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Abstract Reversible and sub-lethal stresses to the mitochondria elicit a program of compensatory responses that ultimately improve mitochondrial function, a conserved anti-aging mechanism termed mitohormesis. Here, we show that harmol, a member of the beta-carbolines family with anti-depressant properties, improves mitochondrial function and metabolic parameters, and extends healthspan. Treatment with harmol induces a transient mitochondrial depolarization, a strong mitophagy response, and the AMPK compensatory pathway both in cultured C2C12 myotubes and in male mouse liver, brown adipose tissue and muscle, even though harmol crosses poorly the blood–brain barrier. Mechanistically, simultaneous modulation of the targets of harmol monoamine-oxidase B and GABA-A receptor reproduces harmol-induced mitochondrial improvements. Diet-induced pre-diabetic male mice improve their glucose tolerance, liver steatosis and insulin sensitivity after treatment with harmol. Harmol or a combination of monoamine oxidase B and GABA-A receptor modulators extend the lifespan of hermaphrodite Caenorhabditis elegans or female Drosophila melanogaster. Finally, two-year-old male and female mice treated with harmol exhibit delayed frailty onset with improved glycemia, exercise performance and strength. Our results reveal that peripheral targeting of monoamine oxidase B and GABA-A receptor, common antidepressant targets, extends healthspan through mitohormesis.

Abstract Background Frailty is a major age‐associated syndrome leading to disability. Oxidative damage plays a significant role in the promotion of frailty. The cellular antioxidant system relies on reduced nicotinamide adenine dinucleotide phosphate (NADPH) that is highly dependent on glucose 6‐P dehydrogenase (G6PD). The G6PD‐overexpressing mouse (G6PD‐Tg) is protected against metabolic stresses. Our aim was to examine whether this protection delays frailty. Methods Old wild‐type (WT) and G6PD‐Tg mice were evaluated longitudinally in terms of frailty. Indirect calorimetry, transcriptomic profile, and different skeletal muscle quality markers and muscle regenerative capacity were also investigated. Results The percentage of frail mice was significantly lower in the G6PD‐Tg than in the WT genotype, especially in 26‐month‐old mice where 50% of the WT were frail vs. only 13% of the Tg ones (P

Dementia is one of the greatest global challenges for health and social care in the 21st century. Alzheimer's disease (AD), the most common type of dementia, is by no means an inevitable consequence of growing old. Several lifestyle factors may increase, or reduce, an individual's risk of developing AD. Much has been written over the ages about the benefits of exercise and physical activity. Among the risk factors associated with AD is a low level of physical activity. The relationship between physical and mental health was established several years ago. In this review, we discuss the role of exercise (aerobic and resistance) training as a therapeutic strategy for the treatment and prevention of AD. Older adults who exercise are more likely to maintain cognition. We address the main protective mechanism on brain function modulated by physical exercise by examining both human and animal studies. We will pay especial attention to the potential role of exercise in the modulation of amyloid β turnover, inflammation, synthesis and release of neurotrophins, and improvements in cerebral blood flow. Promoting changes in lifestyle in presymptomatic and predementia disease stages may have the potential for delaying one-third of dementias worldwide. Multimodal interventions that include the adoption of an active lifestyle should be recommended for older populations.

Research in redox biology of exercise has made considerable advances in the last 70 years. Since the seminal study of George Pake's group calculating the content of free radicals in skeletal muscle in resting conditions in 1954, many discoveries have been made in the field. The first section of this review is devoted to highlight the main research findings and fundamental changes in the exercise redox biology discipline. It includes: i) the first steps in free radical research, ii) the relation between exercise and oxidative damage, iii) the redox regulation of muscle fatigue, iv) the sources of free radicals during muscle contractions, and v) the role of reactive oxygen species as regulators of gene transcription and adaptations in skeletal muscle.In the second section of the manuscript, we review the available biomarkers for assessing health, performance, recovery during exercise training and overtraining in the sport population. Among the set of biomarkers that could be determined in exercise studies we deepen on the four categories of redox biomarkers: i) oxidants, ii) antioxidants, iii) oxidation products (markers of oxidative damage), and iv) measurements of the redox balance (markers of oxidative stress). The main drawbacks, strengths, weaknesses, and methodological considerations of every biomarker are also discussed.

Background: Frailty is a geriatric syndrome associated with negative health outcomes that represents a dynamic condition with a potential of reversibility after physical exercise interventions. Typically, inflammatory and senescence markers are increased in frail individuals. However, the impact that physical exercise exerts on inflammatory and senescence biomarkers remains unknown. We assessed the effect of physical intervention in old individuals and mice and determined the expression of inflammatory and senescence markers. Methods: Twelve elderly individuals were enrolled from a primary care setting to a 3-month intervention. Frailty was measured by SPPB and the expression of biomarkers by cytokine array and RT-qPCR. In addition, 12 aged C57BL/6 mice completed an intervention, and inflammation and senescence markers were studied. Results: The physical intervention improved the SPPB score, reducing frail and pre-frail individuals. This was correlated with a reduction in several pro-inflammatory biomarkers such as IL-6, CXCL-1, CXCL-10, IL-1β, IL-7, GM-CSF as well as p16INK4a and p21CIP1 senescence markers. Otherwise, the levels of anti-inflammatory biomarker IL-4 were significantly increased. Moreover, the physical intervention in mice also improved their functional capacity and restored the expression of inflammatory (Il-1β, Cxcl-10, Il-6, and Cxcl-1) and senescence (p21Cip1) markers. Additionally, PLSDA and ROC curve analysis revealed CXCL-10 and IL-1β to be the biomarkers of functional improvement in both cohorts. Conclusions: Our results showed that a physical intervention improves physical frailty, and reverses inflammation and senescence biomarkers comprising CXCL-10 and IL-1β.

Actualmente, están disponibles en el mercado nuevos modelos de calzado deportivo, como el calzado inestable. Sin embargo, todavía existe una falta de evidencia respecto a los cambios que este tipo de calzado puede producir en la biomecánica de la marcha. Así pues, el objetivo de esta investigación fue analizar los efectos agudos del calzado inestable sobre los impactos de aceleración, así como también sobre la variación de temperatura superficial plantar. Seis deportistas (estudiantes físicamente activos, edad 28±8 años, altura 1.73±0.05 m, masa corporal 68.7±6.7 kg, talla de pie 41±1.6 cm) participaron voluntariamente en el estudio. Las características de la pisada se obtuvieron mediante el test Foot Posture Index. La prueba de marcha se llevó a cabo sobre tapiz rodante (10 minutos a 1.44 m/s) bajo dos condiciones de calzado: zapatillas estables y zapatillas inestables. Se analizaron los impactos de aceleración (en tibia y cabeza), y la temperatura superficial plantar (en antepié, mediopié y retropié) en diferentes momentos de la prueba. Los resultados no mostraron diferencias significativas entre ambos tipos de zapatillas en las variables de acelerometría analizadas en ninguno de los momentos de registro. Sin embargo, sí se encontraron diferencias significativas entre ambos calzados (estable=1.40ºC, inestable=3.10ºC, p=0.004) en la variación de temperatura plantar del mediopié en ΔTPost5 (diferencia entre antes del inicio de la prueba y 5 minutos después de finalizarla). En conclusión, las zapatillas inestables parecen no producir ningún beneficio adicional al calzado tradicional para el deportista durante la marcha. Palabras clave: zapatillas, marcha, biomecánica, acelerometría, termografía. Abstract. Nowadays, new models of sports footwear are available on the market, such as unstable shoes. However, there is still a lack of evidence regarding the changes that this type of footwear can produce on gait biomechanics. Therefore, the aim of this research was to analyze the acute effects of unstable shoes on acceleration impacts, as well as on plantar surface temperature variation. Six athletes (physically active college students, age 28±8 years, height 1.73±0.05 m, body mass 68.7±6.7 kg, shoe size 41±1.6 cm) voluntarily participated in the study. Gait characteristics were obtained by means of the Foot Posture Index test. The walking test was performed on a treadmill (10 minutes at 1.44 m/s) under two footwear conditions: stable shoes and unstable shoes. Acceleration impacts (tibia and head), and plantar surface temperature (forefoot, midfoot and rearfoot) were analysed at different moments during the test. The results showed no significant differences between the two types of shoes in the accelerometry variables analyzed at any of the recording times. However, significant differences were found between both shoes (stable=1.40ºC, unstable=3.10ºC, p=0.004) in the variation of midfoot plantar temperature at ΔTPost5 (difference between before the start of the test and 5 minutes after the end of the test). In conclusion, unstable shoes do not seem to produce any additional benefit to traditional shoes for the athlete during walking. Keywords: sport shoes, gait, biomechanics, accelerometry, thermography.

Hypomorphic Glucose 6-P dehydrogenase (G6PD) alleles, which cause G6PD deficiency, affect around one in twenty people worldwide. The high incidence of G6PD deficiency may reflect an evolutionary adaptation to the widespread prevalence of malaria, as G6PD-deficient red blood cells (RBCs) are hostile to the malaria parasites that infect humans. Although medical interest in this enzyme deficiency has been mainly focused on RBCs, more recent evidence suggests that there are broader implications for G6PD deficiency in health, including in skeletal muscle diseases. G6PD catalyzes the rate-limiting step in the pentose phosphate pathway (PPP), which provides the precursors of nucleotide synthesis for DNA replication as well as reduced nicotinamide adenine dinucleotide phosphate (NADPH). NADPH is involved in the detoxification of cellular reactive oxygen species (ROS) and de novo lipid synthesis. An association between increased PPP activity and the stimulation of cell growth has been reported in different tissues including the skeletal muscle, liver, and kidney. PPP activity is increased in skeletal muscle during embryogenesis, denervation, ischemia, mechanical overload, the injection of myonecrotic agents, and physical exercise. In fact, the highest relative increase in the activity of skeletal muscle enzymes after one bout of exhaustive exercise is that of G6PD, suggesting that the activation of the PPP occurs in skeletal muscle to provide substrates for muscle repair. The age-associated loss in muscle mass and strength leads to a decrease in G6PD activity and protein content in skeletal muscle. G6PD overexpression in Drosophila Melanogaster and mice protects against metabolic stress, oxidative damage, and age-associated functional decline, and results in an extended median lifespan. This review discusses whether the well-known positive effects of exercise training in skeletal muscle are mediated through an increase in G6PD.

Oxidative stress refers to an imbalance between oxidant and antioxidant molecules, which is usually associated with oxidative damage to biomolecules and mitochondrial malfunction. Redox state-related parameters include (1) the direct measurement of ROS, (2) the assessment of the antioxidant defense status, and (3) the analysis of the resulting oxidative damage to molecules. Directly measuring ROS appears to be the preferred method among scientists, but most ROS are extremely unstable and difficult to measure. The processes of determining both the oxidative damage to biomolecules and the antioxidant system status, although both are indirect approaches, provide a reliable method to measure oxidative stress on a given sample. Recently, the Seahorse XF and the Oroboros O2k systems have provided new insights into the redox state from a more dynamic point of view. These techniques assess mitochondrial oxidative phosphorylation function and bioenergetics on isolated mitochondria, cultured cells, or specific tissues such as permeabilized fibers. This review describes a range of methodologies to measure redox state-related parameters, their strengths, and their limitations. In conclusion, all these techniques are valid and none of them can be replaced by another. Indeed, they have the potential to complement each other for a complete evaluation of the redox state of a given sample.