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Telomere Length Change in a Multidomain Lifestyle Intervention to Prevent Cognitive Decline: A Randomized Clinical Trial.
Sindi, S, Solomon, A, Kåreholt, I, Hovatta, I, Antikainen, R, Hänninen, T, Levälahti, E, Laatikainen, T, Lehtisalo, J, Lindström, J, et al
The journals of gerontology. Series A, Biological sciences and medical sciences. 2021;(3):491-498
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Abstract
BACKGROUND Shorter leukocyte telomere length (LTL) is associated with aging and dementia. Impact of lifestyle changes on LTL, and relation to cognition and genetic susceptibility for dementia, has not been investigated in randomized controlled trials (RCTs). METHODS Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability is a 2-year RCT enrolling 1260 participants at risk for dementia from the general population, aged 60-77 years, randomly assigned (1:1) to multidomain lifestyle intervention or control group. The primary outcome was cognitive change (Neuropsychological Test Battery z-score). Relative LTL was measured using quantitative real-time polymerase chain reaction (trial registration: NCT01041989). RESULTS This exploratory LTL substudy included 756 participants (377 intervention, 379 control) with baseline and 24-month LTL measurements. The mean annual LTL change (SD) was -0.016 (0.19) in the intervention group and -0.023 (0.17) in the control group. Between-group difference was nonsignificant (unstandardized β-coefficient 0.007, 95% CI -0.015 to 0.030). Interaction analyses indicated better LTL maintenance among apolipoprotein E (APOE)-ε4 carriers versus noncarriers: 0.054 (95% CI 0.007 to 0.102); younger versus older participants: -0.005 (95% CI -0.010 to -0.001); and those with more versus less healthy lifestyle changes: 0.047 (95% CI 0.005 to 0.089). Cognitive intervention benefits were more pronounced among participants with better LTL maintenance for executive functioning (0.227, 95% CI 0.057 to 0.396) and long-term memory (0.257, 95% CI 0.024 to 0.489), with a similar trend for Neuropsychological Test Battery total score (0.127, 95% CI -0.011 to 0.264). CONCLUSIONS This is the first large RCT showing that a multidomain lifestyle intervention facilitated LTL maintenance among subgroups of older people at risk for dementia, including APOE-ε4 carriers. LTL maintenance was associated with more pronounced cognitive intervention benefits. CLINICAL TRIALS REGISTRATION NUMBER NCT01041989.
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Leukocyte telomere length and serum polyunsaturated fatty acids, dietary habits, cardiovascular risk factors and features of myocardial infarction in elderly patients.
Kalstad, AA, Tveit, S, Myhre, PL, Laake, K, Opstad, TB, Tveit, A, Schmidt, EB, Solheim, S, Arnesen, H, Seljeflot, I
BMC geriatrics. 2019;(1):376
Abstract
BACKGROUND Telomeres are non-coding sequences at the end of eukaryote chromosomes, which in complex with associated proteins serve to protect subtelomeric DNA. Telomeres shorten with each cell division, are regarded as a biomarker for aging and have also been suggested to play a role in atherosclerosis and cardiovascular disease (CVD). The aim of the present study was to explore the associations between leukocyte telomere length and serum polyunsaturated fatty acids, diet, cardiovascular risk factors and features of myocardial infarction (MI) in elderly patients. METHODS The material is based upon the first 299 included patients in the OMEMI trial, where patients aged 70-82 years of age are randomized to receive omega-3 supplements or corn oil (placebo) after MI. Patients were included 2-8 weeks after the index MI. DNA was extracted from whole blood, and leukocyte telomere length (LTL) was analyzed by qPCR and reported as a number relative to a reference gene. Serum long chain polyunsaturated fatty acid (LCPUFA) content was analyzed by gas chromatography. Diet was evaluated with the validated SmartDiet food frequency questionnaire. Medical records, patient interviews and clinical examination provided previous medical history and anthropometric data. Non-parametric statistical tests were used. RESULTS Median (25, 75 percentile) LTL was 0.55 (0.42, 0.72). Patients had a median age of 75 years, 70.2% were male and 45.2% used omega-3 supplements. There was a weak, but significant correlation between LTL and linoleic acid (r = 0.139, p = 0.017), but not with other LCPUFAs. There was a trend towards longer telomeres with a healthier diet, but this did not reach statistical significance (p = 0.073). No associations were found between LTL and CVD risk factors or features of MI. CONCLUSIONS In our population of elderly with a recent myocardial infarction LTL was associated with linoleic acid concentrations, but not with other LCPUFAs. Patients with a healthy diet tended to have longer telomeres. The limited associations may be due to age and the narrow age-span in our population. Further studies, designed to detect longitudinal changes should be performed to explore the role of telomeres in cardiovascular aging. TRIAL REGISTRATION Clinical trials no. NCT01841944, registration date April 29, 2013.
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Higher baseline global leukocyte DNA methylation is associated with MTX non-response in early RA patients.
Gosselt, HR, van Zelst, BD, de Rotte, MCFJ, Hazes, JMW, de Jonge, R, Heil, SG
Arthritis research & therapy. 2019;(1):157
Abstract
BACKGROUND Low-dose methotrexate (MTX) is the first-line therapy in early rheumatoid arthritis (eRA). Up to 40% of eRA patients do not benefit from MTX therapy. MTX has been shown to inhibit one-carbon metabolism, which is involved in the donation of methyl groups. In this study, we investigate baseline global DNA methylation and changes in DNA methylation during treatment in relation to clinical non-response after 3 months of MTX treatment. METHODS Two hundred ninety-four blood samples were collected from the Treatment in the Rotterdam Early Arthritis Cohort (tREACH, ISRCTN26791028), a multicenter, stratified single-blind clinical trial of eRA patients. Global DNA (hydroxy)methylation was quantified using liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) and validated with a global DNA LINE-1 methylation technique. MTX response was determined as ΔDAS28. Additionally, patients were stratified into two response groups according to the European League Against Rheumatism (EULAR) response criteria. Associations between global DNA methylation and response were examined using univariate regression models adjusted for baseline DAS28, baseline erythrocyte folate levels, and body mass index (BMI). RESULTS Higher baseline global DNA methylation was associated with less decrease of DAS28 (β = 0.15, p = 0.013) and with MTX non-response (OR = 0.010, 95% CI = 0.001-0.188). This result was validated in LINE-1 elements (β = 0.22, p = 0.026). Changes in global DNA (hydroxy)methylation were not associated with MTX response over 3 months. CONCLUSIONS These results show that higher baseline global DNA methylation in treatment naïve eRA patients is associated with decreased clinical response after 3 months of treatment of eRA patients and can be further evaluated as a predictor for MTX therapy non-response. TRIAL REGISTRATION ISRCTN, ISRCTN26791028 , registered 23 August 2007-retrospectively registered.
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The red blood cell proportion of arachidonic acid relates to shorter leukocyte telomeres in Mediterranean elders: A secondary analysis of a randomized controlled trial.
Freitas-Simoes, TM, Cofán, M, Blasco, MA, Soberón, N, Foronda, M, Corella, D, Asensio, EM, Serra-Mir, M, Roth, I, Calvo, C, et al
Clinical nutrition (Edinburgh, Scotland). 2019;(2):958-961
Abstract
BACKGROUND & AIMS Shortening of leukocyte telomere length (LTL) is a biomarker of aging. Epidemiologic studies of LTL in relation to dietary fatty acids have reported conflicting results. The red blood cell (RBC) fatty acid status is a valid objective biomarker of long-term dietary intake of C18:2n-6, C18:3n-3 and long-chain n-3 polyunsaturated fatty acids (C20:5n-3 and C22:6n-3). In healthy older individuals, we investigated whether LTL relates to the RBC proportions of the main dietary polyunsaturated fatty acids (PUFA), and to the RBC proportion of arachidonic acid (C20:4n-6), a fatty acid that can generate pro-inflammatory lipid mediators once released from cell membranes. DESIGN Cross-sectional study in 344 subjects (mean age 68.8 y, 68.6% women) who participated in a randomized controlled trial testing whether a diet enriched in walnuts can delay the onset of age-related diseases (https://clinicaltrials.gov/ct2/show/NCT01634841). At baseline, we assessed LTL by high-throughput quantitative fluorescence and determined fatty acids in RBCs by gas chromatography. RESULTS In multivariate models adjusted for age and gender, the RBC proportions of dietary PUFA were unrelated to LTL. In contrast, the RBC proportion of arachidonic acid inversely related to LTL (regression coefficient [95% confidence interval], -0.10 (-0.19 to -0.01), P = 0.023). CONCLUSION An increasing proportion of C20:4n-6 in RBCs is associated with shorter telomeres. Further research is needed to investigate the role of this fatty acid and its derived lipid mediators in the aging process.
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Walnut Consumption for Two Years and Leukocyte Telomere Attrition in Mediterranean Elders: Results of a Randomized Controlled Trial.
Freitas-Simoes, TM, Cofán, M, Blasco, MA, Soberón, N, Foronda, M, Serra-Mir, M, Roth, I, Valls-Pedret, C, Doménech, M, Ponferrada-Ariza, E, et al
Nutrients. 2018;(12)
Abstract
Randomized controlled trials on diet and shortening of leukocyte telomere length (LTL) mostly focus on marine-derived n-3 polyunsaturated fatty acids (PUFA). Walnuts are a sustainable source of n-3 PUFA. We investigated whether inclusion of walnuts (15% of energy) in the diet for 2 years would maintain LTL in cognitively healthy elders (63⁻79 years old) compared to a control group (habitual diet, abstaining from walnuts). This opportunistic sub-study was conducted within the Walnuts and Healthy Aging study, a dual-centre (Barcelona, Spain and Loma Linda University, California) parallel trial. A sub-set of the Barcelona site participants were randomly assigned to the walnut (n = 80) or control group (n = 69). We assessed LTL at baseline and at 2 years and we conducted repeated-measures ANCOVA with 2 factors: time (baseline, 2 years) and group (control, walnut) and their interaction. Adjusted means (95% confidence interval) of LTL (in kb) in controls were 7.360 (7.084,7.636) at baseline and 7.061 (6.835,7.288) after 2 years; corresponding values in the walnut group were 7.064 (6.807,7.320) and 7.074 (6.864,7.284). The time × intervention interaction was nearly significant (p = 0.079), suggestive of a trend of walnut consumption in preserving LTL. This exploratory research finding should be confirmed in trials with adequate statistical power.
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Differential Gene Expression in Peripheral White Blood Cells with Permissive Underfeeding and Standard Feeding in Critically Ill Patients: A Descriptive Sub-study of the PermiT Randomized Controlled Trial.
Arabi, YM, Al-Balwi, M, Hajeer, AH, Jawdat, D, Sadat, M, Al-Dorzi, HM, Tamim, H, Afesh, L, Almashaqbeh, W, Alkadi, H, et al
Scientific reports. 2018;(1):17984
Abstract
The effect of short-term caloric restriction on gene expression in critically ill patients has not been studied. In this sub-study of the PermiT trial (Permissive Underfeeding or Standard Enteral Feeding in Critically Ill Adults Trial- ISRCTN68144998), we examined gene expression patterns in peripheral white blood cells (buffy coat) associated with moderate caloric restriction (permissive underfeeding) in critically ill patients compared to standard feeding. Blood samples collected on study day 1 and 14 were subjected to total RNA extraction and gene expression using microarray analysis. We enrolled 50 patients, 25 in each group. Among 1751 tested genes, 332 genes in 12 pathways were found to be significantly upregulated or downregulated between study day 1 and 14 (global p value for the pathway ≤ 0.05). Using the heatmap, the differential expression of genes from day 1 to 14 in the permissive underfeeding group was compared to the standard feeding group. We further compared gene expression signal intensity in permissive underfeeding compared standard feeding by constructing univariate and multivariate linear regression models on individual patient data. We found differential expression of several genes with permissive underfeeding, most notably those related to metabolism, autophagy and other cellular functions, indicating that moderate differences in caloric intake trigger different cellular pathways.
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Effects of Astaxanthin on Liver and Leukocyte Parameters in Healthy Climacteric Women: Preliminary Data.
Chen, JT, Kotani, K
Journal of medicinal food. 2017;(7):724-725
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Oxidative stress and DNA damage in the cord blood of preterm infants.
Norishadkam, M, Andishmand, S, Zavar Reza, J, Zare Sakhvidi, MJ, Hachesoo, VR
Mutation research. Genetic toxicology and environmental mutagenesis. 2017;:20-24
Abstract
Preterm birth infants are more susceptible to oxidative stress and aftermaths unwanted outcomes such as DNA damage due to hyperoxic stress. In this study, we compared the DNA strand breaks as one of the results of DNA oxidation in white blood cells, malondialdehyde (oxidative stress marker), catalase and superoxide dismutase activity, and total antioxidant capacity (markers of antioxidant defense) in a cord blood plasma of a group of preterm (n=25) and full term births (n=25). The primary DNA damage and plasma oxidative stress markers were significantly higher in a preterm group (p<0.05). Cord plasma activity of superoxide dismutase was significantly lower in preterm infants (p≤0.001). However, there were no significant differences in the cord blood total antioxidant capacity, catalase activity and malondialdehyde in preterm and term infants. Among the oxidative stress markers, the malondialdehyde concentration showed the strongest effect size (1.54; 95%CI: 0.9-2.17). For comet parameters, the most powerful effect size was observed for tail length (5.24; 95% CI: 4.05-6.42). However, tail DNA percent and tail moment were also significantly higher in cases compared to controls. Significant negative correlation was observed between comet assay parameters and birth weight and gestational age when all cases and controls entered into the analysis. There was no significant association between the levels of oxidative stress markers and early DNA damage in cord blood plasma with future nutritional tolerance in preterm infants. In the present study, the primary DNA damage and plasma oxidative stress markers significantly were increased in a preterm group. Preterm babies are more prone to the outcomes related to the early DNA damage. Tail DNA percent does not depend on experimental conditions as other parameters (tail length and thus also tail moment) and can be used for comparison with other studies.
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A role for leukocyte integrins and extracellular matrix remodeling of adipose tissue in the risk of weight regain after weight loss.
Roumans, NJ, Vink, RG, Fazelzadeh, P, van Baak, MA, Mariman, EC
The American journal of clinical nutrition. 2017;(5):1054-1062
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Abstract
Background: Weight loss (WL) is often followed by weight regain after an energy-restricted dietary intervention (DI). When people are following a diet, the volume of an adipocyte decreases by loss of triglycerides, which creates stress between the cell contents and the surrounding extracellular matrix (ECM). Previously, we observed that genetic variations in ECM genes are associated with an increased risk of weight regain.Objective: We investigated the relation between the expression of ECM genes during WL and a period of weight stabilization (WS) and the risk of weight regain.Design: In this randomized controlled trial, 61 healthy overweight or obese participants followed either a 5-wk very-low-calorie diet (VLCD; 500 kcal/d) or a 12-wk low-calorie diet (1250 kcal/d) (WL period) with a subsequent 4-wk WS period and a 9-mo follow-up. The WL and WS periods combined were considered the DI. Abdominal subcutaneous adipose tissue biopsy samples were collected for microarray analysis. Gene expression changes for a broad set of ECM-related genes were correlated with the weight-regain percentage (WR%).Results: A total of 26 of the 277 genes were significantly correlated with WR% during WL, WS, or the DI periods. Most correlations were observed in the VLCD group during the WS period. Four genes code for leukocyte-specific receptors. These and other genes belong to a group of 26 genes, among which the expression changes were highly correlated (r ≥ 0.7, P ≤ 0.001). This group could be divided into 3 subclusters linking to 2 biological processes-leukocyte integrin gene activity and ECM remodeling-and a link to insulin sensitivity was also apparent.Conclusions: Our present findings indicate the importance of adipose tissue leukocytes for the risk of weight regain. ECM modification also seems to be involved, and we observed a link to insulin sensitivity. This trial was registered at clinicaltrials.gov as NCT01559415.
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Baseline Telomere Length and Effects of a Multidomain Lifestyle Intervention on Cognition: The FINGER Randomized Controlled Trial.
Sindi, S, Ngandu, T, Hovatta, I, Kåreholt, I, Antikainen, R, Hänninen, T, Levälahti, E, Laatikainen, T, Lindström, J, Paajanen, T, et al
Journal of Alzheimer's disease : JAD. 2017;(4):1459-1470
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Abstract
Leukocyte telomere length (LTL) is a biomarker of aging, and it is associated with lifestyle. It is currently unknown whether LTL is associated with the response to lifestyle interventions. The goal is to assess whether baseline LTL modified the cognitive benefits of a 2-year multidomain lifestyle intervention (exploratory analyses). The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) was a 2-year randomized controlled trial including 1,260 people at risk of cognitive decline, aged 60-77 years identified from the general population. Participants were randomly assigned to the lifestyle intervention (diet, exercise, cognitive training, and vascular risk management) and control (general health advice) groups. Primary outcome was change in cognition (comprehensive neuropsychological test battery). Secondary outcomes were changes in cognitive domains: memory, executive functioning, and processing speed. 775 participants (392 control, 383 intervention) had baseline LTL (peripheral blood DNA). Mixed effects regression models with maximum likelihood estimation were used to analyze change in cognition as a function of randomization group, time, baseline LTL, and their interaction. Intervention and control groups did not significantly differ at baseline. Shorter LTL was related to less healthy baseline lifestyle. Intervention benefits on executive functioning were more pronounced among those with shorter baseline LTL (p-value for interaction was 0.010 adjusted for age and sex, and 0.007 additionally adjusted for baseline lifestyle factors). The FINGER intervention cognitive benefits were more pronounced with shorter baseline LTL, particularly for executive functioning, indicating that the multidomain lifestyle intervention was especially beneficial among higher-risk individuals.