflammatory and anti-oxidative effects, particularly, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) (27)(28)(29). However, few studies have investigated the correlation between maternal n-3 PUFAs and telomeres in newborns and after birth. ...
... Furthermore, we found that maternal concentrations of DHA and total n-3 PUFAs were positively associated with DNA methylation fractions of the TERT promoter in cord blood cells, and thus influencing TL. This suggests that the mechanisms by which n-3 PUFAs affect TL may reside in both their functions in epigenetic modification and their anti-inflammatory or anti-oxidative stress effects (27)(28)(29). To note, no significant associations of the TERT promoter methylation with TL in the placenta were found in our study, indicating that TL in the placenta might be primarily influenced by inflammation or oxidation instead of the TERT methylation and associated telomerase activity, which are in higher levels in late pregnancy (56). ...
Few studies have investigated the correlation between maternal polyunsaturated fatty acids (PUFAs) and telomeres in offspring, and the underlying influential mechanisms. In this study, we assessed the associations of maternal PUFAs with telomere length (TL) and DNA methylation of the telomerase reverse transcriptase (TERT) promoter in the cord blood and the placenta. A total of 274 pregnant women and their newborn babies were enrolled in this study. Maternal blood before delivery, the cord blood, and the placenta at birth were collected. Fatty acids in maternal erythrocytes and cord blood cells were measured by gas chromatography (GC). TL in the cord blood and the placenta was determined using real-time quantitative PCR (qPCR) by calculating the product ratio of telomeric DNA to the single-copy gene β-globin. The TERT promoter methylation was analyzed by DNA bisulfite sequencing. The associations of maternal fatty acids with TL were analyzed by univariate and multivariate regression. We found that low concentrations of docosapentaenoci acid (DPA, C22: 5n-3) and total n-3 PUFAs, adrenic acid (ADA, C22: 4n-6), and osbond acid (OA, C22: 5n-6) and high concentrations of linoleic acid (LA, C18: 2n-6) in maternal erythrocytes were associated with the shortened TL in cord blood cells (estimated difference in univariate analysis −0.36 to −0.46 for extreme quintile compared with middle quintile), and that low concentrations of cord blood docosahexaenoic acid (DHA, C22: 6n-3) were related to the shortened TL in cord blood cells. Differently, high concentrations of α-linolenic acid (LNA, C18: 3n-3), eicosatrienoic acid (EA, C20: 3n-3), DHA, and γ-linoleic acid (GLA, C18:3n-6) in maternal erythrocytes were associated with the shortened TL in the placenta (estimated difference in univariate analysis −0.36 to −0.45 for higher quintiles compared with the middle quintile). Further examination demonstrated that the concentrations of DHA and total n-3 PUFAs in maternal erythrocytes had positive associations with DNA methylation of the TERT promoter in the cord blood instead of the placenta. These data suggest that maternal PUFAs are closely correlated to infant TL and the TERT promoter methylation, which are differently affected by maternal n-3 PUFAs between the cord blood and the placenta. Therefore, keeping higher levels of maternal n-3 PUFAs during pregnancy may help to maintain TL in the offspring, which is beneficial to long-term health.
... Telomere attrition has also been linked with other potentially modifiable lifestyle factors, such as poor nutrition and physical inactivity, indicating the plasticity of TL [37,38]. Findings from different studies show that a healthy diet, low stress, exercise, and a good sleep pattern are related to longer telomeres [39,40]. In the absence of direct evidence, the positive correlation between sperm telomere length (STL) and sperm DNA fragmentation in young individuals may be due to the activation of telomerase by a low-level adverse factor, such as mild OS, which causes genomic damage in addition to STL extension [41][42][43]. ...
Background: Telomere attrition and mitochondrial dysfunction are two fundamental aspects of aging. Calorie restriction (CR) is the best strategy to postpone aging since it can enhance telomere attrition, boost antioxidant capacity, and lower the generation of reactive oxygen species (ROS). Since ROS is produced by mitochondria and can readily travel to cell nuclei, it is thought to be a crucial molecule for information transfer between mitochondria and cell nuclei. Important variables that affect the quality and functionality of sperm and may affect male reproductive health and fertility include telomere length, mitochondrial content, and the ratio of mitochondrial DNA (mtDNA) to nuclear DNA (nDNA). Telomere damage results from mitochondrial failure, whereas nuclear DNA remains unaffected. This research aims to investigate potential associations between these three variables and how they might relate to body mass index. Methods: Data were collected from 82 men who underwent IVF/ICSI at the University Hospital of Ioannina’s IVF Unit in the Obstetrics and Gynecology Department. Evaluations included sperm morphology, sperm count, sperm motility, and participant history. To address this, male participants who were categorized into three body mass index (ΒΜΙ) groups—normal, overweight, and obese—had their sperm samples tested. Results: For both the normal and overweight groups, our results show a negative connection between relative telomere length and ΒΜI. As an illustration of a potential connection between mitochondrial health and telomere maintenance, a positive correlation was found for the obese group. Only the obese group’s results were statistically significant (p < 0.05). More evidence that longer telomeres are associated with lower mitochondrial content can be found in the negative connection between telomere length and mitochondrial content in both the normal and overweight groups. However, the obese group showed a positive association. The data did not reach statistical significance for any of the three groups. These associations may affect sperm quality since telomere length and mitochondrial concentration are indicators of cellular integrity and health. Moreover, the ratio of mtDNA to nDNA was positively correlated with the relative telomere lengths of the obese group, but negatively correlated with the normal and overweight groups. In every group that was studied, the results were not statistically significant. According to this, male fertility may be negatively impacted by an imbalance in the copy number of the mitochondrial genome compared to the nuclear DNA in sperm. Conclusions: Essentially, the goal of our work is to determine whether mitochondria and telomere length in human sperm interact. Understanding these connections may aid in the explanation of some male infertility causes and possibly contribute to the creation of new treatment modalities for problems pertaining to reproductive health. The functional implications of these connections and their applications in therapeutic settings require further investigation.
... [89][90][91][92] In patients with exposure to coal or silica dust, changes in DNA methylation may contribute to dust-induced lung injury and subsequent fibrosis [93]. Other environmental factors such as smoking [94,95], diet [96][97][98], ambient fine particulate matter (diameter ≤2.5 µm) and environmental air pollutants [99,100], exposure to organic dust and certain inorganic compounds [101,102], have been associated with both risk and progression of PF. Notably, recent studies have investigated the influence of genetic risk factors and environmental exposures together in both early and later disease stages [103]. ...
... There is evidence that dietary fatty acids may hasten aging [8,9]. However, some studies have demonstrated that some fatty acids (e.g., Omega-3 [10,11], non-long-chain saturated fatty acids [12,13], and lower n-6:n-3 PUFA ratios [14], etc.) may mitigate aging. A definitive connection between fatty acids and the aging process has yet to be established [12]. ...
Background:
Observational studies have previously shown a possible link between fatty acids and aging-related diseases, raising questions about its health implications. However, the causal relationship between the two remains uncertain.
Methods:
Univariable and multivariable Mendelian randomization (MR) was used to analyze the relationship between five types of fatty acids-polyunsaturated fatty acid (PUFA), monounsaturated fatty acid (MUFA), saturated fatty acid (SFA), Omega-6 fatty acid (Omega-6 FA), and Omega-3 fatty acid (Omega-3 FA) and three markers of aging: telomere length (TL), frailty index (FI), and facial aging (FclAg). The primary approach for Mendelian randomization (MR) analysis involved utilizing the inverse variance weighted (IVW) method, with additional supplementary methods employed.
Results:
Univariate MR analysis revealed that MUFA, PUFA, SFA, and Omega-6 fatty acids were positively associated with TL (MUFA OR: 1.019, 95% CI: 1.006-1.033; PUFA OR: 1.014, 95% CI: 1.002-1.026; SFA OR: 1.016, 95% CI: 1.002-1.031; Omega-6 FAs OR=1.031, 95% CI: 1.006-1.058). PUFA was also associated with a higher FI (OR: 1.033, 95% CI: 1.009-1.057). In multivariate MR analysis, after adjusting for mutual influences among the five fatty acids, MUFA and PUFA were positively independently associated with TL (MUFA OR: 1.1508, 95% CI = 1.0724-1.2350; PUFA OR: 1.1670, 95% CI = 1.0497-1.2973, while SFA was negatively correlated (OR: 0.8005, 95% CI: 0.7045-0.9096).
Conclusions:
Our research presents compelling evidence of a causal association between certain fatty acids and indicators of the aging process. In particular, MUFA and PUFA may play a role in slowing down the aging process, while SFAs may contribute to accelerated aging. These findings could have significant implications for dietary recommendations aimed at promoting healthy aging.
... The proposed mechanisms underlying these observations include the ability of omega-3s to reduce oxidative stress and systemic inflammation. Moreover, omega-3 fatty acids might modulate the activity of telomerase, and thereby extending telomeric DNA (Farzaneh-Far et al., 2010). O'Callaghan et al. (2014) investigated the potential of omega-3 fatty acid supplementation to attenuate telomere shortening in elderly individuals with mild cognitive impairment. ...
Average life expectancy has been steadily increasing in developed countries worldwide. These demographic changes are associated with an ever-growing social and economic strain to healthcare systems as well as society. The aging process typically manifests as a decline in physiological and cognitive functions, accompanied by a rise in chronic diseases. Consequently, strategies that both mitigate age-related diseases and promote healthy aging are urgently needed. Telomere attrition, characterized by the shortening of telomeres with each cell division, paradoxically serves as both a protective mechanism and a contributor to tissue degeneration and age-related ailments. Based on the essential role of telomere biology in aging, research efforts aim to develop approaches designed to counteract telomere attrition, aiming to delay or reduce age-related diseases. In this review, telomere biology and its role in aging and age-related diseases is summarized along with recent approaches to interfere with telomere shortening aiming at well- and healthy-aging as well as longevity. As aging research enters a new era, this review emphasizes telomere-targeting therapeutics, including telomerase activators and tankyrase inhibitors, while also exploring the effects of antioxidative and anti-inflammatory agents, along with indirectly related approaches like statins.
... The study that reported to regulate the rate of telomere shortening, including certain dietary factors, sleep, stress, and exercise. Here are a few that have been shown to slow telomere shortening, for examples, i) routine and vigorous exercise (Werner et al., 2009) (Du et al., 2012), ii) healthful diet including sufficient omega-3 fats (Farzaneh-Far et al., 2010), iv) multivitamins, particularly vitamin C and vitamin E (Qun et al., 2009), and v) stress reduction and sufficient sleep ). However, individual is different, and it isn't currently known what levels of these different factors are right for each person. ...
The old-age populations are increasing in number in virtually every country. Identifying reliable biological indicators of virtual aging is a key objective in geroscience. Telomeres, the DNA-protein structures located at the ends of chromosomes, have been convincingly proposed a biomarker of aging. Epidemiologic studies show an association between telomere length (TL) in leukocyte and aging. This study investigated TL in blood leukocytes and cells in saliva samples of 108 healthy Thai population at various age ranges. Subjects were divided into four groups (I:21-40 years, II:41-60 years, III:61-80 years and IV:80 years up), The extracted DNA was analysed for TL by qPCR. The mean length of the telomere were found statistically significant different among age groups and decrease with increasing age (p-value < 0.05) in both blood and saliva samples. The means of TL in I, II, III, and IV in blood were 1.03±0.016, 0.92±0.022, 0.82±0.028, and 0.56±0.100, respectively; whereas in saliva were 1.07±0.021, 0.95±0.022, 0.82±0.028, and 0.59±0.040, respectively. In addition, the relationship of TL in blood and saliva was R = 0.418, p-value = 0.00. The preliminary results demonstrated consistent telomere length measurements in saliva as an alternative peripheral source compared to blood. Saliva could be considered as a non-invasive and as a reliable source of DNA for measuring telomere length. __________________________________________________
... As an essential dietary component, n-3 PUFAs, due to their unique biochemical properties, may influence telomere biology. The study by Farzaneh-Far et al. [42] has laid a critical foundation for our understanding of the impact of n-3 PUFAs on TL. They conducted a prospective study involving 608 patients with stable coronary artery disease. ...
(1) Background: The relationship between lipids, apolipoproteins, and telomere length (TL) has been explored in previous studies; however, the causal relationship between the two remains unclear. This study aims to assess the causal relationship between lipids, apolipoproteins, and TL using the two-sample Mendelian randomization (MR) approach; (2) Methods: This study comprehensively employed both univariate MR (uvMR) and multivariate MR (mvMR) methods to genetically evaluate the associations between 21 exposures related to lipids and apolipoproteins and the outcome of TL. During the analysis process, we utilized various statistical methods, including Inverse Variance Weighting (IVW), Weighted Median, MR-Egger regression, MR-PRESSO, and outlier tests. Furthermore, to confirm the robustness of the results, we conducted several sensitivity analyses to explore potential heterogeneity; (3) Results: The uvMR analysis indicated that an increase in MUFA, MUFA/FA ratio, LDL-C, VLDL-C, total cholesterol, ApoB, and triglycerides (TG) was associated with an increase in TL. However, this relationship did not manifest in the mvMR analysis, suggesting that this association may be based on preliminary evidence; (4) Conclusions: MR analysis results suggest potential suggestive positive causal relationships between genetically predicted MUFA, MUFA/FA ratio, LDL-C, VLDL-C, total cholesterol, ApoB, and TG with TL.
... Omega-3 yağ asitlerinin antiinflamatuvar ve antioksidan etkilerinin hücre dönüşümünü ve DNA hasarını önleyerek telomerleri korumuş olabileceği belirtilmiştir (41). ...
Telomer uzunluğu yaşlanma ile ilişkili olduğu bilinen, genetik ve çevresel faktörlerden etkilenen bir biyogöstergeçtir. Telomer uzunluğunun belirlenmesinde etkili olan en önemli faktörlerden biri olan beslenme bir çevresel faktör olarak karşımıza çıkmaktadır. Oksidasyon ve inflamasyon süreçlerini etkileyerek telomerlerin uzamasına veya kısalmasına yol açabilmektedir. Anti-inflamatuvar olduğu bilinen tam tahıllar, yağlı tohumlar ile antioksidan bakımından yüksek içeriğe sahip meyveler ve sebzeler, antioksidan özelliği olan vitaminler, mineraller ve polifenoller telomerlerin uzamasına veya korunmasına yardımcı olabilirler. İnflamasyonu ve oksidasyonu arttırabilen bazı besin grupları ve besin öğeleri ise telomerlerin kısalmasına yol açabilmektedir. Bu derlemenin amacı beslenme ve telomer uzunluğunun ilişkisi ve telomerleri etkileyen potansiyel mekanizmaları incelemektir. Tam tahıllarda bulunan posa ve biyolojik aktif bileşenler, sebze ve meyvelerde bulunan antioksidanlar ve balıkta bulunan omega-3 gibi bileşenler telomerlerin uzamasına yardımcı olurken, özellikle işlenmiş ette bulunan nitrat ve nitrit gibi bileşenler telomerlerin kısalmasına yol açmaktadır. Telomer uzunluğunun diyetsel faktörler açısından korunmasında meyve ve sebzeden zengin, uygun seviyelerde kurubaklagil ve kuruyemiş içeren, kırmızı et bakımından sınırlı ve sağlıklı yağlar içeren bir diyet tüketimi oldukça önemlidir.
... Farzaneh-Far et al. indicated an inverse relationship between the baseline blood levels of n-3 PUFAs and the rate of telomere shortening over 5 years for the first time [31]. Following this pioneer work, lower DHA level was found to be associated with shorter telomere length and increased disease risk in a study of preschool children with obesity and their lean controls [32] and a nested case-control study of coronary artery disease in the Singapore Chinese Health Study [33]. ...
Purpose
Previous evidence indicated anti-ageing potential of docosahexaenoic acid (DHA), but the underlying mechanism remains unclear. We investigated protective effect of DHA on telomere attrition and lipid disturbance in male mice with premature ageing caused by telomerase deficiency.
Methods
Wild-type (WT) and fourth-generation telomerase-deficient (G4 Terc−/−, Terc knockout, KO) male mice (C57BL/6, 2 months old) were fed control diet (WT-C and KO-C groups) or DHA-enriched diet containing 0.80% DHA by weight (WT-DHA and KO-DHA groups) for 10 months. The ageing phenotypes and metabolic level [carbon dioxide emission, oxygen consumption, and respiratory exchange ratio (RER)] were assessed at the end of the experiment. Telomere length in various tissues and the hepatic gene and protein expression for regulating lipid synthesis and lipolysis were measured. Data were tested using one- or two-factor ANOVA.
Results
In KO male mice, DHA prevented weight loss, corrected high RER, and reduced fat loss. Telomere shortening was reduced by 22.3%, 25.5%, and 13.5% in heart, liver, and testes of the KO-DHA group compared with those in the KO-C group. The KO-DHA group exhibited higher gene transcription involved in glycerol-3-phosphate pathway [glycerol-3-phosphate acyltransferase (Gpat)], lower gene expression of β-oxidation [carnitine palmitoyltransferase 1a (Cpt1a)], and upregulation of proteins in lipid synthesis [mammalian target of rapamycin complex 1 (mTORC1) and sterol responsive element binding protein 1 (SREBP1)] in liver than the KO-C group.
Conclusion
Long-term DHA intervention attenuates telomere attrition and promotes lipid synthesis via the tuberous sclerosis complex 2 (TSC2)-mTORC1-SREBP1 pathway in KO male mice.
... In a study by Farzaneh-Far et al. (119), it was discovered that telomere shortening is associated with a diet high in antioxidant omega-3 fatty acids, and is also associated with a diet deficient in these antioxidants. The length of the telomere and blood levels of omega-3 fatty acids in these individuals were tracked by the researchers over a five-year period. ...
Prior research has substantiated the vital role of telomeres in human fertility. Telomeres are prerequisites for maintaining the integrity of chromosomes by preventing the loss of genetic material following replication events. Little is known about the association between sperm telomere length and mitochondrial capacity involving its structure and functions. Mitochondria are structurally and functionally distinct organelles that are located on the spermatozoon's midpiece. Mitochondria produce adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS), which is necessary for sperm motility and generate reactive oxygen species (ROS). While a moderate concentration of ROS is critical for egg—sperm fusion, and fertilization, excessive ROS generation is primarily related to telomere shortening, sperm DNA fragmentation, and alterations in the methylation pattern leading to male infertility. This review aims to highlight the functional connection between mitochondria biogenesis and telomere length in male infertility, as mitochondrial lesions have a damaging impact on telomere length, leading both to telomere lengthening and reprogramming of mitochondrial biosynthesis. Furthermore, it aims to shed light on how both inositol and antioxidants can positively affect male fertility.
... Interestingly, the incidence of telomere shortening over 5 years in patients with coronary artery disease was shown to be inversely correlated with baseline blood levels of marine n-3 PUFAs in an intriguing prospective cohort study by (Farzaneh-Far, 2010). Telomeric attrition, a form of DNA . ...
Radiation is associated with inflammation and oxidative stress, the latter of which contributes to activation of DNA damage and apoptosis. Omega 3 polyunsaturated fatty acids (PUFAs) have been reported to limit oxidative stress and DNA damage. The aim of this study was to evaluate the effect of the Omega 3 PUFA on antioxidant defence in male physiology on mice model. Liver and kidney tissues were obtained from whole body irradiated mice divided under 9 groups (Weight-10mg, 6-8 months old, n=5) and age- matched male controls (6-8 months old, n=5). 6 groups have been orally intubated with (50, 100 and 150) mg/kg BW with Omega 3 fish oil 1hr prior to the radiation exposure. Liver and kidney were surgically obtained after 24 hours and 30 days of radiation exposure. Omega 3 fish oil supplementation increased the level of mRNA expression of Lef1, Axin2, Survivin, Ku70, SOD1, SOD2, Cat, iNOS and decresed the level of Bax and Bcl2 in irradiated with omega 3 fish oil supplementation compare to irradiated alone. Omega 3 fish oil increased SOD scavenging, Catalase, Nitric oxide scavenging activity, Total antioxidant capacity and decrease the lipid peroxidation. The improvements in mRNA level of candidate genes of Wnt canonical pathway, NHEJ pathway, oxidative stress status serve as a stimulus for further investigation of Omega 3 fish oil as supplementation for patients undergo radiation therapy.
... Higher n-3 PUFA levels of red blood cells are associated with a reduced risk of all-cause mortality [26,27]. The intake of n-3 PUFA is also inversely related to the rate of telomere shortening, an important marker of cell aging [28][29][30]. In addition, lower levels of EPA and DHA are linked with an increased risk of cognitive impairment and dementia, making them a potential marker of brain aging [19,21,31,32]. ...
Long-lived individuals (LLIs) are considered an ideal model to study healthy human aging. Blood fatty acid (FA) profile of a cohort of LLIs (90–111 years old, n = 49) from Sicily was compared to adults (18–64 years old, n = 69) and older adults (65–89 years old, n = 54) from the same area. Genetic variants in key enzymes related to FA biosynthesis and metabolism were also genotyped to investigate a potential genetic predisposition in determining the FA profile. Gas chromatography was employed to determine the FA profile, and genotyping was performed using high-resolution melt (HRM) analysis. Blood levels of total polyunsaturated FA (PUFA) and total trans-FA decreased with age, while the levels of saturated FA (SFA) remained unchanged. Interestingly, distinctively higher circulatory levels of monounsaturated FA (MUFA) in LLIs compared to adults and older adults were observed. In addition, among LLIs, rs174537 in the FA desaturase 1/2 (FADS1/2) gene was associated with linoleic acid (LA, 18:2n-6) and docosatetraenoic acid (DTA, 22:4n-6) levels, and the rs953413 in the elongase of very long FA 2 (ELOVL2) was associated with DTA levels. We further observed that rs174579 and rs174626 genotypes in FADS1/2 significantly affect delta-6 desaturase (D6D) activity. In conclusion, our results suggest that the LLIs have a different FA profile characterized by high MUFA content, which indicates reduced peroxidation while maintaining membrane fluidity.
... In recent years, the impact of nutritional status on telomere health is under scrutiny that nutrient intake like n-3 polyunsaturated fatty acids (PUFAs) and other antioxidant nutrients were positively associated with TL via the interaction between telomerase activity and aging-related molecular signals based on telomere biology (O'Callaghan et al. 2014;Galiè et al. 2020). It is likely that circulating n-3 PUFAs are positively associated with TL in MetS over time (Farzaneh-Far et al. 2010;Chang et al. 2020). n-3 PUFAs, which are popularly known as functional lipids, have widely been reported to restore metabolic abnormality, insulin resistance, inflammatory response, hypertension, atherogenic dyslipidemia, and coronary heart dysfunction (Brayner et al. 2018;Bidu et al. 2018;Brown et al. 2019;Hall 2017). ...
Metabolic syndrome (MetS), a cluster of metabolic abnormalities composed of central obesity, elevated blood pressure, glucose disturbances, hypercholesterolemia and dyslipidaemia, has increasingly become a public health problem in the 21st century worldwide. The dysfunction of telomeres, the repetitive DNA with highly conserved sequences (5′-TTAGGG-3′), is remarkably correlated with organismal aging, even suggesting a causal relationship with metabolic disorders. The health benefits of n-3 polyunsaturated fatty acids (PUFAs) in multiple disorders are associated with telomere length in evidence, which have recently drawn wide attention. However, functional targets and pathways for the associations of n-3 PUFAs and telomere with MetS remain scare. Few studies have summarized the role of n-3 PUFAs in DNA damage repair pathways, anti-inflammatory pathways, and redox balance, linking with telomere biology, and other potential telomere-related signaling pathways. This review aims to (i) elucidate how n-3 PUFAs ameliorate telomere attrition in the context of anti-oxidation and anti-inflammation; (ii) unravel the role of n-3 PUFAs in modulating telomere-related neuron dysfunction and regulating the neuro-endocrine-immunological network in MetS; (iii) epidemiologically implicate the associations of metabolic disorders and n-3 PUFAs with telomere length; and (iv) suggest promising biochemical approaches and advancing methodologies to overcome the inter-variation problem helpful for future research.
... Individuals with the largest increase in concentrations of erythrocyte DHA showed the smallest decrease in telomere length over the intervention period of 6 mo among the DHA group, unlike other treatment groups with EPA or LA (27). In addition, a 5-y longitudinal followup study in 608 ambulatory outpatients (82.1% males, 59.5% whites) found that each 1-SD increase in blood concentrations of marine n-3 was associated with a 32% reduction in the odds of telomere shortening (28). It is plausible that the different strengths of the associations may be partially attributable to our use of the data on DHA dietary intake, instead of blood DHA concentrations denoting its dietary bioavailability, biosynthesis from ALA, and potential anti-inflammatory biological status. ...
Background:
Omega-3 (n-3) and omega-6 (n-6) fatty acids may contribute to oxidative stress and inflammation, which are related to telomere shortening. Evidence supporting an association between intake of n-3 or n-6 fatty acids and leukocyte telomere length (LTL) in males has been limited.
Objective:
We conducted a cross-sectional study to examine the associations of total or individual n-3 or total n-6 fatty acid intake with LTL in US males.
Methods:
We included 2,494 US males with LTL measurement from 4 nested case-control studies within the Health Professionals Follow-up Study. Individuals with previous histories of cancers, diabetes, and cardiovascular diseases at or prior to blood collection were excluded. Blood collection was performed between 1993 and 1995, and relevant information including n-3 and n-6 intake was collected in 1994 by questionnaire. The LTL was log-transformed and Z scores of the LTL were calculated for statistical analyses by standardizing the LTL in comparison with the mean within each selected nested case-control study.
Results:
We found that consumption of docosahexaenoic acid (DHA) was positively associated with LTL. In the multivariable-adjusted model, compared to individuals who had the lowest intake of DHA (i.e., first quartile group), the percentage differences [95% confidence intervals (CIs)] of LTL were -3.7 (-13.7, 7.5), 7.0 (-4.3, 19.7), and 8.2 (-3.5, 21.3) for individuals in the second, third, and fourth quartiles of consumption, respectively (P for trend = 0.0498). We did not find significant associations between total n-3 or total n-6 fatty acid intakes and LTL. Additionally, we found that males who consumed canned tuna had longer LTL than those who did not; in the multivariable-adjusted model, the percentage difference (95% CI) of LTL was 10.5 (1.3, 20.4) (P value = 0.02).
Conclusions:
Our results suggest that higher intakes of DHA and canned tuna consumption are associated with longer LTL.
... For example, a recent clinical trial has documented that consumption of marine n-3 PUFAs in subjects with renal transplantation reduces the risk of cellular senescence and SASP damage thereby resulting in improved recovery (Chan et al., 2021). Consumption of omega-3fatty acids has been associated with decreased replicative senescence in human immune cells by preserving their telomere length (Farzaneh-Far et al., 2010;Kiecolt-Glaser et al., 2013). Supplementation of omega-3-fatty acids for 4 months in middle-aged subjects resulted in maintenance of telomerase activity while attenuating markers of stress and inflammation (Madison et al., 2021). ...
The process of cellular senescence is rapidly emerging as a modulator of organismal aging and disease. Targeting the development and removal of senescent cells is considered a viable approach to achieving improved organismal healthspan and lifespan. Nutrition and health are intimately linked and an appropriate dietary regimen can greatly impact organismal response to stress and diseases including during aging. With a renewed focus on cellular senescence, emerging studies demonstrate that both primary and secondary nutritional elements such as carbohydrates, proteins, fatty acids, vitamins, minerals, polyphenols, and probiotics can influence multiple aspects of cellular senescence. The present review describes the recent molecular aspects of cellular senescence-mediated understanding of aging and then studies available evidence of the cellular senescence modulatory attributes of major and minor dietary elements. Underlying pathways and future research directions are deliberated to promote a nutrition-centric approach for targeting cellular senescence and thus improving human health and longevity.
... There is only one prospective study that investigated the association of fatty acids with telomere length. In this study, the Heart and Soul study, increased intake of omega-3 fatty acids (EPA, DHA), over a 6-year period, was associated with a significantly reduced rate of telomere shortening (Farzaneh-Far et al., 2010). Further details of the above studies are provided in Table 2.1. ...
There is much interest on the impact of nutrition on integrity of the genome and its stability because of the deleterious health consequences of DNA damage. One of the main components of the genome is telomeres which are TTAGGG repeats at the ends of chromosomes which are essential for maintenance of chromosome stability by preventing telomere end fusions. This important function of telomeres is impaired when either the telomere sequence length becomes critically shortened or if it is damaged by adducts caused by reactive metabolites. Several studies have explored the association of fatty acids with telomere length in humans but, so far, no clear picture has emerged regarding whether specific dietary fatty acids have a substantially significant impact on telomere integrity and function. Furthermore, knowledge on potential mechanisms is speculative due to a paucity of well-designed studies and great heterogeneity between studies. We provide some suggestions on improving observational and randomized controlled study design to make progress in this field.
... The association of higher oily fish intake with longer LTL is notable because a previous longitudinal study showed that higher intake of marine omega-3 fatty acids was independently associated with a lower rate of telomere shortening over 5 years, 25 suggesting a possible causal association. Using mendelian randomisation analysis, we have recently reported that the association of brisk walking pace with longer LTL is also likely to be causal. ...
Background
Telomere length is associated with risk of several age-related diseases and cancers. We aimed to investigate the extent to which telomere length might be modifiable through lifestyle and behaviour, and whether such modification has any clinical consequences.
Methods
In this population-based study, we included participants from UK Biobank who had leukocyte telomere length (LTL) measurement, ethnicity, and white blood cell count data. We investigated associations of LTL with 117 potentially modifiable traits, as well as two indices of healthy behaviours incorporating between them smoking, physical activity, diet, maintenance of a healthy bodyweight, and alcohol intake, using both available and imputed data. To help interpretation, associations were summarised as the number of equivalent years of age-related change in LTL by dividing the trait β coefficients with the age β coefficient. We used mendelian randomisation to test causality of selected associations. We investigated whether the associations of LTL with 22 diseases were modified by the number of healthy behaviours and the extent to which the associations of more healthy behaviours with greater life expectancy and lower risk of coronary artery disease might be mediated through LTL.
Findings
422 797 participants were available for the analysis (227 620 [53·8%] were women and 400 036 [94·6%] were White). 71 traits showed significant (p<4·27 × 10–4) associations with LTL but most were modest, equivalent to less than 1 year of age-related change in LTL. In multivariable analyses of 17 traits with stronger associations (equivalent to ≥2 years of age-related change in LTL), oily fish intake, educational attainment, and general health status retained a significant association of this magnitude, with walking pace and current smoking being additionally significant at this level of association in the imputed models. Mendelian randomisation analysis suggested that educational attainment and smoking behaviour causally affect LTL. Both indices of healthy behaviour were positively and linearly associated with LTL, with those with the most healthy behaviours having longer LTL equivalent to about 3·5 years of age-related change in LTL than those with the least heathy behaviours (p<0·001). However, healthy behaviours explained less than 0·2% of the total variation in LTL and did not significantly modify the association of LTL with risk of any of the diseases studied. Neither the association of more healthy behaviours on greater life expectancy or lower risk of coronary artery disease were substantially mediated through LTL.
Interpretation
Although several potentially modifiable traits and healthy behaviours have a quantifiable association with LTL, at least some of which are likely to be causal, these effects are not of a sufficient magnitude to substantially alter the association between LTL and various diseases or life expectancy. Attempts to change telomere length through lifestyle or behavioural changes might not confer substantial clinical benefit.
Funding
UK Medical Research Council, UK Biotechnology and Biological Sciences Research Council, and British Heart Foundation.
... In addition, microalgae are used to make fatty acid or omega-3 fatty acid. Marine fatty acids, especially EPA and DHA, have long been utilized to treat heart problems (Farzaneh-Far et al. 2010) and cancer (Patterson et al. 2011). ...
The marine ecosystem is a unique and complicated system that is characterized primarily by the great biodiversity, representing the richness of diverse habitats and the variations of life forms. It involves various marine organisms with great chemical diversity, and they are rich sources of secondary metabolites relative to terrestrial organisms. The oceans thus always offer excellent opportunities for discovering valuable materials from various organisms. Such compounds contain a wide range of chemical structures and functions, which for more specific potentialities are wider. The produced compounds have a vital role in the human and animal life and are widely used as antimicrobial, antioxidants, antiviral, anticancer, and food and feed and in food and pharmaceuticals industry. However, in many fields such as food, cosmetics, dietary supplements, animal feed, bioactive packaging, and industrial products, as well as in high-tech biomedical sectors, applications of novel marine molecules are now found.
... 12,29 However, several studies have shown that lifestyle factors including smoking, diet, physical activity and body mass index also associate with LTL. [30][31][32][33][34] Furthermore, there is evidence from animal studies that restoration of telomere length can reverse age-related phenotypes. 35 Therefore, if the relationship between shorter LTL and increased risk of frailty can be confirmed to be causal, preservation of LTL through lifestyle changes or safe manipulation of telomere length may emerge as a novel target to reduce the risk of frailty. ...
Background: Leucocyte telomere length (LTL), a potential marker of biological age, has been
associated with risk of many diseases. We investigated whether LTL is associated with risk of frailty, a multidimensional syndrome of decline that affects multiple systems and predisposes to adverse health outcomes.
Methods: In a cross–sectional analysis, we studied 441,781 UK Biobank participants (aged 40–70
years), with complete data on LTL and frailty indicators. We defined frailty as the presence of at least three of five indicators: weaker grip strength, slower walking pace, weight loss in the past year, lower physical activity, and exhaustion in the past two weeks. We evaluated association of LTL with frailty using adjusted (chronological age, sex, deprivation, smoking, alcohol intake, body mass index, multimorbidity) multinomial and ordinal regression models. We used Mendelian randomisation (MR), using 131 genetic variants associated with LTL, to assess if the association of LTL with frailty was causal.
Findings: Frail participants (4·6%) were older (median age difference (95% CI): 3 (2·5; 3·5) years),
more likely to be female (61%), and had shorter LTL (-0·13SD vs 0·03SD) than non–frail. In adjusted analyses, both age and LTL were associated with frailty (OR=1·03 (95%CI: 1·02–1·04) per year of older chronological age; 1·10 (1·08; 1·11) per SD shorter LTL). Within each age group (40–49, 50– 59, 60–69 years) the prevalence of frailty was about 33% higher in participants with shorter (-2SD) versus longer telomeres (+2SD). MR analysis showed an association of LTL with frailty that was directionally consistent with the observational association, but not statistically significant.
Interpretation: Inter–individual variation in LTL is associated with the risk of frailty independently
of chronological age and other risk factors. Our findings provide evidence for an additional biological determinant of frailty.
... As mentioned, the ω-3 fatty acids may also exert beneficial effects on TL through their anti-inflammatory properties. Prospective cohort studies found that a higher plasma concentration of ω-3 fatty acids was associated with lower levels of proinflammatory markers and reduced attrition of TL [42,43]. Therefore, this antiinflammatory potential could be a possible mechanism by which ω-3 fatty acids exert their effect on telomere maintenance. ...
Telomeres are protective caps at the end of eukaryotic chromosomes, whose length is correlated with health and lifespan. Telomere attrition is a common feature of the aging process and can be accelerated by oxidative stress and chronic inflammation. Various nutrients influence the telomere length, partially due to their antioxidant and anti-inflammatory properties. The aim of this review was to meta-analytically assess the effect of omega-3 fatty acids on the telomere length. We searched four databases (PubMed, Web of Sciences, Scopus, and the Cochrane Library) from inception until November 2021. Of 573 records, a total of 5 clinical trials were included for the quantitative meta-analysis, comprising a total of 337 participants. The results revealed an overall beneficial effect of omega-3 fatty acids on the telomere length (mean difference = 0.16; 95% CI, 0.02, 0.30; p = 0.02). Despite a limited number of studies, the available evidence suggests that omega-3 fatty acids may positively affect the telomere length. However, larger clinical trials are needed to confirm our findings, along with studies aimed to clarify the underlying molecular mechanisms.
... The effects of dietary macronutrients may also impact health status. In patients with coronary heart disease, it was shown that consumption of marine omega-3 fatty acids [both docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA)] had an inverse relationship with TL [60]. Moreover, dietary intake of both omega-3 and omega-6 fatty acids (linoleic acid) affected TL in healthy sedentary overweight middle-aged and older adults. ...
Telomeres play a critical role in maintaining cellular fate through tight regulation of cell division and DNA damage or repair. Over the years, it is established that biological ageing is defined by a gradual derangement in functionality, productivity, and robustness of biological processes. The link between telomeres and ageing is highlighted when derangement in telomere biology often leads to premature ageing and concomitant accompaniment of numerous age-associated diseases. Unfortunately, given that ageing is a biologically complicated intricacy, measures to reduce morbidity and improve longevity are still largely in the infancy stage. Recently, it was discovered that dietary habits and interventions might play a role in promoting successful healthy ageing. The intricate relationship between dietary components and its potential to protect the integrity of telomeres may provide unprecedented health benefits and protection against age-related pathologies. This review aims to summarise recent findings that investigate the roles of nutrition on telomere biology and provide enough evidence for further studies to consider the topic of nutrigenomics and its contributions toward healthy ageing and concomitant strategy against age-associated diseases.
... For example, Omega-3 Index levels (O3I, a measure of the proportion of DHA and EPA of total fatty acids in erythrocytes) of 8% vs. 4% were related to a 30% reduced risk of fatal coronary heart disease (CHD) [4]. More recently, O3I levels of 8% have also been linked to increased longevity, reduced all-cause mortality, improved depressive symptoms, reduced arthritis risk and improved cognitive function [5][6][7][8][9][10][11]. Despite the well-established health benefits of omega-3 LCPUFA, intakes in Western and most Asian diets are below recommendations [12,13]. ...
Purpose
To evaluate bioavailability of omega-3 long-chain polyunsaturated fatty acids (LCPUFA) from foods enriched with novel vegetable-based encapsulated algal oil across Australian and Singaporean populations.
Methods
27 men ( n = 12 Australian European; n = 15 Singaporean Chinese), 21–50 yr; 18–27.5 kg/m ² , with low habitual intake of omega-3 LCPUFA completed a multicentre randomised controlled acute 3-way cross-over single-blind trial. They consumed, in random order 1-week apart after an overnight fast, standard breakfast meals including 400 mg docosahexanoic acid (DHA) from either extruded rice snacks or soup both containing cauliflower-encapsulated HiDHA ® algal oil or gel capsules containing HiDHA ® algal oil. Blood samples for analysis of plasma DHA and eicosapentaenoic acid (EPA) were taken pre-meal and after 2, 4, 6, 8 and 24 h. Primary analyses comparing 24-h incremental area under the plasma DHA, EPA and DHA + EPA concentration (µg/ml) curves (iAUC 0-24 h ) between test foods were performed using linear mixed models by including ethnicity as an interaction term.
Results
Plasma iAUC 0-24 h did not differ significantly between test foods (adjusted mean [95% CI] plasma DHA + EPA: extruded rice snack, 8391 [5550, 11233] µg/mL*hour; soup, 8862 [6021, 11704] µg/mL*hour; capsules, 11,068 [8226, 13910] µg/mL*hour, P = 0.31) and did not differ significantly between Australian European and Singaporean Chinese (treatment*ethnicity interaction, P = 0.43).
Conclusion
The vegetable-based omega-3 LCPUFA delivery system did not affect bioavailability of omega-3 LCPUFA in healthy young Australian and Singaporean men as assessed after a single meal over 24 h, nor was bioavailability affected by ethnicity. This novel delivery system may be an effective way to fortify foods/beverages with omega-3 LCPUFA.
Trial registration
The trial was registered with clinicaltrials.gov (NCT04610983), date of registration, 22 November 2020.
Background
Elevated levels of ICAM-1 and VCAM-1 are significant risk factors for cardiovascular diseases. Conversely, the regulatory roles of physical activity and omega-3 supplementation in these factors have been reported. The primary aim of the present research was to investigate the impact of an eight-week combined (resistance-endurance) accompanied by omega-3 supplementation on ICAM-1 and VCAM-1 levels in elderly women.
Methods
Forty elderly women, averaging 66.7 ± 4.13 years, were randomly assigned to four groups: placebo, omega-3 supplement, training, and training + omega-3. The combined exercise training program was implemented for eight weeks, three sessions per week. Aerobic training included 20 min of running at 60–70% of the reserve heart rate, while resistance training involved exercises at 70% of 1RM with 10 repetitions per exercise for two sets. The omega-3 and training + omega-3 groups consumed 2000 mg of omega-3 daily. Blood samples were collected 48 h after the last combined exercise training or omega-3 consumption, and the measured variables were analyzed using analysis of covariance test and SPSS-24 software.
Results
ICAM-1 and VCAM-1 levels significantly decreased in the training and training + omega-3 groups (p < 0.001). The decrease in ICAM-1 within the training + omega-3 group was also significant compared to the training group (p = 0.024). Additionally, a significant reduction in insulin resistance and body fat percentage was observed in both the training and training + omega-3 groups (p < 0.001).
Conclusion
The present study's results indicate that omega-3 supplementation can enhance the effectiveness of combined training in regulating cardiovascular risk factors.
The significance of telomere/telomerase biology in the pathogenesis of age-related cardiovascular diseases (CVDs), such as atherosclerosis, hypertension, myocardial infarction (MI), and heart failure, has been increasingly highlighted in recent years. The activation of the DNA damage response (DDR) due to the presence of short telomeres is believed to be a significant upstream signal responsible for inducing a permanent cessation of the cell cycle in cardiomyocytes. Heart failure (HF) is a condition that arises due to the restricted regenerative capacity of the elderly and injured mammalian heart. This limitation may be related to the decreased proliferative potential of cardiac stem cells (CSCs) and cardiomyocytes. The association between CVDs and shorter telomeres provides a foundation for developing therapeutic techniques aimed at elongating telomeres and subsequently restoring the proliferative ability of the adult mammalian heart. This phenomenon offers intriguing prospects for the treatment and prevention of cardiovascular disease (CVD). Further investigation into telomerase gene therapy in the field of cardiac regenerative medicine is justified based on the encouraging outcomes shown in mice models, whereby the reactivation of telomerase in the heart after MI has demonstrated beneficial effects.
Background and Purpose: Aging is a complex physiological process that involves progressive loss of body function and degradation of DNA strands located at the ends of chromosomes-telomeres. The capacity of cells to divide is limited by telomere length, as an excessive shortening of telomeres causes cellular senescence. Exercise training and omega-3 prevent the shortening of telomeres by affecting telomerase. The aim of the present study was to investigate the effect of aerobic training with omega-3 on some shel-terins and telomerase of heart tissue in elderly high-fat diet rats. Materials and Methods: In this experimental study, 40 male Wistar rats (mean weight 311.32±26.95 g) were obtained from the Pasteur Institute and transferred to the laboratory. After transferring the rats to the laboratory, they were randomly divided into five groups: Normal Diet (ND), High-Fat Diet (HFD), High-Fat Diet-Training (HFDT), High-Fat Diet-Omega3 (HFDω3), and High-Fat Diet-Training-Omega3 (HFDTω3). HFD induction was performed using a high-fat diet containing 17% protein, 43% carbohydrate, and 40% fat. The supplement groups received 1 g of Omega3 (per kg of body weight) orally during the intervention period. The aerobic exercise program at the beginning consisted of running on a treadmill at a speed of 10 m/min, 0-degree incline, for 15 minutes. The speed and duration gradually increased to 16 meters per minute and 50 minutes in the last session. Running was carried out for 8 weeks and five days a week. Data were analyzed by one-way analysis of variance and Tukey post hoc test at the P < 0.05. Results: Induction of HFD significantly decreased the expression of TRF2 (P = 0.002), TERT (P = 0.024) and increased TRF1 (P = 0.0001) compared to the ND group. Exercise and omega-3 significantly increased the expression of TRF2 and TERT in HFD rats (P < 0.05). Also, TRF2 and TERT expression changes were higher in the HFDTω3 group compared to HFDT (P = 0.023 and P = 0.044, respectively) and HFDω3 groups (P = 0.021 and P = 0.042, respectively). Conclusion: The results of the present study showed that elderly and HFD are associated with a decrease in TRF2, TERT and an increase in TRF1 in heart tissue, and aerobic exercise and omega-3 consumption can reverse this trend. Considering the role of shelterins and telomerase in cellular function, it seems that changing the levels of these indicators following physical activity and using omega-3 supplements can partially prevent the occurrence of many heart diseases caused by aging and obesity. How to cite this article: Torabi Palat Kaleh G, Abdi A, Abbassi Daloii A. The effect of aerobic exercise and omega-3 on the expression of telomeric repeat binding factor 1 and 2 and telomerase reverse transcriptase enzyme in the heart tissue of elderly HFD rats.
Purpose – The goal of this narrative review was to look at the link between the Mediterranean diet (MD) and the telomere length. Furthermore, this study aims to understand the impact of the MD on obesity-related telomere length.
Design/methodology/approach – Relevant literature was reviewed to explore the potential influence of the MD on telomere length and its association with obesity.
Findings – The MD is one of the healthiest diets of all known dietary patterns, and it is also linked to the telomere length. Except for fruits and vegetables, the main findings for other MD components are inconsistent. In terms of antioxidant and antiinflammatory properties, using the MD as a weight loss approach is a good method. For predicting changes in obesity characteristics, the initial telomere length is critical. However, there are not many studies in the field that have looked at the MD as a weight loss approach and its link to the telomere length. As a result, more research is needed to understand these connections in various groups.
Originality/value – This study is unique since it examines the MD, telomere length and obesity-related consequences. This study examines the MD, telomere length and obesity to determine if the MD can help lose weight while maintaining telomere length. As there are few studies on MD weight loss and telomere length, the work emphasizes the need for greater research in this area. This study fills a research gap and improves the understanding of nutrition, telomere biology and obesity-related outcomes.
With the advent and rapid progress of the novel blue economy, the prospect
of large-scale commercial production of diverse natural bioactive compounds from
aquatic biota is likely to be realized in the near future. The biodiversity of the marine
biota represents a potentially abundant source of new biomolecules with potentially
different economical applications. Most of these biotas are able to survive under stress
conditions, as a result, they produce complex metabolites with unique biological
properties. These natural substances could be used as functional constituents in the
food sector. Moreover, they could aid in the treatment of a broad range of different
diseases, including antitumor, antioxidant, antiaging, anti-inflammatory, and
antimicrobial. The special properties of these compounds make them an attractive
group deserving increasing scientific interest. It is interesting to note that there are
some biomolecules exclusively found in marine biota, including phlorotannins and
sulfated polysaccharides. This chapter explains the bioactive molecules from different
marine biota as well as illustrates their chemical structure and highlights their new
biologically active form.
Taheri Consciousness (T-Consciousness) was introduced and defined by Mohammad Ali Taheri as one of the constituent components of the Cosmos in addition to matter and energy, from which Taheri Consciousness Fields (TCFs) are derived. TCFs are not matter or energy, but they can be proven by scientific experiments. The effect of Faradarmani CF, as one of TCFs, was examined in this study. Telomerase is an important enzyme, which adds DNA sequence repeats to the ends of chromosomes, thus prevents from their shortening. Telomerase activity is associated with cell proliferation, organism growth, and aging. This study aimed to study proliferation, telomerase activity, and telomere length in the Faradarmani CF treated mesenchymal stem cells (MSCs). Human MSCs were isolated from bone marrow and the morphology, proliferation of cells, length of telomere, and activity of telomerase were evaluated in Faradarmani CF treatment and control groups. The results showed that Faradarmani CF significantly increased the proliferation, length of telomere, and activity of telomerase in hMSCs compared with the control group (p<0.05). Considering the effects of Faradarmani on telomere length and telomerase activity, which are two important factors for cures of several age-related diseases, it is recommended that more experiments be performed in this regard to clarify the effect of TCFs on ageing.
محمدعلی طاهری اولین بار وجود میدان های شعوری (ط) را مطرح نمود و چندین میدان شعوری (ط) را تاکنون معرفی کرده است. میدانهای شعوری (ط) نه ماده هستند نه انرژی، اما از طریق آزمایشات علمی قابل اثبات میباشند. میدان شعوری فرادرمانی یکی از میدان های شعوری (ط) است که در این تحقیق به بررسی تأثیر آن پرداخته شده است. تلومراز آنزیم مهمی است که توالی های تکراری DNA را به انتهای کروموزمها اضافه میکند، بدین ترتیب مانع از کوتاه شدن طول آنها میگردد. فعالیت تلومراز با تکثیر سلول، رشد و طول عمر ارگانیسم در ارتباط می باشد. هدف از این تحقیق، بررسی تکثیر، فعالیت تلومراز و طول تلومر در سلولهای بنیادی مزانشیمی (MSCs) تحت اثر میدان شعوری فرادرمانی بود. ابتدا سلولهای MSCs انسان از مغز استخوان جدا شد و مورفولوژی، تکثیر سلولها، طول تلومر و فعالیت تلومراز تحت میدان شعوری فرادرمانی در گروه تیمار در مقایسه با گروه کنترل مورد ارزیابی قرار گرفت. نتایج حاکی از آن بود که میدان شعوری فرادرمانی به طور معنی دار باعث افزایش قابل توجهی در تکثیر، طول تلومر، و فعالیت تلومراز در سلول های MSCs در مقایسه با گروه کنترل گردید (p<0.05). فرادرمانی طول تلومر و فعالیت تلومراز که دو عامل مهم در درمان چندین بیماری مرتبط با سن هستند را تحت تأثیر قرار داد، بنابراین توصیه میشود که آزمایشات بیشتری در این خصوص انجام شده و تأثیر میدانهای شعوری (ط) بر روی روند پیری مورد بررسی قرار گیرد.
Telomerler kromozomların uç kısımlarında bulunan ve hücrenin her bölünmesiyle bir miktar kısalan, kromozomların yapısal bütünlüğünü korumakla görevli kısımlardır. Bu yapıların kısalma hızı vücutta birçok hastalığın oluşmasına zemin hazırlayabilmektedir. Beslenme, telomerlerin korunmasında en etkili faktörlerin başında gelmektedir. Akdeniz diyeti bileşenlerinden çoklu doymamış yağ asitleri ise vücudun inflamatuvar ve oksidatif stres düzeylerine doğrudan etki ettiğinden aynı zamanda telomer yapılarının da korunmasında önemli görevler üstlenmektedir. Bu literatür derlemesi çoklu doymamış yağ asitlerinden omega-3 ve omega-6 yağ asitlerinin telomer yapısının kısalma hızı üzerine etkisini özetlemek amacıyla hazırlanmıştır. Literatür taraması 2002 yılından Mart 2022'ye kadar PubMed, Web of Science, Scopus ve Google Akademik'ten taranan makalelerin referans listesinin manuel incelemesiyle desteklenen elektronik veri tabanları kullanılarak gerçekleştirilmiştir. Web of Science, Scopus ve Google Akademik veri tabanlarından "Telomer" veya "Diyet" veya "Beslenme" veya "Omega-3" veya "Omega-6" veya "Hücresel Yaşlanma" terimleri kullanılarak taranmıştır. Besin öğelerinin ve diyet modellerinin telomer yapısı üzerinde farklı etkileri bulunabilmektedir. Bu derlemenin amacı, telomer yapısının kısalma hızının azaltılmasında veya korunmasında çoklu doymamış yağ asitlerinin olumlu/olumsuz etkilerini yapılan çalışmalar ışığında irdelenmesidir.
Ageing is a universal decline of physiological functions accompanied by an increase in risks of developing morbidity, diseases, and death. Calorie restriction (CR) without malnutrition has been shown to improve lifespan from simple model organisms to mammals, and extensive research over the past decades have identified several universally conserved signalling pathways by which CR regulates lifespan. More recently, emerging evidence has suggested that modulation of intake levels of macronutrients and micronutrients can also impact healthspan and lifespan in model organisms. These findings propose potentially promising and cost-effective approaches to promote healthy ageing and longevity in humans through personalised nutrition. In this review, we summarise the mechanisms by which CR promotes healthspan and longevity, focusing on the mitochondrial reactive oxygen species (ROS) and several universally conserved geroprotective nutrient-sensing pathways (insulin/insulin-like growth factor (IGF-1), AMP-activated protein kinase (AMPK), mTOR). We further discuss the accumulating data supporting that changes in dietary pattern, levels of nutrient intake (both macronutrient and micronutrient) and functional foods can impact healthspan through acting on the key components of nutrient-sensing and immunoprotective pathways, providing fundamental support for future research and development of anti-ageing diets and dietary regimes.
Zusammenfassung
In den letzten Jahrzehnten wurden viele Substanzen als Anti-Aging-Wundermittel gehypt. Selten gab es jedoch belastbare Belege dafür, dass die vollmundigen Versprechungen erfüllt werden konnte. Bei ω-3-Fettsäuren (im Folgenden nur ω-3 genannt) scheint dies anders zu sein, da mittlerweile eine Reihe von Studien und sogar Metaanalysen existieren, die das Postulat einer lebensverlängernden und jungerhaltenden Wirkung von ω-3 stützen.
Fatty acids are long-chain hydrocarbon compounds. If they do not have the maximum number of hydrogen atoms, they are called unsaturated fatty acids. For example, if 2 hydrogen atoms are missing from stearic acid, which is common in animal or vegetable fats and contains 18 carbon atoms, there is a double bond and the resulting acid is oleic acid. The linoleic acid (Omega-6) and linolenic acid (Omega-3) derived from it have two and three double bonds, respectively. The Omega designation indicates which C atom the first double bond is located after.
Evidence suggests antioxidant and anti-inflammatory properties of omega-3 polyunsaturated fatty acids (n-3 PUFA). However, the effect of supplementation of this fatty acid profile on the telomere length and the telomerase enzyme activity was not revised yet. The PubMed and Embase® databases were used to search for clinical trials. A total of six clinical trials were revised. Omega-3 PUFA supplementation did not statistically affect telomere length in three out of three studies but affected telomerase activity in two out of four studies. The supplementation increased telomerase enzyme activity in subjects with first-episode schizophrenia. Besides, it decreased telomerase enzyme activity without modulating the effects of Pro12Ala polymorphism on the PPARγ gene in type 2 diabetes subjects. The methodological differences between the studies and the limited number of studies on the theme suggest that further studies are needed to elucidate the effects of n-3 PUFA supplementation on telomere length and telomerase enzyme activity in humans.
Telomeres are non-coding nucleoprotein structures consisting of a highly conserved tandem repeat DNA sequence that caps the ends of chromosomes in eukaryotes. Telomeres confer chromosomal stability, protect the genome from nucleolytic degradation, avoid aberrant recombination and improper repair, and prevent random fusion of chromosomes. The end-replication problem results in telomere shortening with every cell division, eventually leading to cellular senescence and aging. Telomere length (TL) is thereby an ideal candidate for “biological aging.” Telomeres possess guanine-rich repeats, which are highly susceptible to oxidative stress. Epidemiological studies have indicated the association of telomere attrition with mortality and various age-related diseases. Micronutrients comprising vitamins and minerals act as potential modulators of stress and can influence TL. Research has indicated that vitamin B12 (B12) regulates oxidative stress and maintains genomic stability, thereby influencing telomere integrity and cellular aging. The deficiency of B12 leads to elevated levels of homocysteine, which reduces the methylation potential and increases oxidative stress, thereby compromising the TL. Telomere shortening and mitochondrial dysfunction are independently linked to aging. However, they are connected through telomerase reverse transcriptase activity, which regulates mitochondrial biogenesis. Further, experimental evidence indicated the positive association of B12 with relative TL and mitochondrial DNA copy number, an indirect index of mitochondrial biogenesis. The present chapter provides some insights into the role of B12 in influencing TL. Exploring their association might open new avenues to understand the pathophysiology of aging and age-related diseases.
Telomere length (TL) has been proposed as a marker of mitotic cell age and as a general index of human organismic aging. Short absolute leukocyte telomere length has been linked to cardiovascular-related morbidity and mortality. Our aim was to test whether the rate of change in leukocyte TL is related to mortality in a healthy elderly cohort. We examined a subsample of 236 randomly selected Caucasian participants from the MacArthur Health Aging Study (aged 70 to 79 years). DNA samples from baseline and 2.5 years later were assayed for mean TL of leukocytes. Percent change in TL was calculated as a measure of TL change (TLC). Associations between TL and TLC with 12-year overall and cardiovascular mortality were assessed. Over the 2.5 year period, 46% of the study participants showed maintenance of mean bulk TL, whereas 30% showed telomere shortening, and, unexpectedly, 24% showed telomere lengthening. For women, short baseline TL was related to greater mortality from cardiovascular disease (OR = 2.3; 95% CI: 1.0 - 5.3). For men, TLC (specifically shortening), but not baseline TL, was related to greater cardiovascular mortality, OR = 3.0 (95% CI: 1.1 - 8.2). This is the first demonstration that rate of telomere length change (TLC) predicts mortality and thus may be a useful prognostic factor for longevity.
Evidence of an association between fish and meat consumption and risk of dementia is inconsistent and nonexistent in populations in developing countries.
The objective was to investigate associations between fish and meat consumption with dementia in low- and middle-income countries.
One-phase cross-sectional surveys were conducted in all residents aged > or =65 y in 11 catchment areas in China, India, Cuba, the Dominican Republic, Venezuela, Mexico, and Peru. A total of 14,960 residents were assessed by using the 10/66 standardized protocol, which includes face-to-face interviews for dietary habits and a cross-culturally validated dementia diagnosis.
Dietary intakes and the prevalence of dementia varied between sites. We combined site-specific Poisson regression prevalence ratios (PRs) for the association between fish and meat consumption and dementia in 2 fixed-effect model meta-analyses adjusted for sociodemographic and health characteristics and fish and meat consumption as appropriate. We found a dose-dependent inverse association between fish consumption and dementia (PR: 0.81; 95% CI: 0.72, 0.91) that was consistent across all sites except India and a less-consistent, dose-dependent, direct association between meat consumption and prevalence of dementia (PR: 1.19; 95% CI: 1.07, 1.31).
Our results extend findings on the associations of fish and meat consumption with dementia risk to populations in low- and middle-income countries and are consistent with mechanistic data on the neuroprotective actions of omega-3 (n-3) long-chain polyunsaturated fatty acids commonly found in fish. The inverse association between fish and prevalent dementia is unlikely to result from poorer dietary habits among demented individuals (reverse causality) because meat consumption was higher in those with a diagnosis of dementia.
Diabetes mellitus (DM) and deficiency in n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFAs) are known to increase the incidence of cardiovascular disease (CVD). However, it has not yet been reported whether n-3 LCPUFAs are related to arteriosclerosis in patients under long-term hemodialysis (HD).
Pulse wave velocity from the brachium to the ankle (baPWV) was measured as a marker of arteriosclerosis with a volume-plethysmographic apparatus in 147 long-term HD patients (non-diabetic (non-DM): 51 males/42 females, 62 +/- 14 y; and DM: 33 males/21 females, 67 +/- 9 y). The fatty acid composition of the total phospholipid fraction from washed RBCs was analyzed by gas chromatography. Analyses were adjusted for age, sex, diastolic blood pressure, pulse, body mass index, duration of HD treatment, smoking status, LDL/HDL-cholesterol ratios and diabetes mellitus (DM).
The mean baPWV was 18.9 +/- 5.2 and 23.7 +/- 6.3 m/s in non-DM and DM patients, respectively. The mean baPWV in DM patients was significantly higher than that of non-DM patients after adjustment (p = 0.0002). Multiple regression analysis showed that there was a significant inverse association between baPWV and docosahexaenoic acid (DHA) levels (p = 0.017) and DHA/arachidonic acid (AA) ratios (p = 0.012) in RBC in non-DM patients after adjustment but not in DM patients.
We suggest that n-3 LCPUFAs may be a negative risk factor of CVD also in non-DM HD patients. In DM patients the effects of n-3 PUFAs on the vascular system became undetectable probably because DM overwhelmingly affected PWV. Further studies in a prospective manner are necessary.
Human chromosomes are capped by telomeres, which consist of tandem repeats of DNA and associated proteins. The length of the telomeres is reduced with increasing cell divisions except when the enzyme telomerase is active, as in stem cells and germ cells. Telomere dysfunction has been associated with development of age-related pathologies, including cancer, cardiovascular disease, Alzheimer's disease, and Parkinson's disease. DNA damage in the telomeric region causes attrition of telomeres. Because folate provides precursors for nucleotide synthesis and thus affects the integrity of DNA, including that of the telomeric region, folate status has the potential to influence telomere length. Telomere length is epigenetically regulated by DNA methylation, which in turn could be modulated by folate status. In this study, we determined whether folate status and the 677C > T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene are associated with the telomere length of peripheral blood mononuclear cells in healthy men. The results of our study showed that plasma concentration of folate was associated with telomere length of peripheral blood mononuclear cells in a nonlinear manner. When plasma folate concentration was above the median, there was a positive relationship between folate and telomere length. In contrast, there was an inverse relationship between folate and telomere length when plasma folate concentration was below the median. The MTHFR 677C > T polymorphism was weakly associated (P = 0.065) with increased telomere length at below-median folate status. We propose that folate status influences telomere length by affecting DNA integrity and the epigenetic regulation of telomere length through DNA methylation.
Although telomere length (TL) is known to play a critical role in cellular senescence, the relationship of TL to aging and
longevity in humans is not well understood. In a large biracial population-based cohort, we tested the hypotheses that elderly
persons with shorter TL in peripheral white blood cells have poorer survival, shorter life span, and fewer years of healthy
life (YHL). Associations were evaluated using Cox proportional hazard models and linear regression analyses where appropriate.
TL (in kilo base pairs) was not associated with overall survival (hazard ratio 1.0; 95% confidence interval 0.9–1.1) or death
from any specific underlying cause including infectious diseases, cancer, or cardiac and cerebrovascular diseases. TL, however,
was positively associated with more YHL (β = 0.08 ± 0.04, p = .03). Findings suggest that TL may not be a strong biomarker of survival in older individuals, but it may be an informative
biomarker of healthy aging.
To assess the relationship between baseline dietary fatty acids and 10-year incident age-related macular degeneration (AMD).
In an elderly Australian cohort, 3654 participants were examined at baseline and 2454 were examined 5 and/or 10 years later. We assessed AMD from retinal photographs. Participants completed a semiquantitative food frequency questionnaire.
After adjusting for age, sex, and smoking, 1 serving of fish per week was associated with reduced risk of incident early AMD (relative risk, 0.69 [95% confidence interval, 0.49-0.98]), primarily among participants with less than the median linoleic acid consumption (0.57 [0.36-0.89]). Findings were similar for intake of long-chain omega-3 polyunsaturated fatty acids. One to 2 servings of nuts per week was associated with reduced risk of incident early AMD (relative risk, 0.65 [95% confidence interval, 0.47-0.91]). Protective associations between the intake of nuts and reduced risk of pigmentary abnormalities were seen among nonsmokers, participants with less than the median ratio of serum total to high-density lipoprotein cholesterol, and those with beta carotene intake greater than the median level.
This study provides evidence of protection against early AMD from regularly eating fish, greater consumption of omega-3 polyunsaturated fatty acids, and low intakes of foods rich in linoleic acid. Regular consumption of nuts may also reduce AMD risk. Joint effects from multiple factors are suggested.
Telomere length may be a marker of biological aging. Multivitamin supplements represent a major source of micronutrients, which may affect telomere length by modulating oxidative stress and chronic inflammation.
The objective was to examine whether multivitamin use is associated with longer telomeres in women.
We performed a cross-sectional analysis of data from 586 early participants (age 35-74 y) in the Sister Study. Multivitamin use and nutrient intakes were assessed with a 146-item food-frequency questionnaire, and relative telomere length of leukocyte DNA was measured by quantitative polymerase chain reaction.
After age and other potential confounders were adjusted for, multivitamin use was associated with longer telomeres. Compared with nonusers, the relative telomere length of leukocyte DNA was on average 5.1% longer among daily multivitamin users (P for trend = 0.002). In the analysis of micronutrients, higher intakes of vitamins C and E from foods were each associated with longer telomeres, even after adjustment for multivitamin use. Furthermore, intakes of both nutrients were associated with telomere length among women who did not take multivitamins.
This study provides the first epidemiologic evidence that multivitamin use is associated with longer telomere length among women.
Age-associated telomere shortening is a well documented feature of peripheral blood cells in human population studies, but it is not known to what extent these data can be transferred to the individual level. Telomere length (TL) in two blood samples taken at approximately 10 years interval from 959 individuals was investigated using real-time PCR. TL was also measured in 13 families from a multigenerational cohort. As expected, we found an age-related decline in TL over time (r = -0.164, P<0.001, n = 959). However, approximately one-third of the individuals exhibited a stable or increased TL over a decade. The individual telomere attrition rate was inversely correlated with initial TL at a highly significant level (r = -0.752, P<0.001), indicating that the attrition rate was most pronounced in individuals with long telomeres at baseline. In accordance, the age-associated telomere attrition rate was more prominent in families with members displaying longer telomeres at a young age (r = -0.691, P<0.001). Abnormal blood TL has been reported at diagnosis of various malignancies, but in the present study there was no association between individual telomere attrition rate or prediagnostic TL and later tumor development. The collected data strongly suggest a TL maintenance mechanism acting in vivo, providing protection of short telomeres as previously demonstrated in vitro. Our findings might challenge the hypothesis that individual TL can predict possible life span or later tumor development.
Leukocyte telomere length (LTL) is ostensibly a biomarker of human aging. Cross-sectional analyses have found that LTL is relatively short in a host of aging-related diseases. These studies have also provided indirect estimates of age-dependent LTL shortening. In this paper, the authors report findings of the first comprehensive longitudinal study of 450 whites and 185 African Americans in Louisiana (aged 31.4 and 37.4 years at baseline (1995-1996) and follow-up (2001-2006) examinations, respectively) participating in the Bogalusa Heart Study. Rate of change in LTL was highly variable among individuals, with some displaying a paradoxical gain in LTL during the follow-up period. The most striking observation was that age-dependent LTL shortening was proportional to LTL at baseline examination. At both baseline and follow-up examinations, African Americans had longer LTLs than whites, and smokers had shorter LTLs than nonsmokers. The longer LTL in African Americans than in whites explained in part the faster rate of LTL shortening observed among African Americans. These findings underscore the complexity of leukocyte telomere dynamics in vivo and suggest that determinants in addition to the "end-replication problem" contribute to telomere shortening in vivo.
The objective of most biomedical research is to determine an unbiased estimate of effect for an exposure on an outcome, i.e. to make causal inferences about the exposure. Recent developments in epidemiology have shown that traditional methods of identifying confounding and adjusting for confounding may be inadequate.
The traditional methods of adjusting for "potential confounders" may introduce conditional associations and bias rather than minimize it. Although previous published articles have discussed the role of the causal directed acyclic graph approach (DAGs) with respect to confounding, many clinical problems require complicated DAGs and therefore investigators may continue to use traditional practices because they do not have the tools necessary to properly use the DAG approach. The purpose of this manuscript is to demonstrate a simple 6-step approach to the use of DAGs, and also to explain why the method works from a conceptual point of view.
Using the simple 6-step DAG approach to confounding and selection bias discussed is likely to reduce the degree of bias for the effect estimate in the chosen statistical model.
The mechanisms of particulate matter (PM)-induced health effects are believed to involve inflammation and oxidative stress. Increased intake of omega-3 polyunsaturated fatty acids (n-3 PUFA) appears to have anti-inflammatory effects.
As part of a trial to evaluate whether n-3 PUFA supplementation could protect against the cardiac alterations linked to PM exposure, we measured biomarkers of response to oxidative stimuli [copper/zinc (Cu/Zn) superoxide dismutase (SOD) activity, lipoperoxidation (LPO) products, and reduced glutathione (GSH)] and evaluated the impact of supplementation on plasma levels.
We recruited residents from a nursing home in Mexico City chronically exposed to PM < or = 2.5 microm in aerodynamic diameter (PM(2.5)) and followed them from 26 September 2001 to 10 April 2002. We randomly assigned subjects in a double-blind fashion to receive either fish oil (n-3 PUFA) or soy oil. We measured PM(2.5) levels indoors at the nursing home, and measured Cu/Zn SOD activity, LPO products, and GSH at different times during presupplementation and supplementation phases.
Supplementation with either fish or soy oil was related to an increase of Cu/Zn SOD activity and an increase in GSH plasma levels, whereas exposure to indoor PM(2.5) levels was related to a decrease in Cu/Zn SOD activity and GSH plasma levels.
Supplementation with n-3 PUFA appeared to modulate the adverse effects of PM(2.5) on these biomarkers, particularly in the fish oil group. Supplementation with n-3 PUFA could modulate oxidative response to PM(2.5) exposure.
Telomerase, a ribonucleoprotein that is capable of synthesizing telomeric repeats, is expressed in germline and malignant cells, and is absent in most normal human somatic cells. The selective expression of telomerase has thus been proposed to be a basis for the immortality of the germline and of malignant cells. In the present study, telomerase activity was analyzed in normal human T lymphocytes. It was found that telomerase is expressed at a high level in thymocyte subpopulations, at an intermediate level in tonsil T lymphocytes, and at a low to undetectable level in peripheral blood T lymphocytes. Moreover, telomerase activity is highly inducible in peripheral T lymphocytes by activation through CD3 with or without CD28 costimulation, or by stimulation with phorbol myristate acetate (PMA)/ionomycin. The induction of telomerase by anti-CD3 plus anti-CD28 (anti-CD3/CD28) stimulation required RNA and protein synthesis, and was blocked by herbimycin A, an inhibitor of S pi protein tyrosine kinases. The immunosuppressive drug cyclosporin A selectively inhibited telomerase induction by PMA/ionomycin and by anti-CD3, but not by anti-CD3/CD28. Although telomerase activity in peripheral T lymphocytes was activation dependent and correlated with cell proliferation, it was not cell cycle phase restricted. These results indicate that the expression of telomerase in normal human T lymphocytes is both developmentally regulated and activation induced. Telomerase may thus play a permissive role in T cell development and in determining the capacity of lymphoid cells for cell division and clonal expansion.
In 1971 I published a theory in which I first formulated the DNA end replication problem and explained how it could be solved. The solution to this problem also provided an explanation for the Hayflick Limit, which underpins the discovery of in vitro and in vivo cell senescence. I proposed that the length of telomeric DNA, located at the ends of chromosomes consists of repeated sequences, which play a buffer role and should diminish in dividing normal somatic cells at each cell doubling. I also proposed that the loss of sequences containing important information that could occur after buffer loss could cause the onset of cellular senescence. I also suggested that for germline cells and for the cells of vegetatively propagated organisms and immortal cell populations like most cancer cell lines, an enzyme might be activated that would prevent the diminution of DNA termini at each cell division, thus protecting the information containing part of the genome. In the last few years, most of my suggestions have been authenticated by laboratory evidence. the DNA sequences that shorten in dividing normal cells are telomeres and the enzyme that maintains telomere length constant in immortal cell populations is telomerase.
Moderate food and/or energy (calorie) restriction delays age-related immune dysfunction and prolongs life span in multiple animal models. The amount and type of dietary fatty acids can also profoundly affect life span. Marine-derived fish oils contain (n-3) fatty acids, which have potent anti-inflammatory properties. We therefore examined the influence of food restriction (40% overall reduction in intake of all dietary components) combined with substitution of fish oil for corn oil in a factorial design. Autoimmune-prone (NZB x NZW)F(1) (B/W) mice, which develop fatal autoimmune renal disease, were used. The food-restricted/fish oil diet maximally extended median life span to 645 d (vs. 494 d for the food-restricted corn oil diet). Similarly, fish oil prolonged life span in the ad libitum-fed mice to 345 d (vs. 242 for the ad libitum/corn oil diet). Increased life span was partially associated with decreased body weight, blunting renal proinflammatory cytokine (interferon-gamma, interleukins-10 and -12 and tumor necrosis factor-alpha) levels and lower nuclear factor-kappaB (NF-kappaB). Reductions in NF-kappaB were preceded by enhanced superoxide dismutase, catalase and glutathione peroxidase activities. These findings demonstrate the profound additive effects of food restriction and (n-3) fatty acids in prolonging life span in B/W mice. These observations may have additional implications in the management of obesity, diabetes, cancer and/or the aging process.
Obesity and smoking are important risk factors for many age-related diseases. Both are states of heightened oxidative stress, which increases the rate of telomere erosion per replication, and inflammation, which enhances white blood cell turnover. Together, these processes might accelerate telomere erosion with age. We therefore tested the hypothesis that increased body mass and smoking are associated with shortened telomere length in white blood cells. We investigated 1122 white women aged 18-76 years and found that telomere length decreased steadily with age at a mean rate of 27 bp per year. Telomeres of obese women were 240 bp shorter than those of lean women (p=0.026). A dose-dependent relation with smoking was recorded (p=0.017), and each pack-year smoked was equivalent to an additional 5 bp of telomere length lost (18%) compared with the rate in the overall cohort. Our results emphasise the pro-ageing effects of obesity and cigarette smoking.
Consumption of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) can mitigate the progression of diseases in which oxidative stress represents a common underlying biochemical process. Nrf2-regulated gene expression regulates detoxification of reactive oxygen species. EPA and DHA were subjected to an in vitro free radical oxidation process that models in vivo conditions. Oxidized n-3 fatty acids reacted directly with the negative regulator of Nrf2, Keap1, initiating Keap1 dissociation with Cullin3, thereby inducing Nrf2-directed gene expression. Liquid chromatography-tandem mass spectrometry analyses of oxidized EPA demonstrated the presence of novel cyclopentenone-containing molecules termed J3-isoprostanes in vitro and in vivo and were shown to induce Nrf2-directed gene expression. These experiments provide a biochemical basis for the hypothesis that formation of J-ring compounds generated from oxidation of EPA and DHA in vivo can reach concentrations high enough to induce Nrf2-based cellular defense systems.
BACKGROUND: Telomere length reflects biological aging and may be influenced by environmental factors, including those that affect inflammatory processes.
OBJECTIVE: With data from 840 white, black, and Hispanic adults from the Multi-Ethnic Study of Atherosclerosis, we studied cross-sectional associations between telomere length and dietary patterns and foods and beverages that were associated with markers of inflammation.
DESIGN: Leukocyte telomere length was measured by quantitative polymerase chain reaction. Length was calculated as the amount of telomeric DNA (T) divided by the amount of a single-copy control DNA (S) (T/S ratio). Intake of whole grains, fruit and vegetables, low-fat dairy, nuts or seeds, nonfried fish, coffee, refined grains, fried foods, red meat, processed meat, and sugar-sweetened soda were computed with responses to a 120-item food-frequency questionnaire completed at baseline. Scores on 2 previously defined empirical dietary patterns were also computed for each participant.
RESULTS: After adjustment for age, other demographics, lifestyle factors, and intakes of other foods or beverages, only processed meat intake was associated with telomere length. For every 1 serving/d greater intake of processed meat, the T/S ratio was 0.07 smaller (beta +/- SE: -0.07 +/- 0.03, P = 0.006). Categorical analysis showed that participants consuming >or=1 serving of processed meat each week had 0.017 smaller T/S ratios than did nonconsumers. Other foods or beverages and the 2 dietary patterns were not associated with telomere length.
CONCLUSIONS: Processed meat intake showed an expected inverse association with telomere length, but other diet features did not show their expected associations.
Telomerase, a ribonucleoprotein that is capable of synthesizing telomeric repeats, is expressed in germline and malignant cells, and is absent in most normal human somatic cells. The selective expression of telomerase has thus been proposed to be a basis for the immortality of the germline and of malignant cells. In the present study, telomerase activity was analyzed in normal human T lymphocytes. It was found that telomerase is expressed at a high level in thymocyte subpopulations, at an intermediate level in tonsil T lymphocytes, and at a low to undetectable level in peripheral blood T lymphocytes. Moreover, telomerase activity is highly inducible in peripheral T lymphocytes by activation through CD3 with or without CD28 costimulation, or by stimulation with phorbol myristate acetate (PMA)/ionomycin. The induction of telomerase by anti-CD3 plus anti-CD28 (anti-CD3/CD28) stimulation required RNA and protein synthesis, and was blocked by herbimycin A, an inhibitor of S pi protein tyrosine kinases. The immunosuppressive drug cyclosporin A selectively inhibited telomerase induction by PMA/ionomycin and by anti-CD3, but not by anti-CD3/CD28. Although telomerase activity in peripheral T lymphocytes was activation dependent and correlated with cell proliferation, it was not cell cycle phase restricted. These results indicate that the expression of telomerase in normal human T lymphocytes is both developmentally regulated and activation induced. Telomerase may thus play a permissive role in T cell development and in determining the capacity of lymphoid cells for cell division and clonal expansion.
Background-Our purpose was to assess the time course of the benefit of n-3 polyunsaturated fatty acids (PUFAs) on mortality documented by the GISSI-Prevenzione trial in patients surviving a recent (<3 months) myocardial infarction. Methods and Results-In this study, 11 323 patients were randomly assigned to supplements of n-3 PUFAs, vitamin E (300 mg/d), both, or no treatment (control) on top of optimal pharmacological treatment and lifestyle advice. Intention-to-treat analysis adjusted for interaction between treatments was carried out. Early efficacy of n-3 PUFA treatment for total, cardiovascular, cardiac, coronary, and sudden death; nonfatal myocardial infarction; total coronary heart disease; and cerebrovascular events was assessed by right-censoring follow-up data 12 times from the first month after randomization up to 12 months. Survival curves for n-3 PUFA treatment diverged early after randomization, and total mortality was significantly lowered after 3 months of treatment (relative risk [RR] 0.59; 95% CI 0.36 to 0.97; P=0.037). The reduction in risk of sudden death was specifically relevant and statistically significant already at 4 months (RR 0.47; 95% CI 0.219 to 0.995; P=0.048). A similarly significant, although delayed, pattern after 6 to 8 months of treatment was observed for cardiovascular, cardiac, and coronary deaths. Conclusions-The early effect of low-dose ( I g/d) n-3 PUFAs on total mortality and sudden death supports the hypothesis of an antiarrhythmic effect of this drug. Such a result is consistent with the wealth of evidence coming from laboratory experiments on isolated myocytes, animal models, and epidemiological and clinical studies.
Telomeres are the DNA-protein complexes that protect the ends of eukaryotic chromosomes. The cellular enzyme telomerase counteracts telomere shortening by adding telomeric DNA. A growing body of literature links shorter telomere length and lower telomerase activity with various age-related diseases and earlier mortality. Thus, leukocyte telomere length (LTL) and telomerase activity are emerging both as biomarkers and contributing factors for age-related diseases. However, no clinical study has directly examined telomerase activity and telomere length in different lymphocyte subtypes isolated from the same donors, which could offer insight into the summary measure of leukocyte telomere maintenance. We report the first quantitative data in humans examining both levels of telomerase activity and telomere length in four lymphocyte subpopulations from the same donors-CD4+, CD8+CD28+ and CD8+CD28- T cells and B cells, as well as total PBMCs-in a cohort of healthy women. We found that B cells had the highest telomerase activity and longest telomere length; CD4+ T cells had slightly higher telomerase activity than CD8+CD28+ T cells, and similar telomere length. Consistent with earlier reports that CD8+CD28- T cells are replicatively senescent cells, they had the lowest telomerase activity and shortest telomere length. In addition, a higher percentage of CD8+CD28- T cells correlated with shorter total PBMC TL (r=-0.26, p=0.05). Interestingly, telomerase activities of CD4+ and CD8+CD28+ T cells from the same individual were strongly correlated (r=0.55, r<0.001), indicating possible common mechanisms for telomerase activity regulation in these two cell subtypes. These data will facilitate the understanding of leukocyte aging and its relationship to human health.
Chronic stress can affect human health through a myriad of behavioral and biochemical pathways. Tauhis review focuses on some key hormonal and metabolic pathways that appear important today. In modern society, we are faced with excessive psychological stress, as well as an epidemic of overeating, and the two together appear to have synergistic effects. Chronic stress can lead to overeating, co-elevation of cortisol and insulin, and suppression of certain anabolic hormones. This state of metabolic stress in turn promotes abdominal adiposity. Both the direct stress response and the accumulation of visceral fat can promote a milieu of systemic inflammation and oxidative stress. This biochemical environment appears to be conducive to several cell aging mechanisms, mainly dampening telomerase and leading to telomere length (TL) shortening and cell senescence. Immune cell telomere shortness is linked with many chronic disease states and earlier mortality. In this way, chronic stress may influence a variety of diseases through a biochemical cascade leading to immune cell senescence. Certain psychological temperaments at high risk of this stress cascade (mainly anxiety prone), gene-environment interactions, and potential interventions for interrupting the stress-aging cascade are discussed.
Telomere erosion of EPCs (endothelial progenitor cells) may be a key factor in endothelial cell senescence and is highly dependent on cellular oxidative damage. The aim of the present study was to investigate whether LLT (lipid-lowering therapy) with statins could attenuate EPC telomere erosion in patients with CAD (coronary artery disease). The study included 100 patients with stable CAD and 25 subjects without CAD as controls. CAD patients were randomized to 12 months of intensive LLT with atorvastatin or moderate LLT with pravastatin. EPCs were obtained from peripheral blood at baseline and after 12 months of statin therapy. Telomere length in EPCs was measured by FISH (fluorescence in situ hybridization) and oxidative DNA damage by flow cytometry of oxidized DNA bases. EPC telomere length was shorter in the CAD group than in the controls, and oxidative DNA damage to EPCs was higher in the CAD group compared with controls. After 12 months of therapy, changes in lipid profiles were greater in the intensive LLT group than in the moderate LLT group. Intensive LLT markedly increased EPC number and decreased oxidative DNA damage in EPCs (both P<0.05), with no change in telomere length. In contrast, moderate LLT did not change EPC counts or oxidative DNA damage, but showed telomere shortening (P<0.05). There was a weak negative correlation between changes in EPC number and LDL (low-density lipoprotein)-cholesterol levels after intensive LLT, whereas there was no correlation between them after moderate LLT. With in vitro culturing of EPCs subjected to oxidative stress, atorvastatin led to the prevention of EPC telomere shortening compared with pravastatin. In conclusion, the present study has demonstrated that intensive LLT may prevent EPC telomere erosion in patients with CAD, possibly contributing to the beneficial effects of intensive LLT in this disorder.
Telomere length reflects biological aging and may be influenced by environmental factors, including those that affect inflammatory processes.
With data from 840 white, black, and Hispanic adults from the Multi-Ethnic Study of Atherosclerosis, we studied cross-sectional associations between telomere length and dietary patterns and foods and beverages that were associated with markers of inflammation.
Leukocyte telomere length was measured by quantitative polymerase chain reaction. Length was calculated as the amount of telomeric DNA (T) divided by the amount of a single-copy control DNA (S) (T/S ratio). Intake of whole grains, fruit and vegetables, low-fat dairy, nuts or seeds, nonfried fish, coffee, refined grains, fried foods, red meat, processed meat, and sugar-sweetened soda were computed with responses to a 120-item food-frequency questionnaire completed at baseline. Scores on 2 previously defined empirical dietary patterns were also computed for each participant.
After adjustment for age, other demographics, lifestyle factors, and intakes of other foods or beverages, only processed meat intake was associated with telomere length. For every 1 serving/d greater intake of processed meat, the T/S ratio was 0.07 smaller (beta +/- SE: -0.07 +/- 0.03, P = 0.006). Categorical analysis showed that participants consuming >or=1 serving of processed meat each week had 0.017 smaller T/S ratios than did nonconsumers. Other foods or beverages and the 2 dietary patterns were not associated with telomere length.
Processed meat intake showed an expected inverse association with telomere length, but other diet features did not show their expected associations.
There are neglected but growing problems in the epidemiological field of telomere biology. The focus of the field has been
on leukocyte telomere dynamics, which ostensibly register the accruing burden of oxidative stress and inflammation. Important
as they are, studies that have examined associations between leukocyte telomere length and indices of aging and diseases of
aging also include many that are compromised by poor epidemiological and laboratory methodology. The shortcomings of these
studies muddle findings, undermine conclusions, and compromise the ability of the field to attain its goals, which include
a better understanding of human aging. Specific steps are delineated to resolve these problems. They include a call for an
impartial evaluation of the two major methods (Southern blots and quantitative polymerase chain reaction) currently in use
to measure telomere parameters and a proposal for a working model to test the potential connections of leukocyte telomere
dynamics with human aging and longevity.
Background:
Telomeres are protective DNA-protein complexes at the end of linear chromosomes that promote chromosomal stability. Telomere shortness in human beings is emerging as a prognostic marker of disease risk, progression, and premature mortality in many types of cancer, including breast, prostate, colorectal, bladder, head and neck, lung, and renal cell. Telomere shortening is counteracted by the cellular enzyme telomerase. Lifestyle factors known to promote cancer and cardiovascular disease might also adversely affect telomerase function. However, previous studies have not addressed whether improvements in nutrition and lifestyle are associated with increases in telomerase activity. We aimed to assess whether 3 months of intensive lifestyle changes increased telomerase activity in peripheral blood mononuclear cells (PBMC).
Methods:
30 men with biopsy-diagnosed low-risk prostate cancer were asked to make comprehensive lifestyle changes. The primary endpoint was telomerase enzymatic activity per viable cell, measured at baseline and after 3 months. 24 patients had sufficient PBMCs needed for longitudinal analysis. This study is registered on the ClinicalTrials.gov website, number NCT00739791.
Findings:
PBMC telomerase activity expressed as natural logarithms increased from 2.00 (SD 0.44) to 2.22 (SD 0.49; p=0.031). Raw values of telomerase increased from 8.05 (SD 3.50) standard arbitrary units to 10.38 (SD 6.01) standard arbitrary units. The increases in telomerase activity were significantly associated with decreases in low-density lipoprotein (LDL) cholesterol (r=-0.36, p=0.041) and decreases in psychological distress (r=-0.35, p=0.047).
Interpretation:
Comprehensive lifestyle changes significantly increase telomerase activity and consequently telomere maintenance capacity in human immune-system cells. Given this finding and the pilot nature of this study, we report these increases in telomerase activity as a significant association rather than inferring causation. Larger randomised controlled trials are warranted to confirm the findings of this study.
The DNA of telomeres--the terminal DNA-protein complexes of chromosomes--differs notably from other DNA sequences in both structure and function. Recent work has highlighted its remarkable mode of synthesis by the ribonucleoprotein reverse transcriptase, telomerase, as well as its ability to form unusual structures in vitro. Moreover, telomere synthesis by telomerase has been shown to be essential for telomere maintenance and long-term viability.
A randomised controlled trial with a factorial design was done to examine the effects of dietary intervention in the secondary prevention of myocardial infarction (MI). 2033 men who had recovered from MI were allocated to receive or not to receive advice on each of three dietary factors: a reduction in fat intake and an increase in the ratio of polyunsaturated to saturated fat, an increase in fatty fish intake, and an increase in cereal fibre intake. The advice on fat was not associated with any difference in mortality, perhaps because it produced only a small reduction (3-4%) in serum cholesterol. The subjects advised to eat fatty fish had a 29% reduction in 2 year all-cause mortality compared with those not so advised. This effect, which was significant, was not altered by adjusting for ten potential confounding factors. Subjects given fibre advice had a slightly higher mortality than other subjects (not significant). The 2 year incidence of reinfarction plus death from ischaemic heart disease was not significantly affected by any of the dietary regimens. A modest intake of fatty fish (two or three portions per week) may reduce mortality in men who have recovered from MI.
Telomeres in eukaryotic somatic cells are destined to the age-dependent shortening, which has not been demonstrated to correlate to direct lesion of telomeric DNA by reactive oxygen intermediates (ROI); still less explicable is the inhibitory effect of ROI-scavenging on telomere shortening. Here, we succeeded in artificial slowdown of age-dependent telomere shortening to 52-62% of the untreated control, in human vascular endothelial cells, by addition of the oxidation-resistant type of ascorbic acid (Asc), Asc-2-O-phosphate (Asc2P), which concurrently achieved both extension of cellular life-span and prevention of cell size enlargement indicative of cellular senescence. The results are attributable to a 3.9-fold more marked enrichment of intracellular Asc (Asc(in)) by addition of Asc2P, subsequently dephosphorylated before or during transmembrane influx, than by addition of Asc itself, and also attributed to diminution of intracellular ROI to 53% of the control level by Asc2P; telomerase activity was at a trace level and underwent an age-dependent decline, which was significantly decelerated by Asc2P. Thus, age-dependent telomere-shortening can be decelerated by suppression of intracellular oxidative stress and/or by telomerase retention, both of which are achieved by enriched Asc(in) but not by extracellular Asc overwhelmingly more abundant than Asc(in).
This review describes the structure of telomeres, the protective DNA-protein complexes at eukaryotic chromosomal ends, and several molecular mechanisms involved in telomere functions. Also discussed are cellular responses to compromising the functions of telomeres and of telomerase, which synthesizes telomeric DNA.
Experimental data suggest that long-chain n-3 polyunsaturated fatty acids found in fish have antiarrhythmic properties, and a randomized trial suggested that dietary supplements of n-3 fatty acids may reduce the risk of sudden death among survivors of myocardial infarction. Whether long-chain n-3 fatty acids are also associated with the risk of sudden death in those without a history of cardiovascular disease is unknown.
We conducted a prospective, nested case-control analysis among apparently healthy men who were followed for up to 17 years in the Physicians' Health Study. The fatty-acid composition of previously collected blood was analyzed by gas-liquid chromatography for 94 men in whom sudden death occurred as the first manifestation of cardiovascular disease and for 184 controls matched with them for age and smoking status.
Base-line blood levels of long-chain n-3 fatty acids were inversely related to the risk of sudden death both before adjustment for potential confounders (P for trend = 0.004) and after such adjustment (P for trend = 0.007). As compared with men whose blood levels of long-chain n-3 fatty acids were in the lowest quartile, the relative risk of sudden death was significantly lower among men with levels in the third quartile (adjusted relative risk, 0.28; 95 percent confidence interval, 0.09 to 0.87) and the fourth quartile (adjusted relative risk, 0.19; 95 percent confidence interval, 0.05 to 0.71).
The n-3 fatty acids found in fish are strongly associated with a reduced risk of sudden death among men without evidence of prior cardiovascular disease.
Our purpose was to assess the time course of the benefit of n-3 polyunsaturated fatty acids (PUFAs) on mortality documented by the GISSI-Prevenzione trial in patients surviving a recent (<3 months) myocardial infarction.
In this study, 11 323 patients were randomly assigned to supplements of n-3 PUFAs, vitamin E (300 mg/d), both, or no treatment (control) on top of optimal pharmacological treatment and lifestyle advice. Intention-to-treat analysis adjusted for interaction between treatments was carried out. Early efficacy of n-3 PUFA treatment for total, cardiovascular, cardiac, coronary, and sudden death; nonfatal myocardial infarction; total coronary heart disease; and cerebrovascular events was assessed by right-censoring follow-up data 12 times from the first month after randomization up to 12 months. Survival curves for n-3 PUFA treatment diverged early after randomization, and total mortality was significantly lowered after 3 months of treatment (relative risk [RR] 0.59; 95% CI 0.36 to 0.97; P=0.037). The reduction in risk of sudden death was specifically relevant and statistically significant already at 4 months (RR 0.47; 95% CI 0.219 to 0.995; P=0.048). A similarly significant, although delayed, pattern after 6 to 8 months of treatment was observed for cardiovascular, cardiac, and coronary deaths.
The early effect of low-dose (1 g/d) n-3 PUFAs on total mortality and sudden death supports the hypothesis of an antiarrhythmic effect of this drug. Such a result is consistent with the wealth of evidence coming from laboratory experiments on isolated myocytes, animal models, and epidemiological and clinical studies.
It has long been presumed impossible to measure telomeres in vertebrate DNA by PCR amplification with oligonucleotide primers
designed to hybridize to the TTAGGG and CCCTAA repeats, because only primer dimer-derived products are expected. Here we present
a primer pair that eliminates this problem, allowing simple and rapid measurement of telomeres in a closed tube, fluorescence-based
assay. This assay will facilitate investigations of the biology of telomeres and the roles they play in the molecular pathophysiology
of diseases and aging.
During normal ageing, the gradual loss of telomeric DNA in dividing somatic cells can contribute to replicative senescence, apoptosis, or neoplastic transformation. In the genetic disorder dyskeratosis congenita, telomere shortening is accelerated, and patients have premature onset of many age-related diseases and early death. We aimed to assess an association between telomere length and mortality in 143 normal unrelated individuals over the age of 60 years. Those with shorter telomeres in blood DNA had poorer survival, attributable in part to a 3.18-fold higher mortality rate from heart disease (95% CI 1(.)36-7.45, p=0.0079), and an 8.54-fold higher mortality rate from infectious disease (1.52-47.9, p=0.015). These results lend support to the hypothesis that telomere shortening in human beings contributes to mortality in many age-related diseases.
Omega-3 fatty acids have been shown in epidemiological and clinical trials to reduce the incidence of CVD. Large-scale epidemiological studies suggest that individuals at risk for CHD benefit from the consumption of plant- and marine-derived omega-3 fatty acids, although the ideal intakes presently are unclear. Evidence from prospective secondary prevention studies suggests that EPA+DHA supplementation ranging from 0.5 to 1.8 g/d (either as fatty fish or supplements) significantly reduces subsequent cardiac and all-cause mortality. For α-linolenic acid, total intakes of ≈1.5 to 3 g/d seem to be beneficial. Collectively, these data are supportive of the recommendation made by the AHA Dietary Guidelines to include at least two servings of fish per week (particularly fatty fish). In addition, the data support inclusion of vegetable oils (eg, soybean, canola, walnut, flaxseed) and food sources (eg, walnuts, flaxseeds) high in α-linolenic acid in a healthy diet for the general population (Table 5). The fish recommendation must be balanced with concerns about environmental pollutants, in particular PCB and methylmercury, described in state and federal advisories. Consumption of a variety of fish is recommended to minimize any potentially adverse effects due to environmental pollutants and, at the same time, achieve desired CVD health outcomes. RCTs have demonstrated that omega-3 fatty acid supplements can reduce cardiac events (eg, death, nonfatal MI, nonfatal stroke) and decrease progression of atherosclerosis in coronary patients. However, additional studies are needed to confirm and further define the health benefits of omega-3 fatty acid supplements for both primary and secondary prevention. For example, placebo-controlled, double-blind RCTs are needed to document both the safety and efficacy of omega-3 fatty acid supplements in both high-risk patients (eg, patients with type 2 diabetes, dyslipidemia, and hypertension, and smokers) and coronary patients on drug therapy. Mechanistic studies on their apparent effects on sudden death are also needed. A dietary (ie, food-based) approach to increasing omega-3 fatty acid intake is preferable. Still, for patients with coronary artery disease, the dose of omega-3 (≈1 g/d) may be greater than what can readily be achieved through diet alone (Table 5). These individuals, in consultation with their physician, could consider supplements for CHD risk reduction. Supplements also could be a component of the medical management of hypertriglyceridemia, a setting in which even larger doses (2 to 4 g/d) are required (Table 5). The availability of high-quality omega-3 fatty acid supplements, free of contaminants, is an important prerequisite to their extensive use.
Little is known regarding the extent to which patient-reported health status, including symptom burden, physical limitation, and quality of life, is determined by psychosocial vs physiological factors among patients with chronic disease.
To compare the contributions of depressive symptoms and measures of cardiac function to the health status of patients with coronary artery disease.
Cross-sectional study of 1024 adults with stable coronary artery disease recruited from outpatient clinics in the San Francisco Bay Area between September 2000 and December 2002. Main Measures Measurement of depressive symptoms using the Patient Health Questionnaire (PHQ); assessment of cardiac function by measuring left ventricular ejection fraction on echocardiography, exercise capacity on treadmill testing, and ischemia on stress echocardiography; and measurement of a range of health status outcomes, including symptom burden, physical limitation, and quality of life, using the Seattle Angina Questionnaire. Participants were also asked to rate their overall health as excellent, very good, good, fair, or poor.
Of the 1024 participants, 201 (20%) had depressive symptoms (PHQ score > or =10). Participants with depressive symptoms were more likely than those without depressive symptoms to report at least mild symptom burden (60% vs 33%; P<.001), mild physical limitation (73% vs 40%; P<.001), mildly diminished quality of life (67% vs 31%; P<.001), and fair or poor overall health (66% vs 30%; P<.001). In multivariate analyses adjusting for measures of cardiac function and other patient characteristics, depressive symptoms were strongly associated with greater symptom burden (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.3-2.7; P =.002), greater physical limitation (OR, 3.1; 95% CI, 2.1-4.6; P<.001), worse quality of life (OR, 3.1; 95% CI, 2.2-4.6; P<.001), and worse overall health (OR, 2.0; 95% CI, 1.3-2.9; P<.001). Although decreased exercise capacity was associated with worse health status, left ventricular ejection fraction and ischemia were not.
Among patients with coronary disease, depressive symptoms are strongly associated with patient-reported health status, including symptom burden, physical limitation, quality of life, and overall health. Conversely, 2 traditional measures of cardiac function-ejection fraction and ischemia-are not. Efforts to improve health status should include assessment and treatment of depressive symptoms.
The proliferative capacity of human cells is regulated by telomerase, an enzyme uniquely specialised for telomeric DNA synthesis. The critical role of telomerase activation in tumour progression and tumour maintenance has been well established in studies of cancer and of oncogenic transformation in cell culture. New evidence suggests that telomerase activation has an important role in normal somatic cells, and that failure to activate sufficient telomerase also promotes disease. We review the evidence for premature telomere attrition in proliferative deficiencies of the human haemopoietic system, and discuss the potential use of telomerase activation in telomere-restorative gene therapy.
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. The molecular consequences of telomere failure, and the molecular contributors to telomere function, with an emphasis on telomerase, are discussed here.
Telomeres cap the ends of chromosomes and are essential for the protection of chromosomes, as well as restricting the replicative potential of a cell. These functions are achieved by the regulation of telomeric repeat length, making the measurement of telomere length a useful aid in the elucidation of the replicative history and potential of cells. Previously published techniques employed either hybridization or flow cytometry methods, which are technically demanding and time-consuming. In 2002, R. M. Cawthon published a real-time polymerase chain reaction (PCR)-based method for telomere length measurement using the Applied Biosystems Prism 7700 sequence detection system. The technique measures the factor by which the ratio of telomere repeat copy number to single-gene copy number differs between a sample and that of a reference deoxyribonucleic acid sample. In many laboratories worldwide, including ours, real-time PCR is carried out using the Roche LightCycler, as opposed to the AB Prism 7700 system. This benchmark details the modifications to Cawthon's method and describes the parameters and reagents required to measure telomere length using the Roche LightCycler.
Low intakes or blood levels of eicosapentaenoic and docosahexaenoic acids (EPA + DHA) are independently associated with increased risk of death from coronary heart disease (CHD). In randomized secondary prevention trials, fish or fish oil have been demonstrated to reduce total and CHD mortality at intakes of about 1 g/day. Red blood cell (RBC) fatty acid (FA) composition reflects long-term intake of EPA + DHA. We propose that the RBC EPA + DHA (hereafter called the Omega-3 Index) be considered a new risk factor for death from CHD.
We conducted clinical and laboratory experiments to generate data necessary for the validation of the Omega-3 Index as a CHD risk predictor. The relationship between this putative marker and risk for CHD death, especially sudden cardiac death (SCD), was then evaluated in several published primary and secondary prevention studies.
The Omega-3 Index was inversely associated with risk for CHD mortality. An Omega-3 Index of > or = 8% was associated with the greatest cardioprotection, whereas an index of < or = 4% was associated with the least.
The Omega-3 Index may represent a novel, physiologically relevant, easily modified, independent, and graded risk factor for death from CHD that could have significant clinical utility.
Cultivation of endothelial progenitor cells (EPCs) leads to premature replicative senescence, limiting ex vivo expansion for potential clinical cell therapy. Recent studies have linked senescence to the dysfunction of telomeres, the "ends" of chromosomes, via the so-called mitotic clock or culture-induced stress. The purpose of this study was to elucidate a possible role of telomere biology in the functional augmentation of EPCs by statins.
Human EPCs were isolated from peripheral blood. Using flow cytometry after fluorescence in situ hybridization with a telomere-specific (C3TA2)3 peptide nucleic acid probe (Flow-FISH), we found mean telomere length in untreated EPCs from healthy subjects to range between 8.5+/-0.2 and 11.1+/-0.5 kb with no change over 6 days of culture, excluding telomere erosion as one cause for premature senescence. Although mean telomere length did not differ between statin-treated and untreated EPCs, atorvastatin (0.1 micromol/L) and mevastatin (1.0 micromol/L) both led to a more than 3-fold increase in the expression of the telomere capping protein TRF2 (telomere repeat-binding factor), as shown by immunoblotting, whereas quantitative reverse transcription-polymerase chain reaction demonstrated no increase in TRF2 mRNA. Telomere dysfunction of EPCs was also paralleled by a 4-fold increase in the DNA damage checkpoint-kinase 2 (Chk2). Conversely, statin cotreatment or overexpression of TRF2 completely suppressed Chk2 induction. Finally, overexpression of a dominant negative mutant of the TRF2 protein abrogated statin-induced enhancement of migratory activity down to baseline values.
Ex vivo culturing of EPCs leads to "uncapping" of telomeres, indicated by the loss of TRF2. Statin cotreatment of EPCs prevents impairment of their functional capacity by a TRF2-dependent, posttranscriptional mechanism. This is the first time a beneficial effect of statins on telomere biology has been described.
Biological age may be distinct from chronological age and contribute to the pathogenesis of age-related diseases. Mean telomeres lengths provide an assessment of biological age with shorter telomeres, indicating increased biological age. We investigated whether subjects with premature myocardial infarction (MI) had shorter leukocyte telomeres.
Mean terminal restriction fragment (TRF) length, a measure of average telomere size, was compared in leukocyte DNA of 203 cases with a premature MI (<50 years) and 180 controls. Age- and sex-adjusted mean TRF length of cases was significantly shorter than that of controls (difference 299.7+/-69.3 base pairs, P<0.0001) and on average equivalent to controls 11.3 years older. The difference in mean TRF length between cases and controls was not accounted for by other coronary risk factors. Compared with subjects in the highest quartile for telomere length, the risk of myocardial infarction was increased between 2.8- and 3.2-fold (P<0.0001) in subjects with shorter than average telomeres.
The findings support the concept that biological age may play a role in the etiology of coronary heart disease and have potentially important implications for our understanding of its genetic etiology, pathogenesis, and variable age of onset.
As high telomerase activity is detected in most cancer cells, telomerase represents a promising cancer therapeutic target. We investigated the inhibitory effect of various fatty acids on telomerase, with particular emphasis on those with antitumor properties, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). To evaluate the direct effect of fatty acids on telomerase, cell lysates of DLD-1 human colorectal adenocarcinoma cells were mixed with sample fatty acids, and the telomerase activity was determined. Saturated fatty acids and trans-fatty acids showed very weak or no inhibition of telomerase. In contrast, cis-unsaturated fatty acids significantly inhibited the enzyme, and the inhibitory potency was elevated with an increase in the number of double bonds. Accordingly, polyunsaturated fatty acids (PUFAs), like EPA and DHA, appeared to be powerful telomerase inhibitors. To assess the transcriptional effect, DLD-1 cells were cultured in the presence of sample fatty acids, and telomerase activity and gene expression were subsequently evaluated. Culturing DLD-1 cells with either EPA or DHA resulted in a remarkable decrease in telomerase activity. EPA and DHA inhibited telomerase by down-regulating human telomerase reverse transcriptase (hTERT) and c-myc expression via protein kinase C inhibition. These results indicate that PUFAs can directly inhibit the enzymatic activity of telomerase as well as modulate the telomerase at the transcriptional level.
The present study was conducted to examine the effect of eicosapentaenoic acid supplements on pulse wave velocity (PWV) in patients with dyslipidemia as a prospective open-labeled study. Eicosapentaenoic acid supplements (1,800 mg/day) were prescribed to 40 patients, and diet therapy in consultation with a nutritionist was conducted in 44 patients as a control group. These interventions were continued for 12 months, and PWV and blood examinations were performed at the start and end of these interventions. PWV increased in the control group but not in the eicosapentaenoic acid group. After adjustment for age, gender, the initial PWV, and the changes in mean blood pressure during the study period, a general linear model univariate analysis post hoc comparison demonstrated that the change in PWV during the period of study was significantly larger in the control group (42 +/- 20 cm/s) than in the eicosapentaenoic acid group (-9 +/- 19 cm/s) (p<0.05). Thus, this preliminary study suggested that eicosapentaenoic acid supplements attenuate age-related increases in arterial stiffness in patients with dyslipidemia. A further study with a larger number of subjects is proposed to confirm this beneficial effect of eicosapentaenoic acid supplements on arterial stiffness.
Accumulation of cellular damage with advancing age leads to atherothrombosis and associated cardiovascular disease. Ageing is also characterized by shortening of the DNA component of telomeres, the specialized genetic segments located at the end of eukaryotic chromosomes that protect them from end-to-end fusions. By inducing genomic instability, replicative senescence and apoptosis, shortening of the telomeric DNA is thought to contribute to organismal ageing. In this Review, we discuss experimental and human studies that have linked telomeres and associated proteins to several factors which influence cardiovascular risk (eg, estrogens, oxidative stress, hypertension, diabetes, and psychological stress), as well as to neovascularization and the pathogenesis of atherosclerosis and heart disease. Two chief questions that remain unanswered are whether telomere shortening is cause or consequence of cardiovascular disease, and whether therapies targeting the telomere may find application in treating these disorders (eg, cell "telomerization" to engineer blood vessels of clinical value for bypass surgery, and to facilitate cell-based myocardial regeneration strategies). Given that most research to date has focused on the role of telomerase, it is also of up most importance to investigate whether alterations in additional telomere-associated proteins may contribute to the pathogenesis of cardiovascular disease.
Inter-individual differences in biological ageing could affect susceptibility to coronary heart disease. Our aim was to determine whether mean leucocyte telomere length is a predictor of the development of coronary heart disease.
We compared telomere lengths at recruitment in 484 individuals in the West of Scotland Primary Prevention Study (WOSCOPS) who went on to develop coronary heart disease events with those from 1058 matched controls who remained event free. We also investigated whether there was any association between telomere length and observed clinical benefit of statin treatment in WOSCOPS.
Mean telomere length decreased with age by 9% per decade (95% CI 3.6-14.1; p=0.001) in controls; much the same trend was seen in cases (-5.9% per decade, -3.1 to 14.1; p=0.1902). Individuals in the middle and the lowest tertiles of telomere length were more at risk of developing a coronary heart disease event than were individuals in the highest tertile (odds ratio [OR] for coronary heart disease: 1.51, 95% CI 1.15-1.98; p=0.0029 in the middle tertile; 1.44, 1.10-1.90, p=0.0090 in the lowest). In placebo-treated patients, the risk of coronary heart disease was almost double in those in the lower two tertiles of telomere length compared with those in the highest tertile (1.93, 1.33-2.80, p=0.0005 in the middle tertile; 1.94, 1.33-2.84, p=0.0006 in the lowest). By contrast, in patients treated with pravastatin, the increased risk with shorter telomeres was substantially attenuated (1.12, 0.75-1.69, p=0.5755 in the middle tertile; 1.02, 0.68-1.52, p=0.9380 in the lowest).
Mean leucocyte telomere length is a predictor of future coronary heart disease events in middle-aged, high-risk men and could identify individuals who would benefit most from statin treatment. Our findings lend support to the hypothesis that differences in biological ageing might contribute to the risk--and variability in age of onset--of coronary heart disease.
Diet, along with genetic and environmental factors, is considered a major aspect affecting longevity as well as vascular disease outcome. Yet, inadequate nutritional intake is rampant among the elderly, affecting nearly 44% of otherwise healthy, community-dwellers in developed countries. Thus, malnutrition, both in quali- and quantitative terms and especially as related to micronutrient intake, may exacerbate intrinsic cardiovascular maladaptation associated with aging, affecting vascular disease outcomes as well as longevity. Conversely, there is accumulating evidence that diets enriched in micronutrients, including vitamins, polyphenols, and essential fatty acids, maintain cellular antioxidant status and stress response enzymes, which otherwise decrease with age. Thus, adequate intakes of micronutrients, either consequent to a correct diet or through supplementation, might afford the elderly protection from cardiovascular diseases. In this article we review the known effects of micronutrients on the aging heart and we propose strategies for dietary improvements.