Impact of health literacy and its interventions on health outcomes in those with atrial fibrillation: a systematic review protocol.

INTRODUCTION: Atrial fibrillation (AF) is associated with increased risk of stroke, heart failure and death. Health literacy, an aspect that falls within precision health, has been recognised as an important factor. We will be focusing on the impact of these interventions specifically to AF and its health outcomes. METHODS AND ANALYSIS: This protocol is informed by the Preferred Reporting Items for Systematic review and Meta-Analysis Protocols. The results will be reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses to determine the impacts of health literacy interventions on AF outcomes. Searches will be carried out on databases including MEDLINE, EMBASE, Web of Science, CINAHL, Emcare, Cochrane Library and Google Scholar. Citations will be collected via Endnote 20, then into Covidence for duplicate removal, and article screening. Extraction will occur using a standardised extraction tool and studies will be synthesised using best evidence synthesis. Downs and Black's checklist will be used for risk of bias and assessment of overall quality of evidence will use the Grading of Recommendations, Assessment, Development and Evaluation approach. ETHICS AND DISSEMINATION: Approval from human research ethics committee is not required. Dissemination will occur in peer-reviewed journals and conference presentations. PROSPERO REGISTRATION NUMBER: CRD42022304835.

Trends and gaps in precision health research: a scoping review.

OBJECTIVE: To determine progress and gaps in global precision health research, examining whether precision health studies integrate multiple types of information for health promotion or restoration. DESIGN: Scoping review. DATA SOURCES: Searches in Medline (OVID), PsycINFO (OVID), Embase, Scopus, Web of Science and grey literature (Google Scholar) were carried out in June 2020. ELIGIBILITY CRITERIA: Studies should describe original precision health research; involve human participants, datasets or samples; and collect health-related information. Reviews, editorial articles, conference abstracts or posters, dissertations and articles not published in English were excluded. DATA EXTRACTION AND SYNTHESIS: The following data were extracted in independent duplicate: author details, study objectives, technology developed, study design, health conditions addressed, precision health focus, data collected for personalisation, participant characteristics and sentence defining 'precision health'. Quantitative and qualitative data were summarised narratively in text and presented in tables and graphs. RESULTS: After screening 8053 articles, 225 studies were reviewed. Almost half (105/225, 46.7%) of the studies focused on developing an intervention, primarily digital health promotion tools (80/225, 35.6%). Only 28.9% (65/225) of the studies used at least four types of participant data for tailoring, with personalisation usually based on behavioural (108/225, 48%), sociodemographic (100/225, 44.4%) and/or clinical (98/225, 43.6%) information. Participant median age was 48 years old (IQR 28-61), and the top three health conditions addressed were metabolic disorders (35/225, 15.6%), cardiovascular disease (29/225, 12.9%) and cancer (26/225, 11.6%). Only 68% of the studies (153/225) reported participants' gender, 38.7% (87/225) provided participants' race/ethnicity, and 20.4% (46/225) included people from socioeconomically disadvantaged backgrounds. More than 57% of the articles (130/225) have authors from only one discipline. CONCLUSIONS: Although there is a growing number of precision health studies that test or develop interventions, there is a significant gap in the integration of multiple data types, systematic intervention assessment using randomised controlled trials and reporting of participant gender and ethnicity. Greater interdisciplinary collaboration is needed to gather multiple data types; collectively analyse big and complex data; and provide interventions that restore, maintain and/or promote good health for all, from birth to old age.

Palmitic Acid, but Not Lauric Acid, Induces Metabolic Inflammation, Mitochondrial Fragmentation, and a Drop in Mitochondrial Membrane Potential in Human Primary Myotubes.

The chain length of saturated fatty acids may dictate their impact on inflammation and mitochondrial dysfunction, two pivotal players in the pathogenesis of insulin resistance. However, these paradigms have only been investigated in animal models and cell lines so far. Thus, the aim of this study was to compare the effect of palmitic (PA) (16:0) and lauric (LA) (12:0) acid on human primary myotubes mitochondrial health and metabolic inflammation. Human primary myotubes were challenged with either PA or LA (500 µM). After 24 h, the expression of interleukin 6 (IL-6) was assessed by quantitative polymerase chain reaction (PCR), whereas Western blot was used to quantify the abundance of the inhibitor of nuclear factor κB (IκBα), electron transport chain complex proteins and mitofusin-2 (MFN-2). Mitochondrial membrane potential and dynamics were evaluated using tetraethylbenzimidazolylcarbocyanine iodide (JC-1) and immunocytochemistry, respectively. PA, contrarily to LA, triggered an inflammatory response marked by the upregulation of IL-6 mRNA (11-fold; P < 0.01) and a decrease in IκBα (32%; P < 0.05). Furthermore, whereas PA and LA did not differently modulate the levels of mitochondrial electron transport chain complex proteins, PA induced mitochondrial fragmentation (37%; P < 0.001), decreased MFN-2 (38%; P < 0.05), and caused a drop in mitochondrial membrane potential (11%; P < 0.01) compared to control, with this effect being absent in LA-treated cells. Thus, LA, as opposed to PA, did not trigger pathogenetic mechanisms proposed to be linked with insulin resistance and therefore represents a healthier saturated fatty acid choice to potentially preserve skeletal muscle metabolic health.

The Inhibition of Metabolic Inflammation by EPA Is Associated with Enhanced Mitochondrial Fusion and Insulin Signaling in Human Primary Myotubes.

BACKGROUND: Sustained fuel excess triggers low-grade inflammation that can drive mitochondrial dysfunction, a pivotal defect in the pathogenesis of insulin resistance in skeletal muscle. OBJECTIVES: This study aimed to investigate whether inflammation in skeletal muscle can be prevented by EPA, and if this is associated with an improvement in mitochondrial fusion, membrane potential, and insulin signaling. METHODS: Human primary myotubes were treated for 24 h with palmitic acid (PA, 500 µM) under hyperglycemic conditions (13 mM glucose), which represents nutrient overload, and in the presence or absence of EPA (100 µM). After the treatments, the expression of peroxisome proliferator-activated receptor γ coactivator 1-α (PPARGC1A) and IL6 was assessed by q-PCR. Western blot was used to measure the abundance of the inhibitor of NF-κB (IKBA), mitofusin-2 (MFN2), mitochondrial electron transport chain complex proteins, and insulin-dependent AKT (Ser473) and AKT substrate 160 (AS 160; Thr642) phosphorylation. Mitochondrial dynamics and membrane potential were evaluated using immunocytochemistry and the JC-1 (tetraethylbenzimidazolylcarbocyanine iodide) dye, respectively. Data were analyzed using 1-factor ANOVA followed by Tukey post hoc test. RESULTS: Nutrient excess activated the proinflammatory NFκB signaling marked by a decrease in IKBA (40%; P < 0.05) and the upregulation of IL6 mRNA (12-fold; P < 0.001). It also promoted mitochondrial fragmentation (53%; P < 0.001). All these effects were counteracted by EPA. Furthermore, nutrient overload-induced drop in mitochondrial membrane potential (6%; P < 0.05) was prevented by EPA. Finally, EPA inhibited fuel surplus-induced impairment in insulin-mediated phosphorylation of AKT (235%; P < 0.01) and AS160 (49%; P < 0.05). CONCLUSIONS: EPA inhibited NFκB signaling, which was associated with an attenuation of the deleterious effects of PA and hyperglycemia on both mitochondrial health and insulin signaling in human primary myotubes. Thus, EPA might preserve skeletal muscle metabolic health during sustained fuel excess but this requires confirmation in human clinical trials.

Defining precision health: a scoping review protocol.

INTRODUCTION: Precision health is a nascent field of research that would benefit from clearer operationalisation and distinction from adjacent fields like precision medicine. This clarification is necessary to enable precision health science to tackle some of the most complex and significant health problems that are faced globally. There is a pressing need to examine the progress in human precision health research in the past 10 years and analyse this data to first, find similarities and determine discordances in how precision health is operationalised in the literature and second, identify gaps and future directions for precision health research. METHODS AND ANALYSIS: To define precision health and map research in this field, a scoping review will be undertaken and reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses - Scoping Review Extension guidelines. Systematic searches of scientific databases (Medline, Embase, Scopus, Web of Science and PsycINFO) and grey literature sources (Google Scholar, Google Patents) identified 8053 potentially eligible articles published from 1 January 2010 to 30 June 2020. Following removal of duplicates, a total of 3190 articles were imported for screening. Article data will be extracted using a customised extraction template on Covidence and analysed descriptively using narrative synthesis. ETHICS AND DISSEMINATION: Ethics approval is not required. Findings will be disseminated through professional networks, conference presentations and publication in a scientific journal.

Exploring In Vivo Dynamics of Bovine Milk Derived Gangliosides.

Gangliosides are glycosphingolipids present in mammalian cell membranes, playing important structural and functional roles. Human studies on the health benefits of gangliosides are increasing, but knowledge gaps regarding ganglioside analysis exist. The study aimed to investigate blood sample type (serum/plasma), storage conditions, diurnal, day-to-day variation and acute effects of consuming bovine-derived gangliosides on circulating monosialylated gangliosides. Seventy-one women (18-40 yrs, 20-≤30.0 kg/m2) were enrolled and 61 completed the intervention. They visited the clinic three times following overnight fasting. Serum/plasma gangliosides were analyzed over 2 h (visit-1), 8 h (visit-2) and 8 h following either zero or high ganglioside meals (visit-3). Samples stored at -20 °C and -70 °C were analyzed at 3-, 6-, 12- and 18-months. Plasma and serum GM3-gangliosides did not differ, plasma GM3 did not change diurnally, from day-to-day, in response to a high vs. low ganglioside meal or after 7-days low ganglioside vs. habitual diet (P > 0.05). GM3 concentrations were lower in samples stored at -70 °C vs. -20 °C from 6-months onwards and decreased over time with lowest levels at 12- and 18-months stored at -70 °C. In conclusion, either serum/plasma stored at -20- or -70 °C for up to 6 months, are acceptable for GM3-ganglioside analysis. Blood samples can be collected at any time of the day and participants do not have to be in the fasted state.

Mitochondrial (Dys)function and Insulin Resistance: From Pathophysiological Molecular Mechanisms to the Impact of Diet.

Mitochondrial dysfunction has been implicated in the pathogenesis of insulin resistance, the hallmark of type 2 diabetes mellitus (T2DM). However, the cause-effect relationship remains to be fully elucidated. Compelling evidence suggests that boosting mitochondrial function may represent a valuable therapeutic tool to improve insulin sensitivity. Mitochondria are highly dynamic organelles, which adapt to short- and long-term metabolic perturbations by undergoing fusion and fission cycles, spatial rearrangement of the electron transport chain complexes into supercomplexes and biogenesis governed by peroxisome proliferator-activated receptor γ co-activator 1α (PGC 1α). However, these processes appear to be dysregulated in type 2 diabetic individuals. Herein, we describe the mechanistic link between mitochondrial dysfunction and insulin resistance in skeletal muscle alongside the intracellular pathways orchestrating mitochondrial bioenergetics. We then review current evidence on nutritional tools, including fatty acids, amino acids, caloric restriction and food bioactive derivatives, which may enhance insulin sensitivity by therapeutically targeting mitochondrial function and biogenesis.

Salivary α-amylase copy number is not associated with weight trajectories and glycemic improvements following clinical weight loss: results from a 2-phase dietary intervention study.

BACKGROUND: Several studies recently reported contradicting results regarding the link between amylase 1 (AMY1) copy numbers (CNs), obesity, and type 2 diabetes. OBJECTIVE: The aim of this study was to assess the impact of AMY1 CN on anthropometrics and glycemic outcomes in obese individuals following a 2-phase dietary weight loss intervention. METHODS: Using the paralog ratio test, AMY1 CNs were accurately measured in 761 obese individuals from the DiOGenes study. Subjects first underwent an 8-wk low-calorie diet (LCD, at 800 kcal/d) and then were randomly assigned to a 6-mo weight maintenance dietary (WMD) intervention with arms having different glycemic loads. RESULTS: At baseline, a modest association between AMY1 CN and BMI (P = 0.04) was observed. AMY1 CN was not associated with baseline glycemic variables. In addition, AMY1 CN was not associated with anthropometric or glycemic outcomes following either LCD or WMD. Interaction analyses between AMY1 CN and nutrient intake did not reveal any significant association with clinical parameters (at baseline and following LCD or WMD) or when testing gene × WMD interactions during the WMD phase. CONCLUSION: In the absence of association with weight trajectories or glycemic improvements, the AMY1 CN cannot be considered as an important biomarker for response to a clinical weight loss and weight maintenance programs in overweight/obese subjects. This trial was registered at www.clinicaltrials.gov as NCT00390637.

Effects of Intermittent Versus Continuous Energy Intakes on Insulin Sensitivity and Metabolic Risk in Women with Overweight.

OBJECTIVE: This study aimed to compare intermittent fasting (IF) versus continuous energy intakes at 100% or 70% of calculated energy requirements on insulin sensitivity, cardiometabolic risk, body weight, and composition. METHODS: Women with overweight (n = 88; 50 ± 1 years, BMI 32.3 ± 0.5 kg/m2 ) were randomized to one of four diets (IF70, IF100, dietary restriction [DR70], or control) in a 2:2:2:1 ratio for 8 weeks. IF groups fasted for 24 hours after breakfast on three nonconsecutive days per week. All foods were provided and diets matched for macronutrient composition (35% fat, 15% protein, 50% carbohydrate). Insulin sensitivity by hyperinsulinemic-euglycemic clamp, weight, body composition, and plasma markers were assessed following a "fed" day (12-hour fast) and a 24-hour fast (IF only). RESULTS: IF70 displayed greater reductions in weight, fat mass, total- and low-density lipoprotein cholesterol, and nonesterified fatty acids compared with DR70 and IF100 (all P ≤ 0.05). IF100 lost more weight and fat than control. However, fasting insulin was increased. There were no group differences in insulin sensitivity by clamp; however, a 24-hour fast transiently reduced insulin sensitivity. CONCLUSIONS: When prescribed at matched energy restriction, IF reduced weight and fat mass and improved total and low-density lipoprotein cholesterol more than DR. IF prescribed in energy balance did not improve health compared with other groups, despite modest weight loss.

An 18-mo randomized, double-blind, placebo-controlled trial of DHA-rich fish oil to prevent age-related cognitive decline in cognitively normal older adults.

Background: Fish oil trials in cognitively healthy older adults have yielded inconsistent results. Supplementation may differentially affect the domains that underpin cognitive performance, and effects may differ across sex or genotype. Objective: The aim of this study was to test whether docosahexaenoic acid (DHA)-rich fish oil slows 18-mo cognitive decline in cognitively healthy elders. Design: In a double-blind, randomized, placebo-controlled, parallel-group trial, cognitively healthy Australian community-dwelling adults (aged 65-90 y) consumed either 1720 mg DHA and 600 mg eicosapentaenoic acid or low-polyphenolic olive oil daily, as capsules, for 18 mo. Groups were allocated by permuted-block randomization and stratified by age. Cognitive assessment was conducted at baseline and then every 6 mo. Primary analyses tested the difference between groups in the rate of 18-mo cognitive change via latent growth curve models on any of the following: reasoning, working memory, short-term memory, retrieval fluency, and cognitive speed-related constructs. Treatment interactions with sex and APOE-ε4 were tested. Secondary outcomes were self-reported changes in well-being and everyday functioning, blood pressure, biomarkers of n-3 (ω-3) long-chain polyunsaturated fatty acids (LC PUFAs), lipids, glucose metabolism, inflammation, oxidative stress, DNA damage, and Mini-Mental State Examination. Results: A total of 403 people were randomly assigned. Data from those who completed baseline were analyzed (n = 390; intervention n = 194, control n = 196). Daily supplementation with 2.3 g DHA-rich fish oil for 18 mo did not maintain or improve cognitive performance. A small negative main effect was found on psychomotor speed (intervention = -0.02, 95% CI: -0.04 to 0.00; d = 0.24, P = 0.03). Treatment effects differed according to sex on retrieval fluency and some speed-based domains, including psychomotor speed, and according to APOE-ε4 carrier status on reaction time and reasoning. For secondary outcomes, treatment was associated with increased perceived cognitive mistakes (d = 0.24; P = 0.003), increased oxidative stress, and expected changes in fatty acid metabolism. Conclusions: Findings do not support supplementing older adults with fish oil to prevent cognitive decline. Treatment interactions with sex and APOE-ε4 carrier status warrant further investigation. This trial was registered at the Australia and New Zealand Clinical Trials Register (ANZCTR) as ACTRN12607000278437.

n-3 Fatty Acid Supplementation and Leukocyte Telomere Length in Patients with Chronic Kidney Disease.

DNA telomere shortening associates with the age-related increase cardiovascular disease (CVD) risk. Reducing oxidative stress, could modify telomere erosion during cell replication, and CVD risk in patients with chronic kidney disease (CKD). The effect of n-3 fatty acids and coenzyme Q10 (CoQ) on telomere length was studied in a double-blind placebo-controlled trial in CKD. Eighty-five CKD patients were randomized to: n-3 fatty acids (4 g); CoQ (200 mg); both supplements; or control (4 g olive oil), daily for 8 weeks. Telomere length was measured in neutrophils and peripheral blood mononuclear cells (PBMC) at baseline and 8 weeks, with and without correction for cell counts. Main and interactive effects of n-3 fatty acids and CoQ on telomere length were assessed adjusting for baseline values. F2-isoprostanes were measured as markers of oxidative stress. There was no effect of n-3 fatty acids or CoQ on neutrophil or PBMC telomere length. However, telomere length corrected for neutrophil count was increased after n-3 fatty acids (p = 0.015). Post-intervention plasma F2-isoprostanes were negative predictors of post-intervention telomere length corrected for neutrophil count (p = 0.025).The effect of n-3 fatty acids to increased telomere length corrected for neutrophil count may relate to reduced oxidative stress and increased clearance of neutrophils with shorter telomeres from the circulation. This may be a novel mechanism of modifying CVD risk in CKD patients.

Blood micronutrients and DNA damage in children.

SCOPE: Maintenance of normal cellular phenotype depends largely on accurate DNA replication and repair. DNA damage causes gene mutations and predisposes to cancer and other chronic diseases. Growing evidence indicates that nutritional factors are associated with DNA damage in adults; here, we investigate these associations in children. METHODS AND RESULTS: We conducted a cross-sectional study among 462 healthy children 3, 6, and 9 years of age. Blood was collected and micronutrient levels were measured. The cytokinesis-block micronucleus cytome assay was used to measure chromosomal DNA damage (micronuclei, nucleoplasmic bridges, and nuclear buds) in lymphocytes. Cell apoptosis, necrosis, and the nuclear division index were also measured. Nine loci in genes involved in folate metabolism and DNA repair were genotyped. Data were analyzed using linear regression with adjustment for potential confounders. Plasma calcium was positively associated with micronuclei and necrosis, and α-tocopherol negatively associated with apoptosis, nuclear division index, and nucleoplasmic bridges; lutein was positively associated with nucleoplasmic bridges. α-tocopherol was positively associated with necrosis. CONCLUSION: DNA damage in healthy children may be influenced by blood micronutrient levels and certain genotypes. Further investigation of associations between nutritional status and genomic integrity in children is needed to shed additional light on potential mechanisms.

Plasma micronutrient levels and telomere length in children.

OBJECTIVE: Telomeres are long hexamer (TTAGGG) repeats at the ends of chromosomes, and contribute to maintenance of chromosomal stability. Telomere shortening has been linked to cancers and other chronic diseases in adults, although evidence for causal associations is limited. The aim of this study was to determine whether nutritional factors are associated with telomere length (TL) in children. METHODS: We conducted a cross-sectional study of nutritional factors and TL in 437 children between 2009 and 2011. Healthy children ages 3, 6, and 9 y provided blood samples, and their parents completed a food frequency questionnaire and a telephone interview about relevant environmental exposures. TL and blood micronutrient levels were measured, and genotyping at 10 loci was undertaken. Associations between the micronutrients and other variables were assessed using linear regression. RESULTS: No significant main or interactive effects of age or sex were seen. After adjustment for age, sex, parental education, and month of blood collection, TL was inversely associated with plasma zinc, and shorter in children with the homozygous mutant genotype of the RFC G80A (rs1051266) polymorphism. CONCLUSIONS: To the best of our knowledge, this is the first investigation of the association between telomere length and micronutrients in healthy children. The reason for the inverse relationship of TL with zinc is unknown but could be the result of an increase in telomere sequence deletions caused by labile zinc induction of oxidative stress. These findings should be corroborated in other studies before nutritional recommendations might be considered.

Absolute qPCR for measuring telomere length in bone marrow samples of plasma cell disorders.

Telomere length (TL) is currently used as an emerging biomarker in understanding the development/progression of hematological malignancies. The absolute quantitative PCR (qPCR) methodology has allowed the study of TL from a variety of mammalian tissues, but it has not been tested for bone marrow (BM) samples. In this study, we have examined the relationship between TL data generated by absolute qPCR versus those obtained by terminal restriction fragments (TRF) in 102 BM samples from patients with plasma cell disorders. A significant linear correlation between both methodologies was observed (p < 0.0001; r (2) = 0.70). Results were also analyzed in relation to clinical characteristics and significant associations between telomere shortening and parameters of adverse prognosis were observed. Furthermore, another set of 47 BM samples from patients with low quantity of DNA for TRF assay were suitably analyzed by qPCR, indicating the usefulness of the absolute qPCR methodology for the inclusion of patients with scarce material to the study. Taken together, these findings are of interest considering the importance of telomere dysfunction in the pathogenesis of cancer and give a new alternative to measure TL in hematologic disorders with substantial time and cost savings.

Oxidative stress induces persistent telomeric DNA damage responsible for nuclear morphology change in mammalian cells.

One main function of telomeres is to maintain chromosome and genome stability. The rate of telomere shortening can be accelerated significantly by chemical and physical environmental agents. Reactive oxygen species are a source of oxidative stress and can produce modified bases (mainly 8-oxoG) and single strand breaks anywhere in the genome. The high incidence of guanine residues in telomeric DNA sequences makes the telomere a preferred target for oxidative damage. Our aim in this work is to evaluate whether chromosome instability induced by oxidative stress is related specifically to telomeric damage. We treated human primary fibroblasts (MRC-5) in vitro with hydrogen peroxide (100 and 200 µM) for 1 hr and collected data at several time points. To evaluate the persistence of oxidative stress-induced DNA damage up to 24 hrs after treatment, we analysed telomeric and genomic oxidative damage by qPCR and a modified comet assay, respectively. The results demonstrate that the genomic damage is completely repaired, while the telomeric oxidative damage persists. The analysis of telomere length reveals a significant telomere shortening 48 hrs after treatment, leading us to hypothesise that residual telomere damage could be responsible for the telomere shortening observed. Considering the influence of telomere length modulation on genomic stability, we quantified abnormal nuclear morphologies (Nucleoplasmic Bridges, Nuclear Buds and Micronuclei) and observed an increase of chromosome instability in the same time frame as telomere shortening. At subsequent times (72 and 96 hrs), we observed a restoration of telomere length and a reduction of chromosome instability, leaving us to conjecture a correlation between telomere shortening/dysfunction and chromosome instability. We can conclude that oxidative base damage leads to abnormal nuclear morphologies and that telomere dysfunction is an important contributor to this effect.

Ultraviolet radiation exposure and serum vitamin D levels in young children.

AIM: Health benefits of adequate vitamin D levels in the blood include better bone health and a reduced incidence of a range of chronic diseases and infections. Ultraviolet (UV) radiation exposure from the sun is the main source of vitamin D; however, such exposure, especially from a young age, is also a potential risk factor for skin cancer. The current study examined the association of UV exposure with vitamin D production in young children to determine the period of weekly exposure prior to blood testing that affected serum 25-hydroxyvitamin D (25(OH)D) levels. METHODS: Between 2009 and 2011, healthy children aged 3, 6 and 9 years were recruited from the community for a cross-sectional study of nutritional factors and DNA damage. Parents of 464 children provided information on the children's average weekly sun exposure and level of sun protection during each of the 16 weeks before blood sample collection by a domiciliary phlebotomist. RESULTS: Serum 25(OH)D levels were best predicted from UV exposure during the week before blood collection for samples drawn in autumn, summer or spring. For samples drawn in winter, serum 25(OH)D levels were best predicted by UV exposure during the 2 weeks before blood collection. CONCLUSIONS: Consistent weekly sun exposure may be beneficial for young children, especially in winter, to maintain healthy vitamin D levels in the blood. However, confirmation of these results is needed before their public health significance can be fully evaluated.

Telomere shortening in elderly individuals with mild cognitive impairment may be attenuated with ω-3 fatty acid supplementation: a randomized controlled pilot study.

OBJECTIVES: Excessive shortening of the telomeric ends of chromosomes is a marker of accelerated aging. Oxidative stress and nutritional deficiency may influence this process. The aim of this study was to investigate the effect of ω-3 polyunsaturated fatty acid (ω-3 PUFA) supplementation on telomeric shortening in elderly individuals with mild cognitive impairment (MCI). METHODS: Thirty-three adults ages > 65 y with MCI were randomized to receive a supplement rich in the long-chain ω-3 PUFAs eicosapentaenoic acid (EPA; 1.67 g EPA + 0.16 g docosahexaenoic acid DHA/d; n = 12) or DHA (1.55 g DHA + 0.40 g EPA/d; n = 12), versus ω-6 PUFA linoleic acid (LA; 2.2 g/d; n = 9) for 6 mo. RESULTS: The intervention did not show an increase in telomere length with treatment and there was a trend toward telomere shortening during the intervention period. Linear mixed modeling produced a robust model although statistically underpowered. Telomere shortening was greatest in the LA group (d = 0.21) than in the DHA (d = 0.12) and EPA groups (d = 0.06). Increased erythrocyte DHA levels were associated with reduced telomere shortening (r = -0.67; P = 0.02) in the DHA group. CONCLUSION: Telomeric shortening may be attenuated by ω-3 PUFA supplementation, requiring further investigation in larger samples.

Folate deficiency induces dysfunctional long and short telomeres; both states are associated with hypomethylation and DNA damage in human WIL2-NS cells.

The essential role of dietary micronutrients for genome stability is well documented, yet the effect of folate deficiency or excess on telomeres is not known. Accordingly, human WIL2-NS cells were maintained in medium containing 30, 300, or 3,000 nmol/L folic acid (FA) for 42 days to test the hypothesis that chronic folate deficiency would cause telomere shortening and dysfunction. After 14 days, telomere length (TL) in FA-deficient (30 nmol/L) cultures was 26% longer than that of 3,000 nmol/L FA cultures; however, this was followed by rapid telomere attrition over the subsequent 28 days (P trend, P < 0.0001); both long and short telomere status was positively correlated with biomarkers of chromosome instability (P ≤ 0.003) and mitotic dysfunction (P = 0.01), measured by the cytokinesis-block micronucleus cytome (CBMN-cyt) assay. The early increase in TL was associated with FA-deficiency-induced global DNA hypomethylation (P = 0.05), with an effect size similar to that induced by the DNA methyltransferase inhibitor, 5-aza-2'-deoxycytidine. Quantitative PCR analysis indicated a negative association between FA concentration and uracil incorporation into telomeric DNA (r = -0.47, P = 0.1), suggesting a possible plausible mechanism for uracil as a cause of folate deficiency-induced telomere dysfunction or deletion. Peptide nucleic acid-FISH (PNA-FISH) analysis showed that FA deficiency resulted in 60% of micronuclei containing acentric terminal fragments, an observation consistent with the 3-fold increase in terminal deletions (P = 0.0001). Together, these results demonstrate the impact of folate deficiency on biomarkers of telomere maintenance and integrity, and provide evidence that dysfunctional long telomeres may be as important as critically short telomeres as a cause of chromosomal instability.

Defective repair of oxidative base lesions by the DNA glycosylase Nth1 associates with multiple telomere defects.

Telomeres are chromosome end structures and are essential for maintenance of genome stability. Highly repetitive telomere sequences appear to be susceptible to oxidative stress-induced damage. Oxidation may therefore have a severe impact on telomere integrity and function. A wide spectrum of oxidative pyrimidine-derivatives has been reported, including thymine glycol (Tg), that are primarily removed by a DNA glycosylase, Endonuclease III-like protein 1 (Nth1). Here, we investigate the effect of Nth1 deficiency on telomere integrity in mice. Nth1 null (Nth1(-/-) ) mouse tissues and primary MEFs harbor higher levels of Endonuclease III-sensitive DNA lesions at telomeric repeats, in comparison to a non-telomeric locus. Furthermore, oxidative DNA damage induced by acute exposure to an oxidant is repaired slowly at telomeres in Nth1(-/-) MEFs. Although telomere length is not affected in the hematopoietic tissues of Nth1(-/-) adult mice, telomeres suffer from attrition and increased recombination and DNA damage foci formation in Nth1(-/-) bone marrow cells that are stimulated ex vivo in the presence of 20% oxygen. Nth1 deficiency also enhances telomere fragility in mice. Lastly, in a telomerase null background, Nth1(-/-) bone marrow cells undergo severe telomere loss at some chromosome ends and cell apoptosis upon replicative stress. These results suggest that Nth1 plays an important role in telomere maintenance and base repair against oxidative stress-induced base modifications. The fact that telomerase deficiency can exacerbate telomere shortening in Nth1 deficient mouse cells supports that base excision repair cooperates with telomerase to maintain telomere integrity.