Flavanol-Rich Cocoa Supplementation Inhibits Mitochondrial Biogenesis Triggered by Exercise.

The potential role of cocoa supplementation in an exercise context remains unclear. We describe the effects of flavanol-rich cocoa supplementation during training on exercise performance and mitochondrial biogenesis. Forty-two male endurance athletes at the beginning of the training season received either 5 g of cocoa (425 mg of flavanols) or maltodextrin (control) daily for 10 weeks. Two different doses of cocoa (equivalent to 5 g and 15 g per day of cocoa for a 70 kg person) were tested in a mouse exercise training study. In the athletes, while both groups had improved exercise performance, the maximal aerobic speed increased only in the control group. A mitochondrial DNA analysis revealed that the control group responded to training by increasing the mitochondrial load whereas the cocoa group showed no increase. Oxidative stress was lower in the cocoa group than in the control group, together with lower interleukin-6 levels. In the muscle of mice receiving cocoa, we corroborated an inhibition of mitochondrial biogenesis, which might be mediated by the decrease in the expression of nuclear factor erythroid-2-related factor 2. Our study shows that supplementation with flavanol-rich cocoa during the training period inhibits mitochondrial biogenesis adaptation through the inhibition of reactive oxygen species generation without impacting exercise performance.

Physical Condition and Risk of Hospitalization and Polypharmacy in Older Adults.

Hospitalization in older population leads to a decline in physical function, physical condition, and independency. However, a scarce number of studies has addressed the effect of being in good physical condition on the risk of hospitalization and polypharmacy in older people. Therefore, this study aims to examine the relationship between physical condition and other health factors, and the incidence of hospitalization and polypharmacy in Spanish older persons. For this cross-sectional study we recruited 102 institutionalized persons aged 80 years or older, who were being treated at three primary care centers. The data collected were number of hospitalizations and medications, dietary habits, nutrition status, quality of life, independence in activities of daily life, physical performance, and associated genotype data. Scoring higher in the tests Chair stand and 8-Foot Up-and-go was found associated with reduced risks of hospitalization (odds ratio [OR] = 0.45 [95% CI = 0.2-0.99]; OR 0.32 [95% CI = 0.12-0.86]) and polypharmacy (OR = 0.36 [95% CI = 0.16-0.8]; OR = 0.28 [95% CI = 0.1-0.78]). The number of medications was also lower in individuals with a greater aerobic capacity and activities of daily life independence (OR = 0.28 [95% CI = 0.1-0.78]; OR = 0.37 [95% CI = 0.16-0.82]). No associations were found with the remaining physical performance tests or other factors assessed. Our findings point to benefits of greater strength, balance, and aerobic capacity in terms of reducing the risk of hospitalization and polypharmacy.

Acute Impacts of Different Types of Exercise on Circulating α-Klotho Protein Levels.

Introduction: Elevated plasma α-klotho (αKl) protects against several ageing phenotypes and has been proposed as a biomarker of a good prognosis for different diseases. The beneficial health effects of elevated plasma levels of soluble αKl (SαKl) have been likened to the positive effects of exercise on ageing and chronic disease progression. It has also been established that molecular responses and adaptations differ according to exercise dose. The aim of this study is to compare the acute SαKl response to different exercise interventions, cardiorespiratory, and strength exercise in healthy, physically active men and to examine the behavior of SαKl 72h after acute strength exercise. Methods: In this quasi-experimental study, plasma SαKl was measured before and after a cardiorespiratory exercise session (CR) in 43 men, and strength exercise session (ST) in 39 men. The behavior of SαKl was also examined 24, 48, and 72h after ST. Results: Significant differences (time×group) were detected in SαKl levels (p=0.001; d=0.86) between CR and ST. After the ST intervention, SαKl behavior varied significantly (p=0.009; d=0.663) in that levels dropped between pre- and post-exercises (p=0.025; d=0.756) and were also significantly higher compared to pre ST values at 24h (p=0.033; d=0.717) and at 48h (p=0.015; d=0.827). Conclusions: SαKl levels increased in response to a single bout of cardiorespiratory exercise; while they decreased immediately after strength exercise, levels were elevated after 24h indicating different klotho protein responses to different forms of exercise.

Genetic variations associated with non-contact muscle injuries in sport: A systematic review.

INTRODUCTION: Non-contact muscle injuries (NCMI) account for a large proportion of sport injuries, affecting athletes' performance and career, team results and financial aspects. Recently, genetic factors have been attributed a role in the susceptibility of an athlete to sustain NCMI. However, data in this field are only just starting to emerge. OBJECTIVES: To review available knowledge of genetic variations associated with sport-related NCMI. METHODS: The databases Pubmed, Scopus, and Web of Science were searched for relevant articles published until February 2021. The records selected for review were original articles published in peer-reviewed journals describing studies that have examined NCMI-related genetic variations in adult subjects (17-60 years) practicing any sport. The data extracted from the studies identified were as follows: general information, and data on genetic polymorphisms and NCMI risk, incidence and recovery time and/or severity. RESULTS: Seventeen studies examining 47 genes and 59 polymorphisms were finally included. 29 polymorphisms affecting 25 genes were found significantly associated with NCMI risk, incidence, recovery time, and/or severity. These genes pertain to three functional categories: (i) muscle fiber structural/contractile properties, (ii) muscle repair and regeneration, or (iii) muscle fiber external matrix composition and maintenance. CONCLUSION: Our review confirmed the important role of genetics in NCMI. Some gene variants have practical implications such as differences of several weeks in recovery time detected between genotypes. Knowledge in this field is still in its early stages. Future studies need to examine a wider diversity of sports and standardize their methods and outcome measures.

Circulating microRNAs fluctuations in exercise-induced cardiac remodeling: A systematic review.

MicroRNAs (miRNAs) are small non-coding RNAs that participate in gene expression regulation. It has been observed that circulating levels of miRNAs may fluctuate during exercise, showing numerous cardiac biological and physiological effects such as structural and functional adaptations. We aimed to provide an overview of the currently available information concerning the role of circulating miRNAs in cardiovascular adaptations in response to acute and/or chronic exercise training. Relevant studies published were searched in three databases: PubMed, Web of Science and Scopus. A combination of the following keywords was used: ("microRNA" OR "miRNA" OR "miR" AND "exercise" OR "training" OR "physical activity") AND "(heart hypertrophy" OR "cardiac remodeling" OR "cardiac muscle mass" OR "cardiac hypertrophy"). Only experimental studies, written in English and conducted in healthy individuals were included. Five articles met the inclusion criteria and were finally included in this systematic review after reviewing both title, abstract and full-text. A total of thirty-six circulating cardiac-related miRNAs were analyzed, but only five of them (miR-1, miR-133a, miR-146a, miR-206 and miR-221) were directly associated with cardiac adaptations parameters, while two of them (miR-1 and miR-133a) were related to cardiac hypertrophy. Most of them were upregulated immediately after a marathon and returned to basal levels at longer times. Therefore, we conclude that, although evidence is still limited, and long-term studies are needed to obtain more robust evidence, exercise is more likely to affect circulating cardiac-related miRNAs levels.

The Genetics of Spondyloarthritis.

The term spondyloarthritis (SpA) encompasses a group of chronic inflammatory diseases with common features in terms of clinical presentation and genetic predisposition. SpA is characterized by inflammation of the spine and peripheral joints, and is also be associated with extra-articular inflammatory manifestations such as psoriasis, uveitis, or inflammatory bowel disease (IBD). The etiology of SpA is not completely understood, but it is known to have a strong genetic component dominated by the human leukocyte antigen (HLA)-B27. In the last few years, our understanding of genetic susceptibility to SpA, particularly ankylosing spondylitis (AS), has greatly improved thanks to the findings derived from powered genome-wide association studies (GWAS) based on single nucleotide polymorphism (SNP) arrays. These studies have identified many candidate genes, therefore providing new potential directions in the exploration of disease mechanisms, especially with regard to the key role of the immune system in the pathogenesis of SpA. SpA is a complex disease where genetic variability, environmental factors, and random events interact to trigger pathological pathways. The aim of this review is to summarize current findings on the genetics of SpA, some of which might help to study new treatment approaches.

Physical performance, plasma S-klotho, and all-cause mortality in elderly dialysis patients: A prospective cohort study.

The secreted protein form of the α-klotho gene, S-klotho, is gaining popularity as a predictor of overall morbimortality, and its role in dialysis patients has been recently highlighted. However, physical performance -which can be assessed through practical field-tests- might be a more practical prognostic marker. The present study aimed to analyze the relationship between physical performance, plasma S-klotho and all-cause mortality in this population. 30 male hemodialysis patients (71 ±â€¯9 years) participated in this prospective, cohort study. Their plasma S-klotho levels and physical performance (assessed by means of the 6-minute walk test [6MWT], handgrip strength, and the sit-to-stand test [STS]) were determined at baseline, and the incidence of mortality was assessed 18-month later. Lower S-klotho levels were associated with a worse performance in all physical tests (all p < 0.05). 12 participants died during the 18 months following baseline measurements. An increased mortality risk was observed in those patients with a worse performance in the STS (RR: 3.0 [95%CI: 1.01-8.95], p < 0.05), the handgrip test (RR: 3.0 [95%CI: 1.01-8.95], p < 0.05) and the 6MWT (RR: 5.0 [95%CI: 1.31-19.07], p < 0.01), being the latter the best predictor of mortality. By contrast, this relationship was not found for plasma S-klotho (RR: 1.6 [95%CI: 0.65-1.35], p > 0.05). In summary, low plasma S-klotho levels are related to impaired physical performance in male dialysis patients. However, physical performance appears as a better and more practical predictor of mortality in this patient population.

Association of HTR2A-1438G/A Genetic Polymorphism With Smoking and Chronic Obstructive Pulmonary Disease / Asociación del polimorfismo genético HTR2A-1438G/A con el tabaco y la enfermedad pulmonar obstructiva crónica

Introduction: Cigarette smoking is a major risk factor in the development of chronic obstructive pulmonary disease (COPD). Serotonin levels have been associated with COPD and smoking has been as a significant modulator. Elevated levels of serotonin are responsible for bronchoconstriction and pulmonary vasoconstriction and also nicotine dependence, thus serotonin response could be affected by genetic polymorphisms in transporters and receptors of serotonin. Objectives: The aim of the current study was to analyze the effect of SLC6A4 (5HTT_LPR) (rs25531) and HTR2A-1438G/A (rs6311) genetic polymorphisms on the relation between smoking habits and COPD. Methods: The association between SLC6A4 (5HTT_LPR) (rs25531), HTR2A-1438G/A (rs6311), smoking degree and COPD was analyzed in a total of 77 COPD patients (active smokers) and 90 control subjects (active healthy smokers). The DNA was extracted of peripheral leukocytes samples and genotyping was performed using an allele specific polymerase chain reaction. Results: The distribution of SLC6A4 genotypes did not vary between healthy smokers and COPD patients (P = 0.758). On the other hand, the A allele of HTR2A (rs6311) was significantly associated with COPD incidence in the trend model (P = 0.02; 1.80 [1.04-3.11]). Among all smokers, this allele was also associated with the number of pack years smoked (P = 0.02) and also, we observed a marginal association with FEV1/FVC values (P = 0.06). Conclusion: Our results point a possible role of the A allele of HTR2A (rs6311) in COPD pathogenesis, suggesting that this effect depends partly on tobacco consumption due to a gene-by-environment interaction

Introducción: El consumo de tabaco es el principal riesgo para desarrollar enfermedad pulmonar obstructiva crónica (EPOC). Los niveles de serotonina se han relacionado con el riesgo de desarrollo de EPOC, siendo el consumo de tabaco un modulador significativo. Los niveles elevados de serotonina producen broncoconstricción y vasoconstricción pulmonar, así como dependencia a la nicotina. Así, la respuesta a serotonina podría verse afectada por los polimorfismos genéticos en los transportadores y receptores de este neurotransmisor. Objetivos: El objetivo de este estudio fue analizar el papel de los polimorfismos genéticos SLC6A4 (5HTT_LPR) (rs25531) y HTR2A -1438G/A (rs6311) en la relación entre el consumo de tabaco y la EPOC. Métodos: Se analizó la asociación entre SLC6A4 (5HTT_LPR) (rs25531), HTR2A -1438G/A (rs6311), grado de tabaquismo y EPOC en 77 pacientes con EPOC (fumadores activos) y 90 sujetos control (fumadores activos sanos). El ADN se extrajo a partir de leucocitos de sangre periférica y la genotipificación se realizó utilizando la reacción en cadena de la polimerasa alelo-específica. Resultados: No se observaron diferencias en la distribución de genotipos SLC6A4 entre fumadores sanos y fumadores con EPOC (p = 0,758). Se encontró una asociación significativa entre el alelo A de HTR2A (rs6311) y la incidencia de EPOC en el modelo predictivo (p = 0,02; 1,80 [1,04-3,11]). En los fumadores, este alelo también se asoció al número de paquetes fumados al año (p = 0,02) y, además, de forma marginal con los valores de FEV1/FVC (p = 0,06). Conclusión: Nuestros resultados apuntan a un posible papel del alelo A de HTR2A (rs6311) en la patogénesis de EPOC, indicando que este efecto dependería en parte del consumo de tabaco a través de una interacción gen-ambiente

Association of HTR2A-1438G/A Genetic Polymorphism With Smoking and Chronic Obstructive Pulmonary Disease.

INTRODUCTION: Cigarette smoking is a major risk factor in the development of chronic obstructive pulmonary disease (COPD). Serotonin levels have been associated with COPD and smoking has been as a significant modulator. Elevated levels of serotonin are responsible for bronchoconstriction and pulmonary vasoconstriction and also nicotine dependence, thus serotonin response could be affected by genetic polymorphisms in transporters and receptors of serotonin. OBJECTIVES: The aim of the current study was to analyze the effect of SLC6A4 (5HTT_LPR) (rs25531) and HTR2A-1438G/A (rs6311) genetic polymorphisms on the relation between smoking habits and COPD. METHODS: The association between SLC6A4 (5HTT_LPR) (rs25531), HTR2A-1438G/A (rs6311), smoking degree and COPD was analyzed in a total of 77 COPD patients (active smokers) and 90 control subjects (active healthy smokers). The DNA was extracted of peripheral leukocytes samples and genotyping was performed using an allele specific polymerase chain reaction. RESULTS: The distribution of SLC6A4 genotypes did not vary between healthy smokers and COPD patients (P=0.758). On the other hand, the A allele of HTR2A (rs6311) was significantly associated with COPD incidence in the trend model (P=0.02; 1.80 [1.04-3.11]). Among all smokers, this allele was also associated with the number of pack years smoked (P=0.02) and also, we observed a marginal association with FEV1/FVC values (P=0.06). CONCLUSION: Our results point a possible role of the A allele of HTR2A (rs6311) in COPD pathogenesis, suggesting that this effect depends partly on tobacco consumption due to a gene-by-environment interaction.

Red Bull® energy drink increases consumption of higher concentrations of alcohol.

Mixing alcohol with caffeinated energy drinks is a common practice, especially among young people. In humans, the research on this issue has mainly focused on the use of the mass-marketed energy drinks themselves, whereas in animal models, it has focused on the individual effects of their active ingredients (i.e. caffeine). Here, we have characterized how Red Bull®, one of the most consumed caffeinated energy drink worldwide, modulates operant alcohol self-administration in Wistar rats. We found that animals readily and steadily responded for Red Bull (mean: 90 responses, 30 minutes and fixed-ratio 1), which was accompanied by locomotor stimulating effects (26 percent increase). The higher the concentration of alcohol (3-20 percent), the higher the consumption of alcohol (g/kg) and associated blood alcohol levels (91.76 percent) in the mixed Red Bull-alcohol group (60 percent increase). Blood caffeine levels in the Red Bull group were 4.69 µg/ml and 1.31 µg/ml in the Red Bull-alcohol group after the 30-minute session. Because Red Bull also contains 11 percent sucrose, we examined the time course of blood glucose as well as insulin and corticosterone. The correlation between intake of Red Bull and blood glucose levels was higher at 90 minutes than 5 minutes after its consumption, and there was no relationship with blood insulin or blood corticosterone levels. Red Bull did not alter extinction and reacquisition of responding for alcohol nor did it affect relapse-like drinking. Overall, our results suggest that Red Bull might be a vulnerability factor to develop alcoholism given that it intensifies the consumption of higher concentrations of alcohol.

Telomere Length in Elite Athletes.

Growing evidence suggests that regular moderate-intensity physical activity is associated with an attenuation of leukocyte telomere length (LTL) shortening. However, more controversy exists regarding higher exercise loads such as those imposed by elite-sport participation. METHODS: The authors investigated LTL differences between young elite athletes (n = 61, 54% men, age [mean ± SD] 27.2 ± 4.9 y) and healthy nonsmoker, physically inactive controls (n = 64, 52% men, 28.9 ± 6.3 y) using analysis of variance (ANOVA). RESULTS: Elite athletes had, on average, higher LTL than control subjects, 0.89 ± 0.26 vs 0.78 ± 0.31, P = .013 for the group effect, with no significant sex (P = .995) or age effect (P = .114). CONCLUSIONS: The results suggest that young elite athletes have longer telomeres than their inactive peers. Further research might assess the LTL of elite athletes of varying ages compared with both age-matched active and inactive individuals.

A Paradox: α-Klotho Levels and Smoking Intensity.

Reports regarding smoking differences in α-klotho expression have provided conflicting results. In the current study we focused on the influence of smoking intensity to serum levels of the aging molecule α-klotho in healthy smokers. 40 middle aged healthy smokers without airway obstruction or restriction were selected for the analysis. Serum levels of soluble α-klotho were significantly higher in heavy smokers (P < 0.001). These results are in agreement with the possibility that α-klotho acts as anti-inflammatory molecule and strengthen the hypothesis that an increase of serum levels of α-klotho might be a compensatory response to smoking stress in healthy population.

Effect of Genetic Polymorphisms and Long-Term Tobacco Exposure on the Risk of Breast Cancer.

INTRODUCTION: Tobacco smoke contains many potentially harmful compounds that may act differently and at different stages in breast cancer development. The focus of this work was to assess the possible role of cigarette smoking (status, dose, duration or age at initiation) and polymorphisms in genes coding for enzymes involved in tobacco carcinogen metabolism (CYP1A1, CYP2A6) or in DNA repair (XRCC1, APEX1, XRCC3 and XPD) in breast cancer development. METHODS: We designed a case control study with 297 patients, 217 histologically verified breast cancers (141 smokers and 76 non-smokers) and 80 healthy smokers in a cohort of Spanish women. RESULTS: We found an association between smoking status and early age at diagnosis of breast cancer. Among smokers, invasive carcinoma subtype incidence increased with intensity and duration of smoking (all Ptrend < 0.05). When smokers were stratified by smoking duration, we only observed differences in long-term smokers, and the CYP1A1 Ile462Ile genotype was associated with increased risk of breast cancer (OR = 7.12 (1.98-25.59)). CONCLUSIONS: Our results support the main effect of CYP1A1 in estrogenic metabolism rather than in tobacco carcinogen activation in breast cancer patients and also confirmed the hypothesis that CYP1A1 Ile462Val, in association with long periods of active smoking, could be a breast cancer risk factor.

No Evidence of a Common DNA Variant Profile Specific to World Class Endurance Athletes.

There are strong genetic components to cardiorespiratory fitness and its response to exercise training. It would be useful to understand the differences in the genomic profile of highly trained endurance athletes of world class caliber and sedentary controls. An international consortium (GAMES) was established in order to compare elite endurance athletes and ethnicity-matched controls in a case-control study design. Genome-wide association studies were undertaken on two cohorts of elite endurance athletes and controls (GENATHLETE and Japanese endurance runners), from which a panel of 45 promising markers was identified. These markers were tested for replication in seven additional cohorts of endurance athletes and controls: from Australia, Ethiopia, Japan, Kenya, Poland, Russia and Spain. The study is based on a total of 1520 endurance athletes (835 who took part in endurance events in World Championships and/or Olympic Games) and 2760 controls. We hypothesized that world-class athletes are likely to be characterized by an even higher concentration of endurance performance alleles and we performed separate analyses on this subsample. The meta-analysis of all available studies revealed one statistically significant marker (rs558129 at GALNTL6 locus, p = 0.0002), even after correcting for multiple testing. As shown by the low heterogeneity index (I2 = 0), all eight cohorts showed the same direction of association with rs558129, even though p-values varied across the individual studies. In summary, this study did not identify a panel of genomic variants common to these elite endurance athlete groups. Since GAMES was underpowered to identify alleles with small effect sizes, some of the suggestive leads identified should be explored in expanded comparisons of world-class endurance athletes and sedentary controls and in tightly controlled exercise training studies. Such studies have the potential to illuminate the biology not only of world class endurance performance but also of compromised cardiac functions and cardiometabolic diseases.

The Effect of Polymorphisms in DNA Repair Genes and Carcinogen Metabolizers on Leukocyte Telomere Length: A Cohort of Healthy Spanish Smokers.

INTRODUCTION: Smoking implies exposure to carcinogenic agents that causes DNA damage, which could be suspected to enhance telomere attrition. To protect and deal with DNA damage, cells possess mechanisms that repair and neutralize harmful substances. Polymorphisms altering DNA repair capacity or carcinogen metabolism may lead to synergistic effects with tobacco carcinogen-induced shorter telomere length independently of cancer interaction. The aim of this study was to explore the association between leukocyte telomere length (LTL) and several genetic polymorphisms in DNA repair genes and carcinogen metabolizers in a cohort of healthy smokers. METHODS: We evaluated the effect of six genetic polymorphisms in cytochrome P1A1 (Ile462Val), XRCC1 (Arg399Gln), APEX1 (Asp148Glu), XRCC3 (Thr241Met), and XPD (Asp312Asn; Lys751Gln) on LTL in a cohort of 145 healthy smokers in addition to smoking habits. RESULTS: Logistic regression analysis showed an association between XRCC1 399Gln allele and shorter telomere length (OR = 5.03, 95% CI = 1.08% to 23.36%). There were not association between the rest of polymorphisms analyzed and LTL. CONCLUSIONS: Continuous exposure to tobacco could overwhelm the DNA repair machinery, making the effect of the polymorphisms that reduce repair capacity more pronounced. Analyzing the function of smoking-induced DNA-repair genes and LTL is an important goal in order to identify therapeutic targets to treat smoking-induced diseases.

Are SNP-Smoking Association Studies Needed in Controls? DNA Repair Gene Polymorphisms and Smoking Intensity.

Variations in tobacco-related cancers, incidence and prevalence reflect differences in tobacco consumption in addition to genetic factors. Besides, genes related to lung cancer risk could be related to smoking behavior. Polymorphisms altering DNA repair capacity may lead to synergistic effects with tobacco carcinogen-induced lung cancer risk. Common problems in genetic association studies, such as presence of gene-by-environment (G x E) correlation in the population, may reduce the validity of these designs. The main purpose of this study was to evaluate the independence assumption for selected SNPs and smoking behaviour in a cohort of 320 healthy Spanish smokers. We found an association between the wild type alleles of XRCC3 Thr241Met or KLC3 Lys751Gln and greater smoking intensity (OR = 12.98, 95% CI = 2.86-58.82 and OR=16.90, 95% CI=2.09-142.8; respectively). Although preliminary, the results of our study provide evidence that genetic variations in DNA-repair genes may influence both smoking habits and the development of lung cancer. Population-specific G x E studies should be carried out when genetic and environmental factors interact to cause the disease.

Effects of cigarette smoking and nicotine metabolite ratio on leukocyte telomere length.

Studies of the effects of smoking on leukocyte telomere length (LTL) using cigarettes smoked per day or pack years smoked (PYS) present limitations. Reported high levels of smoking may not increase toxin exposure levels proportionally. Nicotine metabolism ratio (NMR) predicts total cigarette puff volume and overall exposure based on total N-nitrosamines, is highly reproducible and independent of time since the last cigarette. We hypothesized that smokers with higher NMRs will exhibit increased total puff volume, reflecting efforts to extract more nicotine from their cigarettes and increasing toxin exposure. In addition, higher levels of smoking could cause a gross damage in LTL. The urinary cotinine, 3-OH cotinine and nicotine levels of 147 smokers were analyzed using a LC/MS system Triple-Q6410. LTL and CYP2A6 genotype was determined by PCR in blood samples. We found a significant association between NMR and CYP2A6 genotype. Reduction in LTL was seen in relation to accumulated tobacco consumption and years smoking when we adjusted for age and gender. However, there were no significant differences between NMR values and LTL. In our study the higher exposure was associated with lower number of PYS. Smokers with reduced cigarette consumption may exhibit compensatory smoking behavior that results in no reduced tobacco toxin exposure. Our results suggest that lifetime accumulated smoking exposure could cause a gross damage in LTL rather than NMR or PYS. Nevertheless, a combination of smoking topography (NMR) and consumption (PYS) measures may provide useful information about smoking effects on health outcomes.

Physical-capacity-related genetic polymorphisms in children with cystic fibrosis.

In patients with cystic fibrosis (CF), physical capacity (PC) has been correlated with mortality risk. In turn, PC is dependent on genetic factors. This study examines several polymorphisms associated with PC and health-related phenotype traits (VO2peak, FEV1, FVC, PImax and muscular strength) in a group of children with CF (n = 66, primary purpose). The same analyses were also performed in a control group of healthy children (n = 113, secondary purpose). The polymorphisms determined were classified as muscle function polymorphisms (ACE rs1799752; AGT rs699; ACTN3 rs1815739; PTK2 rs7843014 and rs7460; MSTN rs1805086; TRHR rs7832552; NOS3 rs2070744) or energy metabolism polymorphisms (PPARGC1A rs8192678; NRF1 rs6949152; NRF2 rs12594956; TFAM rs1937; PPARD rs2267668; ACSL1 rs6552828). No significant polymorphism/phenotype correlations were detected in children with CF, with marginal associations being observed between NOS3 rs2070744 and VO2peak and FEV1, as well as between PPARGC1A rs8192678 and FEV1. Overall, similar findings were observed in the control group, i.e., no major associations. The PC-related polymorphisms examined seem to have no effects on the PC or health of children with CF.

FNDC5 (irisin) gene and exceptional longevity: a functional replication study with rs16835198 and rs726344 SNPs.

Irisin might play an important role in reducing the risk of obesity, insulin resistance, or several related diseases, and high irisin levels may contribute to successful aging. Thus, the irisin precursor (FNDC5) gene is a candidate to influence exceptional longevity (EL), i.e., being a centenarian. It has been recently shown that two single-nucleotide polymorphisms (SNPs) in the FNDC5 gene, rs16835198 and rs726344, are associated with in vivo insulin sensitivity in adults. We determined luciferase gene reporter activity in the two above-mentioned SNPs and studied genotype distributions among centenarians (n = 175, 144 women) and healthy controls (n = 347, 142 women) from Spain. We also studied an Italian [79 healthy centenarians (40 women) and 316 healthy controls (156 women)] and a Japanese cohort [742 centenarians (623 women) and 499 healthy controls (356 women)]. The rs726344 SNP had functional significance, as shown by differences in luciferase activity between the constructs of this SNP (all P ≤ 0.05), with the variant A-allele having higher luciferase activity compared with the G-allele (P = 0.04). For the rs16835198 SNP, the variant T-allele tended to show higher luciferase activity compared with the G-allele (P = 0.07). However, we found no differences between genotype/allele frequencies of the two SNPs in centenarians versus controls in any cohort, and no significant association (using logistic regression adjusted by sex) between the two SNPs and EL. Further research is needed with different cohorts as well as with additional variants in the FNDC5 gene or in other genes involved in irisin signaling.

Exome sequencing of three cases of familial exceptional longevity.

Exceptional longevity (EL) is a rare phenotype that can cluster in families, and co-segregation of genetic variation in these families may point to candidate genes that could contribute to extended lifespan. In this study, for the first time, we have sequenced a total of seven exomes from exceptionally long-lived siblings (probands ≥ 103 years and at least one sibling ≥ 97 years) that come from three separate families. We have focused on rare functional variants (RFVs) which have ≤ 1% minor allele frequency according to databases and that are likely to alter gene product function. Based on this, we have identified one candidate longevity gene carrying RFVs in all three families, APOB. Interestingly, APOB is a component of lipoprotein particles together with APOE, and variants in the genes encoding these two proteins have been previously associated with human longevity. Analysis of nonfamilial EL cases showed a trend, without reaching statistical significance, toward enrichment of APOB RFVs. We have also identified candidate longevity genes shared between two families (5-13) or within individual families (66-156 genes). Some of these genes have been previously linked to longevity in model organisms, such as PPARGC1A, NRG1, RAD52, RAD51, NCOR1, and ADCY5 genes. This work provides an initial catalog of genes that could contribute to exceptional familial longevity.