Longer leukocyte telomeres are associated with ultra-endurance exercise independent of cardiovascular risk factors
- Authors: Denham, Joshua , Nelson, Christopher , O'Brien, Brendan , Nankervis, Scott , Denniff, Matthew , Harvey, Jack , Marques, Francine , Codd, Veryan , Zukowska-Szczechowska, Ewa , Samani, Nilesh , Tomaszewski, Maciej , Charchar, Fadi
- Date: 2013
- Type: Text , Journal article
- Relation: PLoS ONE Vol. 8, no. 7 (2013), p.
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- Description: Telomere length is recognized as a marker of biological age, and shorter mean leukocyte telomere length is associated with increased risk of cardiovascular disease. It is unclear whether repeated exposure to ultra-endurance aerobic exercise is beneficial or detrimental in the long-term and whether it attenuates biological aging. We quantified 67 ultra-marathon runners' and 56 apparently healthy males' leukocyte telomere length (T/S ratio) using real-time quantitative PCR. The ultra-marathon runners had 11% longer telomeres (T/S ratio) than controls (ultra-marathon runners: T/S ratio = 3.5±0.68, controls: T/S ratio = 3.1±0.41;
- Description: 2003011219
121 Telomere attrition is attenuated in ultra-marathon runners
- Authors: Denham, Joshua , Nankervis, Scott , Debiec, Radek , Harvey, Jack , Pascoe, Deborah , Marques, Francine , O’Brien, Brendan , Zukowska-Szczechowska, Ewa , Tomaszewski, Maciej , Charchar, Fadi
- Date: 2012
- Type: Text , Journal article
- Relation: Journal of Hypertension Vol. 30, no. e-Supplement (September 2012), p. e37
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- Description: Background: Leukocyte telomere length is a marker of biological ageing and its shortening is associated with cardiovascular disease. Engagement in regular moderate-intensity physical activity is a recognised method of cardiovascular disease prevention. However, it is not clear whether repeated exposure to ultra-strenuous physical exercise is beneficial long-term and whether it may attenuate biological ageing. Methods: We compared leukocyte telomere length in context of inflammation and endothelial dysfunction between 67 male ultra-marathon runners and 67 age-, sex- and BMI-matched apparently healthy controls. Genomic DNA was extracted from peripheral blood and leukocyte telomere length was measured by quantitative polymerase chain reaction assays. Adhesion molecules (sICAM-1, sE-selectin) and inflammatory markers (IL-6, C-reactive protein) concentrations were measured in 67 ultra-marathon runners by quantitative sandwich enzyme immunoassay technique, high-sensitive immunoassay and ultra-sensitive double antibody sandwich ELISA, respectively. Results: Adjusted (for age, BMI, blood pressure and lipids) leukocyte telomere length was approximately 13.8% greater in the ultra-marathon runners than in the controls (P<0.001). This translates into approximately 32.9 years difference in age-related telomere length attrition. There was a strong negative linear correlation between sICAM-1 and leukocyte telomere length in the ultra-marathon runners (r=-0.33; P=0.007) and this association retained its statistical significance after adjustment for age, BMI, blood pressure and lipids in multiple regression (P=0.026). Conclusion: Prolonged, intense physical exercise may attenuate cellular ageing possibly through a protective effect on endothelial function.
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Exercise : Putting action into our epigenome
- Authors: Denham, Joshua , Marques, Francine , O'Brien, Brendan , Charchar, Fadi
- Date: 2014
- Type: Text , Journal article
- Relation: Sports Medicine Vol. 44, no. 2 (2014), p. 189-209
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
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- Description: Most human phenotypes are influenced by a combination of genomic and environmental factors. Engaging in regular physical exercise prevents many chronic diseases, decreases mortality risk and increases longevity. However, the mechanisms involved are poorly understood. The modulating effect of physical (aerobic and resistance) exercise on gene expression has been known for some time now and has provided us with an understanding of the biological responses to physical exercise. Emerging research data suggest that epigenetic modifications are extremely important for both development and disease in humans. In the current review, we summarise findings on the effect of exercise on epigenetic modifications and their effects on gene expression. Current research data suggest epigenetic modifications (DNA methylation and histone acetylation) and microRNAs (miRNAs) are responsive to acute aerobic and resistance exercise in brain, blood, skeletal and cardiac muscle, adipose tissue and even buccal cells. Six months of aerobic exercise alters whole-genome DNA methylation in skeletal muscle and adipose tissue and directly influences lipogenesis. Some miRNAs are related to maximal oxygen consumption (VO 2max) and VO2max trainability, and are differentially expressed amongst individuals with high and low VO2max. Remarkably, miRNA expression profiles discriminate between low and high responders to resistance exercise (miR-378, -26a, -29a and -451) and correlate to gains in lean body mass (miR-378). The emerging field of exercise epigenomics is expected to prosper and additional studies may elucidate the clinical relevance of miRNAs and epigenetic modifications, and delineate mechanisms by which exercise confers a healthier phenotype and improves performance. © 2013 Springer International Publishing Switzerland. Funded by NHMRC; National Health and Medical Research Council
Changes in the leukocyte methylome and its effect on cardiovascular-related genes after exercise
- Authors: Denham, Joshua , O'Brien, Brendan , Marques, Francine , Charchar, Fadi
- Date: 2015
- Type: Text , Journal article
- Relation: Journal of Applied Physiology Vol. 118, no. 4 (2015), p. 475-488
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
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- Description: Physical exercise has proven cardiovascular benefits, yet there is no clear understanding of the related molecular mechanisms leading to this. Here we determined the beneficial epigenetic effects of exercise after sprint interval training, a form of exercise known to improve cardiometabolic health. We quantified genome-wide leukocyte DNA methylation of 12 healthy young (18-24 yr) men before and after 4 wk (thrice weekly) of sprint interval training using the 450K BeadChip (Illumina) and validated gene expression changes in an extra seven subjects. Exercise increased subjects' cardiorespiratory fitness and maximal running performance, and decreased low-density lipoprotein cholesterol concentration in conjunction with genome-wide DNA methylation changes. Notably, many CpG island and gene promoter regions were demethylated after exercise, indicating increased genome-wide transcriptional changes. Among genes with DNA methylation changes, epidermal growth factor (EGF), a ligand of the epidermal growth factor receptor known to be involved in cardiovascular disease, was demethylated and showed decreased mRNA expression. Additionally, we found that in microRNAs miR-21 and miR-210, gene DNA methylation was altered by exercise causing a cascade effect on the expression of the mature microRNA involved in cardiovascular function. Our findings demonstrate that exercise alters DNA methylation in circulating blood cells in microRNA and protein-coding genes associated with cardiovascular physiology. Copyright © 2015 the American Physiological Society
Genome-wide sperm DNA methylation changes after 3 months of exercise training in humans
- Authors: Denham, Joshua , O'Brien, Brendan , Harvey, Jack , Charchar, Fadi
- Date: 2015
- Type: Text , Journal article
- Relation: Epigenomics Vol. 7, no. 5 (2015), p. 717-731
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- Description: Aim: DNA methylation programs gene expression and is involved in numerous biological processes. Accumulating evidence supports transgenerational inheritance of DNA methylation changes in mammals via germ cells. Our aim was to determine the effect of exercise on sperm DNA methylation. Materials & methods: Twenty-four men were recruited and assigned to an exercise intervention or control group. Clinical parameters were measured and sperm samples were donated by subjects before and after the 3-month time-period. Mature sperm global and genome-wide DNA methylation was assessed using an ELISA assay and the 450K BeadChip (Illumina). Results: Global and genome-wide sperm DNA methylation was altered after 3 months of exercise training. DNA methylation changes occurred in genes related to numerous diseases such as schizophrenia and Parkinson's disease. Conclusions: Our study provides the first evidence showing exercise training reprograms the sperm methylome. Whether these DNA methylation changes are inherited to future generations warrants attention.
Increased expression of telomere-regulating genes in endurance athletes with long leukocyte telomeres
- Authors: Denham, Joshua , O'Brien, Brendan , Prestes, Priscilla , Brown, Nicholas , Charchar, Fadi
- Date: 2015
- Type: Text , Journal article
- Relation: Journal of Applied Physiology Vol. 120, no. 2 (2015), p. 148-158
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
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- Description: Leukocyte telomeres shorten with age, and excessive shortening is associated with age-related cardiometabolic diseases. Exercise training may prevent disease through telomere length maintenance although the optimal amount of exercise that attenuates telomere attrition is unknown. Furthermore, the underlying molecular mechanisms responsible for the enhanced telomere maintenance observed in endurance athletes is poorly understood. We quantified the leukocyte telomere length and analyzed the expression of telomere-regulating genes in endurance athletes and healthy controls (both n = 61), using quantitative PCR. We found endurance athletes have significantly longer (7.1%, 208-416 nt) leukocyte telomeres and upregulated TERT (2.0-fold) and TPP1 (1.3-fold) mRNA expression compared with controls in age-adjusted analysis. The telomere length and telomere-regulating gene expression differences were no longer statistically significant after adjustment for resting heart rate and relative (V) over dotO(2 max) (all P > 0.05). Resting heart rate emerged as an independent predictor of leukocyte telomere length and TERT and TPP1 mRNA expression in stepwise regression models. To gauge whether volume of exercise was associated with leukocyte telomere length, we divided subjects into running and cycling tertiles (distance covered per week) and found individuals in the middle and highest tertiles had longer telomeres than individuals in the lowest tertile. These data emphasize the importance of cardiorespiratory fitness and exercise training in the prevention of biological aging. They also support the concept that moderate amounts of exercise training protects against biological aging, while higher amounts may not elicit additional benefits.
Aortic augmentation index in endurance athletes : A role for cardiorespiratory fitness
- Authors: Denham, Joshua , Brown, Nicholas , Tomaszewski, Maciej , Williams, Bryan , O’Brien, Brendan , Charchar, Fadi
- Date: 2016
- Type: Text , Journal article
- Relation: European Journal of Applied Physiology Vol. 116, no. 8 (2016), p. 1537-1544
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
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- Description: Purpose: Endurance exercise improves cardiovascular health and reduces mortality risk. Augmentation index (AIx) reflects adverse loading exerted on the heart and large arteries and predicts future cardiovascular disease. The purpose of this study was to establish whether endurance athletes possess lower AIx and aortic blood pressure compared to healthy controls, and to determine the association between AIx and cardiorespiratory fitness. Methods: Forty-six endurance athletes and 43 healthy controls underwent central BP and AIx measurements by non-invasive applanation tonometry before a maximal exercise test. Peak oxygen uptake (V˙ O 2 peak) was assessed by pulmonary analysis. Results: Relative to controls, athletes had significantly lower brachial diastolic blood pressure (BP, −4.8 mmHg, p < 0.01), central systolic BP (−3.5 mmHg, p = 0.07), and AIx at a heart rate of 75 beats min−1 (AIx@75, −11.9 %, p < 0.001). No AIx@75 differences were observed between athletes and controls when adjusted for age and V˙ O 2 peak [athletes vs controls mean (%) ± SE: −6.9 ± 2.2 vs −5.7 ± 2.3, p = 0.76]. Relative to men with low V˙ O 2 peak, those with moderate and high V˙ O 2 peak had lower age-adjusted AIx@75 (p < 0.001). In women, those with high V˙ O 2 peak had lower AIx@75 than those with low and moderate V˙ O 2 peak (p < 0.01). Conclusions: The lower AIx@75 in endurance athletes is partly mediated by V˙ O 2 peak. While an inverse relationship between AIx@75 and V˙ O 2 peak was found in men, women with the highest V˙ O 2 peak possessed lowest AIx@75 compared to females with moderate or poor cardiorespiratory fitness. We recommend aerobic training aimed at achieving a minimum V˙ O 2 peak of 45 ml kg−1 min−1 to decrease the risk of future cardiovascular events and all-cause mortality.
- Description: Purpose: Endurance exercise improves cardiovascular health and reduces mortality risk. Augmentation index (AIx) reflects adverse loading exerted on the heart and large arteries and predicts future cardiovascular disease. The purpose of this study was to establish whether endurance athletes possess lower AIx and aortic blood pressure compared to healthy controls, and to determine the association between AIx and cardiorespiratory fitness. Methods: Forty-six endurance athletes and 43 healthy controls underwent central BP and AIx measurements by non-invasive applanation tonometry before a maximal exercise test. Peak oxygen uptake (V˙ O 2 peak) was assessed by pulmonary analysis. Results: Relative to controls, athletes had significantly lower brachial diastolic blood pressure (BP, −4.8 mmHg, p < 0.01), central systolic BP (−3.5 mmHg, p = 0.07), and AIx at a heart rate of 75 beats min−1 (AIx@75, −11.9 %, p < 0.001). No AIx@75 differences were observed between athletes and controls when adjusted for age and V˙ O 2 peak [athletes vs controls mean (%) ± SE: −6.9 ± 2.2 vs −5.7 ± 2.3, p = 0.76]. Relative to men with low V˙ O 2 peak, those with moderate and high V˙ O 2 peak had lower age-adjusted AIx@75 (p < 0.001). In women, those with high V˙ O 2 peak had lower AIx@75 than those with low and moderate V˙ O 2 peak (p < 0.01). Conclusions: The lower AIx@75 in endurance athletes is partly mediated by V˙ O 2 peak. While an inverse relationship between AIx@75 and V˙ O 2 peak was found in men, women with the highest V˙ O 2 peak possessed lowest AIx@75 compared to females with moderate or poor cardiorespiratory fitness. We recommend aerobic training aimed at achieving a minimum V˙ O 2 peak of 45 ml kg−1 min−1 to decrease the risk of future cardiovascular events and all-cause mortality. © 2016, Springer-Verlag Berlin Heidelberg.
Telomere length maintenance and cardio-metabolic disease prevention through exercise training
- Authors: Denham, Joshua , O'Brien, Brendan , Charchar, Fadi
- Date: 2016
- Type: Text , Journal article , Review
- Relation: Sports Medicine Vol. 46, no. 9 (2016), p. 1213-1237
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
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- Description: Telomeres are tandem repeat DNA sequences located at distal ends of chromosomes that protect against genomic DNA degradation and chromosomal instability. Excessive telomere shortening leads to cellular senescence and for this reason telomere length is a marker of biological age. Abnormally short telomeres may culminate in the manifestation of a number of cardio-metabolic diseases. Age-related cardio-metabolic diseases attributable to an inactive lifestyle, such as obesity, type 2 diabetes mellitus and cardiovascular disease, are associated with short leukocyte telomeres. Exercise training prevents and manages the symptoms of many cardio-metabolic diseases whilst concurrently maintaining telomere length. The positive relationship between exercise training, physical fitness and telomere length raises the possibility of a mediating role of telomeres in chronic disease prevention via exercise. Further elucidation of the underpinning molecular mechanisms of how exercise maintains telomere length should provide crucial information on how physical activity can be best structured to combat the chronic disease epidemic and improve the human health span. Here, we synthesise and discuss the current evidence on the impact of physical activity and cardiorespiratory fitness on telomere dynamics. We provide the molecular mechanisms with a known role in exercise-induced telomere length maintenance and highlight unexplored, alternative pathways ripe for future investigations.
Epigenetic changes in leukocytes after 8 weeks of resistance exercise training
- Authors: Denham, Joshua , Marques, Francine , Bruns, Emma , O'Brien, Brendan , Charchar, Fadi
- Date: 2016
- Type: Text , Journal article
- Relation: European Journal of Applied Physiology Vol. 116, no. 6 (2016), p. 1245-1253
- Relation: http://purl.org/au-research/grants/nhmrc/1009490
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- Description: PURPOSE: Regular engagement in resistance exercise training elicits many health benefits including improvement to muscular strength, hypertrophy and insulin sensitivity, though the underpinning molecular mechanisms are poorly understood. The purpose of this study was to determine the influence 8 weeks of resistance exercise training has on leukocyte genome-wide DNA methylation and gene expression in healthy young men. METHODS: Eight young (21.1 +/- 2.2 years) men completed one repetition maximum (1RM) testing before completing 8 weeks of supervised, thrice-weekly resistance exercise training comprising three sets of 8-12 repetitions with a load equivalent to 80 % of 1RM. Blood samples were collected at rest before and after the 8-week training intervention. Genome-wide DNA methylation and gene expression were assessed on isolated leukocyte DNA and RNA using the 450K BeadChip and HumanHT-12 v4 Expression BeadChip (Illumina), respectively. RESULTS: Resistance exercise training significantly improved upper and lower body strength concurrently with diverse genome-wide DNA methylation and gene expression changes (p = 0. 01). DNA methylation changes occurred at multiple regions throughout the genome in context with genes and CpG islands, and in genes relating to axon guidance, diabetes and immune pathways. There were multiple genes with increased expression that were enriched for RNA processing and developmental proteins. Growth factor genes-GHRH and FGF1-showed differential methylation and mRNA expression changes after resistance training. CONCLUSIONS: Our findings indicate that resistance exercise training improves muscular strength and is associated with reprogramming of the leukocyte DNA methylome and transcriptome.
Leukocyte telomere length variation due to DNA extraction method
- Authors: Denham, Joshua , Marques, Francine , Charchar, Fadi
- Date: 2014
- Type: Text , Journal article
- Relation: BMC research notes Vol. 7, no. (2014), p. 877
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- Description: Telomere length is indicative of biological age. Shorter telomeres have been associated with several disease and health states. There are inconsistencies throughout the literature amongst relative telomere length measured by quantitative PCR (qPCR) and different extraction methods or kits used. We quantified whole-blood leukocyte telomere length using the telomere to single copy gene (T/S) ratio by qPCR in 20 young (18-25 yrs) men after extracting DNA using three common extraction methods: Lahiri and Nurnberger (high salt) method, PureLink Genomic DNA Mini kit (Life Technologies) and QiaAmp DNA Mini kit (Qiagen). Telomere length differences of DNA extracted from the three extraction methods was assessed by one-way analysis of variance (ANOVA).