Late life metformin treatment limits cell survival and shortens lifespan by triggering an aging-associated failure of energy metabolism, bioRxiv, 2019-12-04
SummaryThe diabetes drug metformin is to be clinically tested in aged humans to achieve health span extension, but little is known about responses of old non-diabetic individuals to this drug. By in vitro and in vivo tests we found that metformin shortens life span and limits cell survival when provided in late life, contrary to its positive early life effects. Mechanistically, metformin exacerbates aging-associated mitochondrial dysfunction towards respiratory failure, aggravated by the inability of old cells to upregulate glycolysis in response to metformin, leading to ATP exhaustion. The beneficial dietary restriction effect of metformin on lipid reserves is abrogated in old animals, contributing to metabolic failure, while ectopic stabilization of cellular ATP levels alleviates late life metformin toxicity in vitro and in vivo. The toxicity is also suspended in nematodes carrying diabetes-like insulin receptor insufficiency and showing prolonged resilience to metabolic stress induced by metformin. In sum, we uncovered an alarming metabolic decay triggered by metformin in late life which may limit its benefits for non-diabetic elderly patients. Novel regulators of life extension by metformin are also presented.Highlights<jatslist list-type=bullet><jatslist-item>Late life metformin treatment limits cell survival and shortens lifespan.<jatslist-item><jatslist-item>Metformin exacerbates aging-associated mitochondrial dysfunction causing fatal ATP exhaustion.<jatslist-item><jatslist-item>Old cells fail to upregulate glycolysis as a compensatory response to metformin.<jatslist-item><jatslist-item>The dietary restriction (DR) mimetic response to metformin is abrogated in old animals.<jatslist-item><jatslist-item>PKA and not AMPK pathway instigates the early life DR response to metformin.<jatslist-item><jatslist-item>Stabilization of cellular ATP levels alleviates late life metformin toxicity in vitro and in vivo.<jatslist-item>
biorxiv physiology 200-500-users 2019Muscle strength, size and composition following 12 months of gender-affirming treatment in transgender individuals retained advantage for the transwomen, bioRxiv, 2019-09-27
AbstractObjectivesThis study explored the effects of gender-affirming treatment, which includes inhibition of endogenous sex hormones and replacement with cross-sex hormones, on muscle function, size and composition in 11 transwomen (TW) and 12 transmen (TM).MethodsIsokinetic knee extensor and flexor muscle strength was assessed at baseline (T00), 4 weeks after gonadal suppression of endogenous hormones but before hormone replacement (T0), and 3 (T3) and 11 (T12) months after hormone replacement. In addition, at T00 and T12, we assessed lower-limb muscle volume using MRI, and cross-sectional area (CSA) and radiological density using CT.ResultsThigh muscle volume increased (15%) in TM, which was paralleled by increased quadriceps CSA (15%) and radiological density (6%). In TW, the corresponding parameters decreased by −5% (muscle volume) and −4% (CSA), while density remained unaltered. The TM increased strength over the assessment period, while the TW generally maintained or slightly increased in strength. Baseline muscle volume correlated highly with strength (R>0.75), yet the relative change in muscle volume and strength correlated only moderately (R=0.65 in TW and R=0.32 in TM). The absolute levels of muscle volume and knee extension strength after the intervention still favored the TW.ConclusionCross-sex hormone treatment markedly affects muscle strength, size and composition in transgender individuals. Despite the robust increases in muscle mass and strength in TM, the TW were still stronger and had more muscle mass following 12 months of treatment. These findings add new knowledge that could be relevant when evaluating transwomen’s eligibility to compete in the women’s category of athletic competitions.
biorxiv physiology 500+-users 2019Prevalence estimate of blood doping in elite track and field at the introduction of the Athlete Biological Passport, bioRxiv, 2019-08-19
AbstractIn elite sport, the Athlete Biological Passport (ABP) was invented to tackle cheaters by monitoring closely changes in biological parameters, flagging atypical variations. The haematological module of the ABP was indeed adopted in 2011 by the International Association of Athletics Federations (IAAF). This study estimates the prevalence of blood doping based on haematological parameters in a large cohort of track & field athletes measured at two international major events (2011 & 2013 IAAF World Championships) with a hypothesized decrease in prevalence due to the ABP introduction.A total of 3683 blood samples were collected and analysed from all participating athletes originating from 209 countries. The estimate of doping prevalence was obtained by using a Bayesian network with seven variables, as well as “doping” as a variable mimicking doping with low-doses of recombinant human erythropoietin (rhEPO), to generate reference cumulative distribution functions (CDFs) for the Abnormal Blood Profile Score (ABPS) from the ABP.Our results from robust haematological parameters indicate an estimation of an overall blood doping prevalence of 18% in average in endurance athletes (95% Confidence Interval (C.I.) 14-22%). A higher prevalence was observed in female athletes (22%, C.I. 16-28%) than in male athletes (15%, C.I. 9-20%). In conclusion, this study presents the first comparison of blood doping prevalence in elite athletes based on biological measurements from major international events that may help scientists and experts to use the ABP in a more efficient and deterrent way.What are the new findings ?<jatslist list-type=bullet><jatslist-item>This study presents the first comparison of blood doping prevalence in elite track & field athletes based on biological measurements from major international events<jatslist-item><jatslist-item>Our results from robust haematological parameters indicate an estimation of an overall blood doping prevalence of 18% in average in endurance athletes.<jatslist-item><jatslist-item>The confidence intervals for blood doping prevalence range from 9-28% with wide discrepancies between certain countries.<jatslist-item>How might it impact on clinical practice in the near future<jatslist list-type=bullet><jatslist-item>The further development of the Athlete Biological Passport with a careful monitoring of biological parameters still represents the most consistent approach to thwart athletes using undetectable prohibited substances or methods.<jatslist-item><jatslist-item>This study describes a method to define blood doping prevalence with the analysis of robust haematological parameters<jatslist-item><jatslist-item>Estimates of doping prevalence in subpopulations of athletes may represent a valuable tool for the antidoping authorities to perform a risk assessment in their sport.<jatslist-item>
biorxiv physiology 0-100-users 2019Weak and uneven associations of home, neighborhood and school environments with stress hormone output across multiple time scales, bioRxiv, 2019-07-18
ABSTRACTThe progression of lifelong trajectories of socioeconomic inequalities in health and mortality begins in childhood. Dysregulation in cortisol, a stress hormone that is the primary output of the hypothalamus-pituitary-adrenal (HPA) axis, has been hypothesized to be a mechanism for how early environmental adversity compromises health. However, despite the popularity of cortisol as a biomarker for stress and adversity, little is known about whether cortisol output differs in children being raised in socioeconomically disadvantaged environments. Here, we show that there are few differences between advantaged and disadvantaged children in their cortisol output. In 8- to 14-year-old children from the population-based Texas Twin Project, we measured cortisol output at three different time-scales (1) diurnal fluctuation in salivary cortisol (n = 400), (2) salivary cortisol reactivity and recovery after exposure to the Trier Social Stress Test (n = 444), and (3) and cortisol concentration in hair (n = 1,210). These measures converged on two moderately correlated, yet distinguishable, dimensions of HPA function. We then tested differences in cortisol output across nine aspects of social disadvantage at the home (e.g., family socioeconomic status), school (e.g., average levels of academic achievement), and neighborhood (e.g., concentrated poverty). Children living in neighborhoods with higher concentrated poverty had higher diurnal cortisol output, as measured in saliva; otherwise, child cortisol output was unrelated to any other aspect of social disadvantage. Overall, we find limited support for alteration in HPA axis functioning as a general mechanism for the health consequences of socioeconomic inequality in childhood.
biorxiv physiology 100-200-users 2019Inhibition of mTORC1 signaling in aged rats counteracts the decline in muscle mass and reverses multiple parameters of muscle signaling associated with sarcopenia, bioRxiv, 2019-03-28
AbstractThere is a lack of pharmacological interventions available for sarcopenia, a progressive age-associated loss of muscle mass, leading to a decline in mobility and quality of life. We found mTORC1 (mammalian target of rapamycin complex 1), a well-established critical positive modulator of mass, to be hyperactivated in sarcopenic muscle. Furthermore, inhibition of the mTORC1 pathway counteracted sarcopenia as determined by observing an increase in muscle mass and fiber type cross sectional area, surprising because mTORC1 signaling has been shown to be required for muscle mass gains in some settings. Additionally, several genes related to senescence were downregulated, while gene expression indicators of neuromuscular junction denervation were diminished using a low dose of a rapalog. Therefore mTORC1 inhibition may delay the progression of sarcopenia by directly and indirectly modulating multiple age-associated pathways, implicating mTORC1 as a therapeutic target to treat sarcopenia.
biorxiv physiology 100-200-users 2019Carbs versus fat does it really matter for maintaining lost weight?, bioRxiv, 2018-11-28
The most read article of 2018 published in The BMJ (httpsdoi.org10.1136bmj.k4583) claimed that restricting dietary carbohydrates offers a metabolic advantage to burn more calories and thereby help patients maintain lost weight. However, analyzing the data according to the original pre-registered statistical plan resulted in no statistically significant effects of diet composition on energy expenditure. The large reported diet effects on energy expenditure calculated using the revised analysis plan depended on data from subjects with excessive amounts of unaccounted energy. Adjusting the data to be commensurate with energy conservation resulted in a diet effect that was less than half the value reported in The BMJ paper. Furthermore, the measured daily average CO2 production rates were not significantly different between the diets and the reported expenditure differences were due to inaccurate calculations based on false assumptions about diet adherence.
biorxiv physiology 200-500-users 2018