Impact of supplementation with vitamins B6 , B12 , and/or folic acid on the reduction of homocysteine levels in patients with mild cognitive impairment: A systematic review.

Hyperhomocysteinemia is an independent predictor of the risk for cognitive decline and may be a result of low levels of vitamins B12 , B6 , and folate. Previous findings suggest that adequate intake of these vitamins may reduce homocysteine levels. This review aimed to assess the effects of treatment with vitamins B6, B12 , and/or folic acid in the homocysteine levels in patients with mild cognitive impairment (MCI). A systematic literature review was conducted in EMBASE, MEDLINE®, PsycINFO, and Cochrane Central Register of Controlled Trials. The research question was formulated using the Population, Intervention, Comparison, and Outcome (PICO) framework: in patients with MCI (P); what is the efficacy of vitamins B6 , B12 , and/or folic acid intake (I); compared with baseline values, and/or compared with controls (C); in reducing homocysteine levels from baseline (O). A total of eight primary studies with a total of 1,140 participants were included in the review. Four were randomized controlled trials, one was a quasi-controlled trial, and three were observational studies. All studies included folic acid in their intervention, seven vitamin B12 , and four vitamin B6 . Mean (SD) length of the intervention period was 18.8 (19.3) months, ranging from 1 to 60 months. All studies showed a statistically significant decrease in homocysteine levels in groups treated with vitamins B6, B12 , and/or folic acid compared to controls, with a mean decline of homocysteine concentration of 31.9% in the intervention arms whereas it increased by 0.7% in the control arm. This review identified evidence of a reduction of plasma homocysteine levels in MCI patients taking vitamins B6, B12 , and/or folic acid supplements, with statistically significant declines being observed after 1 month of supplementation. Findings support that supplementation with these vitamins might be an option to reduce homocysteine levels in people with MCI and elevated plasma homocysteine.

Transcriptomic profile of epileptic children treated with ketogenic therapies.

Background: Ketogenic dietary therapies (KDT) are used as a treatment in childhood epilepsy. However, their mechanism has not yet been established. The main objective of this study was to determine the changes in the transcriptomic profile induced by KDT in children with epilepsy in order to shed light on its possible mechanisms. Methods: Eight children with refractory epilepsy were enrolled in the study. Peripheral blood mononuclear cells were obtained before and after the children were treated with KDT for a minimum of 6 months. RNA was extracted and mRNA and miRNA profiling were performed and analyzed. Results: Our intervention with KDT significantly reduced the seizure number in seven of the eight paediatric patients treated and caused important changes in their gene expression profile. Our study reveals modifications in the transcription of 4630 genes and 230 miRNAs. We found that the genes involved in the protection against epileptic crises were among those mainly changed. These genes collectively encode for ion channels, neurotransmitter receptors, and synapse structural proteins. Conclusions: Together our results explain the possible mechanisms of KDT and reinforce its clinical importance in the treatment of epilepsy.

Glucose 6 phosphate dehydrogenase overexpression rescues the loss of cognition in the double transgenic APP/PS1 mouse model of Alzheimer's disease.

Mice models of Alzheimer's disease (APP/PS1) typically experience cognitive decline with age. G6PD overexpressing mice (G6PD-Tg) exhibit better protection from age-associated functional decline including improvements in metabolic and muscle functions as well as reduced frailty compared to their wild-type counterparts. Importantly G6PD-Tg mice show diminished accumulation of DNA oxidation in the brain at different ages in both males and females. To further explore the potential benefits of modulating the G6PD activity in neurodegenerative diseases, triple transgenic mice (3xTg G6PD) were generated, overexpressing APP, PSEN1, and G6PD genes. The cognitive decline characteristic of APP/PS1 mice was prevented in 3xTg G6PD mice, despite similar amyloid-ß (Aß) levels in the hippocampus. This challenges the dominant hypothesis in Alzheimer's disease (AD) etiology and the majority of therapeutic efforts in the field, based on the notion that Aß is pivotal in cognitive preservation. Notably, the antioxidant properties of G6PD led to a decrease in oxidative stress parameters, such as improved GSH/GSSG and GSH/CysSSG ratios, without major changes in oxidative damage markers. Additionally, metabolic changes in 3xTg G6PD mice increased brain energy status, countering the hypometabolism observed in Alzheimer's models. Remarkably, a higher respiratory exchange ratio suggested increased carbohydrate utilization. The relative failures of Aß-targeted clinical trials have raised significant skepticism on the amyloid cascade hypothesis and whether the development of Alzheimer's drugs has followed the correct path. Our findings highlight the significance of targeting glucose-metabolizing enzymes rather than solely focusing on Aß in Alzheimer's research, advocating for a deeper exploration of glucose metabolism's role in cognitive preservation.

Glucose 6-P Dehydrogenase-An Antioxidant Enzyme with Regulatory Functions in Skeletal Muscle during Exercise.

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.

Real-Life Outcomes of a Multicomponent Exercise Intervention in Community-Dwelling Frail Older Adults and Its Association with Nutritional-Related Factors.

Most of the studies on physical exercise in older adults have been conducted through randomized clinical trials performed under tight experimental conditions. Data regarding Real-Life physical exercise intervention programs in older adults with different conditions and in different settings, are lacking. This is an interventional, prospective and pragmatic Real-Life study in which fifty sedentary and frail individuals were enrolled. We aimed at determining if a Real-Life exercise intervention outweighs previously reported improvements in a Clinical Trial (NCT02331459). We found higher improvements in the Real-Life exercise intervention vs. the Clinical Trial in functional parameters, such as Fried's frailty criteria, Tinetti, Barthel and Lawton & Brody scales. Similar results were found in the dietary habits, emotional and social networking outcomes determined through the Short-MNA, Yesavage, EuroQol and Duke scales. The Real-Life intervention led to a significant reduction in the number of falls, visits to the primary care centers and emergency visits when compared to the results of our previously published Clinical Trial. The implementation of a Real-Life exercise intervention is feasible and should be a major priority to improve health-span in the older population.

Glucosamine Supplementation Improves Physical Performance in Trained Mice.

INTRODUCTION: d-Glucosamine (GlcN) is one of the most widely consumed dietary supplements and complementary medicines in the world and has been traditionally used to attenuate osteoarthritis in humans. GlcN extends life span in different animal models. In humans, its supplementation has been strongly associated with decreased total mortality and improved vascular endothelial function. GlcN acts as a suppressor of inflammation, and by inhibiting glycolysis, it can activate the metabolism of stored fat and mitochondrial respiration. METHODS: The conventional human GlcN dose is 1500 mg·d-1, but extensive evidence indicates that much higher doses are well tolerated. GlcN is one of the supplements that has experienced a greater use in the last years in elite athletes mainly because of its potential chondroprotective effects that may promote cartilage health. However, the possibility of it being an ergogenic aid has not been explored. We aimed to study the potential beneficial effects of GlcN on mitochondrial content, physical performance, and oxidative stress in mice that were aerobically trained and supplemented with three different doses of glucosamine (250, 500, and 1000 mg·kg-1) for 6 wk. We measured exercise performance (grip strength, motor coordination, and running capacity) before and after the training period. Proteins involved in mitochondrial biogenesis (AMPK, PGC-1, NRF-1, SIRT-1, cytochrome c, citrate synthase), markers of oxidative stress (GSSG/GSH) or damage (malondialdehyde, carbonylated proteins), antioxidant enzymes (NRF-2, SOD1, SOD2, catalase, and PRDX6), and MAPKs (p38 and ERK1/2 were also determined in skeletal muscle. RESULTS AND CONCLUSIONS: Our results show that GlcN supplementation in aerobically trained mice, at doses equivalent to those conventionally used in humans, increases the protein levels of mitochondrial biogenesis markers, improves motor coordination, and may have a synergistic effect with exercise training on running distance.

Living at high altitude in combination with sea-level sprint training increases hematological parameters but does not improve performance in rats.

The regimen of aerobic training at sea level with recovery at high altitude has been used by athletes to improve performance. However, little is known about the effects of hypoxia when combined with sprint interval training on performance. The aim of the present study was to determine the effect of a "living high-sprint training low" strategy on hemoglobin, hematocrit and erythropoietin levels in rats. We also wanted to test whether the addition of a hypoxic stress to the program of daily treadmill running at high speeds induces expressional adaptations in skeletal muscle and affects performance. The protein content of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), cytochrome C, pyruvate dehydrogenase kinase (PDK1), heat shock protein 70 (HSP70), manganese superoxide dismutase (MnSOD) and citrate synthase activity were determined in different muscle fiber types in our animals (red and white gastrocnemius muscle). We also determined the maximal aerobic velocity (MAV) before and after the training period. A total of 24 male Wistar rats (3 month old) were randomly divided into four experimental groups: the normoxic control group (n = 6), the normoxic trained group (n = 6), the hypoxic control group (12 h pO(2) 12%/12 h pO(2) 21%) (n = 6) and the hypoxic trained group (12 h pO(2) 12%/12 h pO(2) 21%). Living in normobaric hypoxia condition for 21 days significantly increased hemoglobin, hematocrit and erythropoietin levels in both the rest and the trained groups. The trained animals (normoxia and hypoxia) significantly increased their maximal aerobic velocity. No changes were found in the skeletal muscle in PGC-1α, cytochrome C, PDK1, HSP70, MnSOD protein content and in the citrate synthase activity in any experimental group. Regardless of whether it is combined with sprint interval training or not, after 21 days of living at high altitude we found a significant increase in the hematological values determined in our study. However, contrary to our starting hypothesis, the combination of normobaric hypoxia and sprint training did not improve MAV in our animals.

Anti-Inflammatory Properties of Diet: Role in Healthy Aging.

Inflammation is a physiological process involved in the defenses of the body and the repair of tissues. It is acutely activated by infections, trauma, toxins, or allergic reactions. However, if it becomes chronic, inflammation can end up stimulating the development of diseases such as cardiovascular disease, autoimmune disease, neurological disease, or cancer. Additionally, during aging, inflammation becomes increasingly more chronic. Furthermore, we found that certain foods, such as saturated fats, have pro-inflammatory activity. Taking this into account, in this review we have discussed different diets with possible anti-inflammatory activity, the commonly ingested components of each diet and their active compounds. In addition, we have proposed some dietary guidelines, as well as a list of compounds present in foods with anti-inflammatory activity, outlining how to combine them to achieve optimal anti-inflammatory effects. Therefore, we can conclude that the compounds in our diet with anti-inflammatory activity could help alleviate the inflammatory processes derived from diseases and unhealthy diets, and thereby promote healthy aging.

Pharmacological Properties of Polyphenols: Bioavailability, Mechanisms of Action, and Biological Effects in In Vitro Studies, Animal Models, and Humans.

Drugs are bioactive compounds originally discovered from chemical structures present in both the plant and animal kingdoms. These have the ability to interact with molecules found in our body, blocking them, activating them, or increasing or decreasing their levels. Their actions have allowed us to cure diseases and improve our state of health, which has led us to increase the longevity of our species. Among the molecules with pharmacological activity produced by plants are the polyphenols. These, due to their molecular structure, as drugs, also have the ability to interact with molecules in our body, presenting various pharmacological properties. In addition, these compounds are found in multiple foods in our diet. In this review, we focused on discussing the bioavailability of these compounds when we ingested them through diet and the specific mechanisms of action of polyphenols, focusing on studies carried out in vitro, in animals and in humans over the last five years. Knowing which foods have these pharmacological activities could allow us to prevent and aid as concomitant treatment against various pathologies.

Moderate Red Wine Consumption Increases the Expression of Longevity-Associated Genes in Controlled Human Populations and Extends Lifespan in Drosophila melanogaster.

The beneficial effects of moderate red wine consumption on cardiovascular health are well known. The composition of red wine includes several compounds, such as the phytoestrogen resveratrol, that exert these beneficial effects, although not all the mechanisms by which they act are known. Our aim was to study the effect of red wine consumption on longevity-related genes in controlled human populations, such as cloistered nuns. We found that the expression of catalase, manganese-superoxide dismutase, Sirt1, and p53 was increased in peripheral blood mononuclear cells after 14 days of moderate red wine consumption. This increase was accompanied by an enhanced metabolic wellness: fatty acids, cholesterol, branched chain amino acids (isoleucine and leucine), ketone bodies (acetoacetate), bacterial co-metabolites (trimethylamine), and cellular antioxidants (taurine) contributed to a change in metabolic profile after moderate red wine consumption by the nuns. No serious unwanted side effects were observed. Finally, we tested the effect of moderate red wine consumption on longevity in a controlled animal population, such as D. melanogaster, and found that it increased average life span by 7%. In conclusion, moderate red wine consumption increases the expression of key longevity-related genes and improves metabolic health in humans and increases longevity in flies.

Redox-related biomarkers in physical exercise.

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.

Glucose 6-P dehydrogenase delays the onset of frailty by protecting against muscle damage.

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 < 0.001). Skeletal muscle transcriptomic analysis showed an up-regulation of respiratory chain and oxidative phosphorylation (P = 0.009) as well as glutathione metabolism (P = 0.035) pathways in the G6PD-Tg mice. Accordingly, the Tg animals exhibited an increase in reduced glutathione (34.5%, P < 0.01) and a decrease on its oxidized form (-69%, P < 0.05) and in lipid peroxidation (4-HNE: -20.5%, P < 0.05). The G6PD-Tg mice also showed reduced apoptosis (BAX/Bcl2: -25.5%, P < 0.05; and Bcl-xL: -20.5%, P < 0.05), lower levels of the intramuscular adipocyte marker FABP4 (-54.7%, P < 0.05), and increased markers of mitochondrial content (COX IV: 89.7%, P < 0.05; Grp75: 37.8%, P < 0.05) and mitochondrial OXPHOS complexes (CII: 81.25%, P < 0.01; CIII: 52.5%, P < 0.01; and CV: 37.2%, P < 0.05). Energy expenditure (-4.29%, P < 0.001) and the respiratory exchange ratio were lower (-13.4%, P < 0.0001) while the locomotor activity was higher (43.4%, P < 0.0001) in the 20-month-old Tg, indicating a major energetic advantage in these mice. Short-term exercise training in young C57BL76J mice induced a robust activation of G6PD in skeletal muscle (203.4%, P < 0.05), similar to that achieved in the G6PD-Tg mice (142.3%, P < 0.01). CONCLUSIONS: Glucose 6-P dehydrogenase deficiency can be an underestimated risk factor for several human pathologies and even frailty. By overexpressing G6PD, we provide the first molecular model of robustness. Because G6PD is regulated by pharmacological and physiological interventions like exercise, our results provide molecular bases for interventions that by increasing G6PD will delay the onset of frailty.

Modulating Oxidant Levels to Promote Healthy Aging.

Significance: Free radicals although originally thought of as damaging molecules, inevitable side effects of the utilization of oxygen by cells, are now considered as signals that by modifying, among others, the thiol-disulfide balance regulate many cell processes from metabolism to cell cycle. Recent Advances: This review discusses the importance of the modulation of the oxidant levels through physiological strategies such as physical exercise or genetic manipulations such as the overexpression of antioxidant enzymes, in the promotion of healthy aging. Critical Issues: We have divided the review into five different sections. In the first two sections of the article "Oxidants are signals" and "Exercise training is an antioxidant," we discuss the main sources of free radicals during muscle contraction and their role, as hormetic substances, in the regulation of two main muscle adaptations to exercise in skeletal muscle; that is, mitochondrial biogenesis and the endogenous antioxidant defense. In the third section of the review, we deal with "the energy collapse in aging." The increased rate of reactive oxygen species (ROS) production and the low rate of mitochondria biosynthesis in the old cells are examined. Finally, in the fourth and fifth sections entitled "Overexpression of antioxidants enzymes in healthy aging" and "Exercise, longevity, and frailty," we consider the importance of the potentiation of the cellular defenses in health span and in life span. Future Directions: A correct manipulation of the ROS generation, directing these species to their physiological signaling role and preventing their deleterious effects, would allow the promotion of healthy aging. Antioxid. Redox Signal. 33, 570-579.

Physical exercise in the prevention and treatment of Alzheimer's disease.

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 ß 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.

The role of adenine excimers in the photophysics of oligonucleotides.

Energies and structures of different arrangements of the stacked adenine homodimer have been computed at the ab initio CASPT2 level of theory in isolation and in an aqueous environment. Adenine dimers are shown to form excimer singlet states with different degrees of stacking and interaction. A model for a 2-fold decay dynamics of adenine oligomers can be supported in which, after initial excitation in the middle UV range, unstacked or slightly stacked pairs of nucleobases will relax by an ultrafast internal conversion to the ground state, localizing the excitation in the monomer and through the corresponding conical intersection with the ground state. On the other hand, long-lifetime intrastrand stacked excimer singlet states will be formed in different conformations, including neutral and charge transfer dimers, which originate the red-shifted emission observed in the oligonucleotide chains and that will evolve toward the same monomer decay channel after surmounting an energy barrier. By computing the transient absorption spectra for the different structures considered and their relative stability in vacuo and in water, it is concluded that in the adenine homodimers the maximum-overlap face-to-face orientations are the most stable excimer conformations observed in experiment.

Electrostatic control of the photoisomerization efficiency and optical properties in visual pigments: on the role of counterion quenching.

Hybrid QM(CASPT2//CASSCF/6-31G*)/MM(Amber) computations have been used to map the photoisomerization path of the retinal chromophore in Rhodopsin and explore the reasons behind the photoactivity efficiency and spectral control in the visual pigments. It is shown that while the electrostatic environment plays a central role in properly tuning the optical properties of the chromophore, it is also critical in biasing the ultrafast photochemical event: it controls the slope of the photoisomerization channel as well as the accessibility of the S(1)/S(0) crossing space triggering the ultrafast decay. The roles of the E113 counterion, the E181 residue, and the other amino acids of the protein pocket are explicitly analyzed: it appears that counterion quenching by the protein environment plays a key role in setting up the chromophore's optical properties and its photochemical efficiency. A unified scenario is presented that discloses the relationship between spectroscopic and mechanistic properties in rhodopsins and allows us to draw a solid mechanism for spectral tuning in color vision pigments: a tunable counterion shielding appears as the elective mechanism for L<-->M spectral modulation, while a retinal conformational control must dictate S absorption. Finally, it is suggested that this model may contribute to shed new light into mutations-related vision deficiencies that opens innovative perspectives for experimental biomolecular investigations in this field.

Molecular basis of DNA photodimerization: intrinsic production of cyclobutane cytosine dimers.

Based on CASPT2 results, the present contribution establishes for the first time that cytosine photodimer formation (C< >C) is mediated along the triplet and singlet manifold by a singlet-triplet crossing, (T1/S0)X, and by a conical intersection, (S1/S0)CI, respectively. The former can be accessed in a barrierless way from a great variety of photochemical avenues and exhibits a covalent single bond between the ethene C6-C6' carbon atoms of each monomer. The efficiency of the stepwise triplet mechanism, however, would be modulated by the effectiveness of the intersystem crossing mechanism. The results provide the grounds for the understanding of the potential photogenotoxicity of endogenous and exogenous compounds via triplet-triplet sensitization, with a lower bound for cytosine oligonucleotides predicted to be 2.70 eV, and give support to the traditional view of the primary role of triplet excited states in the photochemistry of DNA, a well-known source of photoproducts in solution under triplet photosensitization conditions. The function played by singlet excimers (excited dimers) to explain both the red-shifted fluorescence and photoreaction is highlighted. A rationale on the pronounced wavelength dependence of the observed fluorescence is offered. Geometrical arrangements at the time of light irradiation close to, but energetically above, (S1/S0)CI are suggested as reactive orientations that become prone to produce C< >C directly, with no energy barrier. Because of the outstanding intrinsic ability of cytosine to form stable relaxed excimers, the system located near the bound relaxed excimer has to accumulate enough vibrational energy to surmount a small barrier of 0.2 eV to reach (S1/S0)CI, making the overall process to proceed at a slower relative rate as compared to other compounds such as thymine, which is not susceptible of forming so stable excimers.

Allopurinol partially prevents disuse muscle atrophy in mice and humans.

Disuse muscle wasting will likely affect everyone in his or her lifetime in response to pathologies such as joint immobilization, inactivity or bed rest. There are no good therapies to treat it. We previously found that allopurinol, a drug widely used to treat gout, protects muscle damage after exhaustive exercise and results in functional gains in old individuals. Thus, we decided to test its effect in the prevention of soleus muscle atrophy after two weeks of hindlimb unloading in mice, and lower leg immobilization following ankle sprain in humans (EudraCT: 2011-003541-17). Our results show that allopurinol partially protects against muscle atrophy in both mice and humans. The protective effect of allopurinol is similar to that of resistance exercise which is the best-known way to prevent muscle mass loss in disuse human models. We report that allopurinol protects against the loss of muscle mass by inhibiting the expression of ubiquitin ligases. Our results suggest that the ubiquitin-proteasome pathway is an appropriate therapeutic target to inhibit muscle wasting and emphasizes the role of allopurinol as a non-hormonal intervention to treat disuse muscle atrophy.

A New Frailty Score for Experimental Animals Based on the Clinical Phenotype: Inactivity as a Model of Frailty.

The development of animal models to study human frailty is important to test interventions to be translated to the clinical practice. The aim of this work was to develop a score for frailty in experimental animals based in the human frailty phenotype. We also tested the effect of physical inactivity in the development of frailty as determined by our score. Male C57Bl/6J mice, individually caged, were randomly assigned to one of two groups: sedentary (inactive) or spontaneous wheel-runners. We compared the sedentary versus the active lifestyle in terms of frailty by evaluating the clinical criteria used in humans: unintentional weight loss; poor endurance (running time); slowness (running speed); weakness (grip strength), and low activity level (motor coordination) at five different ages: 17, 20, 23, 26 and 28 months of age. Each criterion had a designated cut-off point to identify the mice with the lowest performance. Lifelong spontaneous exercise significantly retards frailty. On the contrary sedentary animals become frail as they age. Thus, physical inactivity is a model of frailty in experimental animals. Our frailty score provides a tool to evaluate interventions in mice prior to translating them to clinical practice.