The association of circulating bioenergetic metabolites with healthy human aging.

Aging is an inevitable and gradual decline in several biological functions. Mitochondrial dysfunction is one of the most important hallmarks of aging. In this context, alterations in metabolites associated with mitochondrial dysfunction may serve as a significant biomarker. This study aimed to investigate the existence of a relationship between the key metabolites involved in bioenergetics metabolism and aging. 53 volunteers ranged 20-85 years participated in the study. We tested the association between different tricarboxylic acid (TCA) cycle metabolites, fatty acid metabolism, and amino acid metabolism with age, sex, body composition, and proxy markers of aging such as walking speed, grip strength and chair test. We found that lactic acid negatively correlated with age while several fatty acid metabolites, such as azelaic, sebacic, and linoleic acids, showed positive correlations with age (p < 0.05). Sex-specific trends, such as glycerol, and dodecanoic acid, were also observed for certain metabolites. Furthermore, citric acid levels were found to have a significant association with physical function and body composition measures. Participants with higher citric acid levels displayed improved performance in physical tests and favorable body composition indices. Additionally, fumaric acid and adipic acid showed positive correlations with fat-free body mass, while sebacic acid was negatively associated with measures of fat mass. These findings underscore the importance of understanding the role of circulating bioenergetics metabolites with age, sex variations, and their potential implications in body composition and physical performance.

Thyroid as a target of adjuvant autoimmunity/inflammatory syndrome due to mRNA-based SARS-CoV2 vaccination: from Graves' disease to silent thyroiditis.

BACKGROUND: As COVID-19 became a pandemic, the urgent need to find an effective treatment vaccine has been a major objective. Vaccines contain adjuvants which are not exempt from adverse effects and can trigger the autoimmune/inflammatory syndrome induced by adjuvants (ASIA). There is very little information about autoimmune endocrine disease and the ASIA after the use of mRNA-based SARS-CoV2 vaccination. CASE SERIES: We report three cases and also review the literature showing that the thyroid gland can be involved in the ASIA induced by the mRNA-based SARS-CoV2 vaccination. We present the first case to date of silent thyroiditis described in the context of SARS-CoV2 vaccination with Pfizer/BioNTech. Also, we discuss the first subacute thyroiditis in the context of SARS-CoV2 vaccination with the Moderna's vaccine. Finally, we provide another case to be added to existing evidence on Graves' disease occurring post-vaccination with the Pfizer/BioNTech vaccine. DISCUSSION: Adjuvants play an important role in vaccines. Their ability to increase the immunogenicity of the active ingredient is necessary to achieve the desired immune response. Both the Moderna and the Pfizer/BioNTech vaccines use mRNA coding for the SARS-CoV2 S protein enhanced by adjuvants. In addition, the cross-reactivity between SARS-CoV2 and thyroid antigens has been reported. This would explain, at least, some of the autoimmune/inflammatory reactions produced during and after SARS-CoV2 infection and vaccination. CONCLUSION: The autoimmune/inflammatory syndrome induced by adjuvants involving the thyroid could be an adverse effect of SARS-CoV2 vaccination and could be underdiagnosed.

Can we predict top-level sports performance in power vs endurance events? A genetic approach.

The goal of our study was to discriminate potential genetic differences between humans who are in both endpoints of the sports performance continuum (i.e. world-class endurance vs power athletes). We used DNA-microarray technology that included 36 genetic variants (within 20 different genes) to compare the genetic profile obtained in two cohorts of world-class endurance (N=100) and power male athletes (N=53) of the same ethnic origin. Stepwise multivariate logistic regression showed that the rs1800795 (IL6-174 G/C), rs1208 (NAT2 K268R) and rs2070744 (NOS3-786 T/C) polymorphisms significantly predicted sport performance (model χ(2) =25.3, df=3, P-value <0.001). Receiver-operating characteristic (ROC) curve analysis showed a significant discriminating accuracy of the model, with an area under the ROC curve of 0.72 (95% confidence interval: 0.66-0.81). The contribution of the studied genetic factors to sports performance was 21.4%. In summary, although an individual's potential for excelling in endurance or power sports can be partly predicted based on specific genetic variants (many of which remain to be identified), the contribution of complex gene-gene interactions, environmental factors and epigenetic mechanisms are also important contributors to the "complex trait" of being an athletic champion. Such trait is likely not reducible to defined genetic polymorphisms.

Is there an association between ACTN3 R577X polymorphism and muscle power phenotypes in young, non-athletic adults?

We investigated the association between ACTN3 R577X polymorphism and jumping (vertical squat and counter-movement jump tests) and sprint ability (30 m dash) in non-athletic, healthy young adults [N=284 (217 male), mean (SD) age: 21 (2) years]. We analyzed the differences in the study phenotypes among ACTN3 R577X genotypes by one-way analysis of covariance before and after adjusting for sex, age, weight and height (confounders). We also compared the genotype and allele frequencies between those with the best and worst results in the aforementioned tests (≥90th vs <90th of the sex-specific percentile, respectively). We used logistic regression to calculate the odds ratio (OR) for having the best performance. We did not observe a significant association between ACTN3 R577X genotypes and the study phenotypes before and after adjusting for potential confounders, nor after analyzing males and females separately. We did not observe significant differences in genotype frequencies between those with the best or the worst performance. The OR for an individual with the RR genotype to be in the top 10 percentile was <1.00 for jump tests and <1.015 for sprint tests (all P>0.05). In summary, α-actinin-3 deficiency does not negatively influence the ability to generate explosive leg muscle power in a young non-athletic population.

Does the polygenic profile determine the potential for becoming a world-class athlete? Insights from the sport of rowing.

We determined whether the polygenic profile computed with seven candidate polymorphisms (i.e., ACE, ACTN3, AMPD1, CKMM, HFE, GDF-8 and PPARGC1A) for endurance performance is different in 39 world-class and 15 national-class Spanish (Caucasian) lightweight rowers. The second purpose was to examine the impact of possessing a "preferable" polygenic profile on the sport success in terms of the number of medals won in World and National Championships. Finally, we also compared the polygenic profile of world- and national-class Spanish rowers with that of the general Spanish population. The polygenic profile did not differ between groups of rowers. We did not observe an association between having a preferable polygenic profile and medals won in World and National Championships. Finally, we observed that rowers tend to have a more "favorable" polygenic profile than the general Spanish population. These findings argue against the idea that genetic endowment differentiates athletic champions from elite, yet less accomplished athletes. In contrast, we cannot discard the fact that, overall, elite athletes are endowed with a more "favorable" polygenic profile than the general population.

Genotype distributions in top-level soccer players: a role for ACE?

We determined the genotype and allelic frequency of several genetic polymorphisms (ACE I/D, GDF-8K153R [and also E164K, P198A and I225T] and AMPD1 C34T) that are candidates to influence sports performance in a group of 54 male professional soccer players. Their results were compared with those of elite endurance male athletes (52 runners) and 123 sedentary, healthy men (controls). We found statistical significance for the ACE ID (chi (2)((2))=8.176, P=0.017) and II genotypes (chi(2)((2))=16.137, P<0.001) with a higher and lower frequency of ID ( P=0.005) and II (P<0.001), respectively, in soccer players than in endurance runners. Statistical significance was also reached for AMPD1 (with a higher frequency of the CT genotype in soccer players than in runners [chi(2)((2))=7.538, P=0.006]) but not for GDF-8 K153R. Since the ACE II genotype is associated with improved potential for endurance performance but with decreased training gains in muscle mass and strength, these findings together with previous results support the notion that elite soccer players tend to have a power/strength oriented genotype.

Endurance performance: genes or gene combinations?

We assessed the possible association between variants of the genes encoding for the angiotensin-converting enzyme ( ACE) and alpha-actinin-3 ( ACTN3) (both individually and combined) and several endurance phenotypic traits, e.g., peak power output (PPO), ventilatory (VT) and respiratory compensation threshold (RCT), among others, in professional road cyclists and sedentary controls (n = 46 each). We applied an ANCOVA test using the aforementioned phenotype traits as dependent variables, ACE and/or ACTN3 genotype as the fixed (independent) factor and age and body mass as covariates. We only found a significant genotype effect with no concomitant covariate effect for ACTN3, with cyclists who were not alpha-actinin-3 deficient (RR + RX genotypes) having higher PPO and VT values than their XX counterparts (mean [SEM]: 7.4 (0.1) vs. 7.1 (0.1) W/kg, p = 0.035; and 4.5 (0.1) vs. 4.3 (0.1) W/kg, p = 0.029, respectively). Cyclists with an "extreme" ACTN3 and ACE genotype combination, i.e., most strength/power oriented (DD + RR/RX), had higher RCT values than those with the "intermediate" combinations (II + RX/RR, p = 0.036; and DD + XX, p = .0004) but similar to those with the most endurance oriented genotype (II + XX). No significant differences (p > 0.05) were found in controls. In summary, in world-class cyclists, we only found an association between ACTN3 genotypes and VT and PPO, and between ACTN3/ACE genotype combinations and RCT.

Unique among unique. Is it genetically determined?

The cross-country world championship is one of the best models to study characteristics needed to achieve top-level endurance athletic capacity. We report the genotype combination of a recent cross-country champion (12 km race) in polymorphisms of seven genes that are candidates to influence endurance phenotype traits (ACTN3, ACE, PPARGC1A, AMPD1, CKMM, GDF8 (myostatin) and HFE). His data were compared with those of eight other runners (world-class but not world champions). The only athlete with the genotype theoretically more suited to attaining world-class endurance running performance was the case study subject. A favourable genetic endowment, together with exceptional environmental factors (years of altitude living and training in this case), seems to be necessary to attain the highest possible level of running endurance performance.

ACTN3 genotype in professional soccer players.

The authors studied the frequency distribution of alpha-actinin-3 (ACTN3) R577X genotypes in 60 top-level professional soccer players. The results were compared with those of 52 elite endurance athletes and 123 sedentary controls. The per cent distribution of RR and RX genotypes in soccer players (48.3% and 36.7%) was significantly higher and lower, respectively, than controls (28.5% and 53.7%) and endurance athletes (26.5% and 52%) (p = 0.041). Although there are notable exceptions, elite soccer players tend to have the sprint/power ACTN3 genotype.