Peroxiredoxin 6 suppresses ferroptosis in lung endothelial cells.

Peroxiredoxin 6 (Prdx6) repairs peroxidized membranes by reducing oxidized phospholipids, and by replacing oxidized sn-2 fatty acyl groups through hydrolysis/reacylation by its phospholipase A2 (aiPLA2) and lysophosphatidylcholine acyltransferase activities. Prdx6 is highly expressed in the lung, and intact lungs and cells null for Prdx6 or with single-point mutations that inactivate either Prdx6-peroxidase or aiPLA2 activity alone exhibit decreased viability, increased lipid peroxidation, and incomplete repair when exposed to paraquat, hyperoxia, or organic peroxides. Ferroptosis is form of cell death driven by the accumulation of phospholipid hydroperoxides. We studied the role of Prdx6 as a ferroptosis suppressor in the lung. We first compared the expression Prdx6 and glutathione peroxidase 4 (GPx4) and visualized Prdx6 and GPx4 within the lung. Lung Prdx6 mRNA levels were five times higher than GPx4 levels. Both Prdx6 and GPx4 localized to epithelial and endothelial cells. Prdx6 knockout or knockdown sensitized lung endothelial cells to erastin-induced ferroptosis. Cells with genetic inactivation of either aiPLA2 or Prdx6-peroxidase were more sensitive to ferroptosis than WT cells, but less sensitive than KO cells. We then conducted RNA-seq analyses in Prdx6-depleted cells to further explore how the loss of Prdx6 sensitizes lung endothelial cells to ferroptosis. Prdx6 KD upregulated transcriptional signatures associated with selenoamino acid metabolism and mitochondrial function. Accordingly, Prdx6 deficiency blunted mitochondrial function and increased GPx4 abundance whereas GPx4 KD had the opposite effect on Prdx6. Moreover, we detected Prdx6 and GPx4 interactions in intact cells, suggesting that both enzymes cooperate to suppress lipid peroxidation. Notably, Prdx6-depleted cells remained sensitive to erastin-induced ferroptosis despite the compensatory increase in GPx4. These results show that Prdx6 suppresses ferroptosis in lung endothelial cells and that both aiPLA2 and Prdx6-peroxidase contribute to this effect. These results also show that Prdx6 supports mitochondrial function and modulates several coordinated cytoprotective pathways in the pulmonary endothelium.

Duodenal tuberculosis.

Gastrointestinal tuberculosis (TB) is a rare disease and only involves the duodenum in 2-2,5% of all cases. A 60-year-old female with no reported medical history, presented with constitutional syndrome with a 10 kg weight loss in three months, epigastric pain, bloating and vomiting. She denied fever or respiratory symptoms. Laboratory examination revealed elevated C-reactive protein levels and low prealbumin. Abdominal computed tomography (CT) showed duodenal wall thickening, mainly in its third part, with infiltration of the root of the mesentery and numerous subcentimeter adenopathies at that level.

Spanish Paediatricians' Knowledge, Attitudes and Practices Regarding Oral Health of Children under 6 Years of Age: A Cross-Sectional Study.

BACKGROUND: Early Childhood Caries (ECC) is a prevalent chronic pathology, and it has a negative impact on the oral and general health of the child patient. AIM: To evaluate the knowledge, attitudes and practices of Spanish paediatricians regarding early childhood caries according to the professional's years of experience. MATERIAL AND METHODS: A cross-sectional questionnaire was conducted by Spanish paediatricians via WhatsApp and e-mails from January to April 2021. Data were analysed using Chi-squared test, Fisher's exact test and Cramer's V test. RESULTS: There were a total of 359 participants. Most respondents were women (81.3%) with up to 10 years of professional experience (31.2%) in primary health care and public health. In most cases, participants had an excellent knowledge of primary dentition (90.8%), but they ignored (56%) when the first visit to the dentist should occur. Regarding the aetiological factors of caries, oral hygiene and prevention, a lower rate of knowledge was observed. The majority of participants (80.8%) were not able to identify white spot lesions and enamel defects (76%). They considered that their knowledge in oral health was deficient, highlighting the need to increase their training. Less experienced paediatricians were found to have higher success rates. CONCLUSIONS: The level of knowledge and attitudes regarding early childhood caries of the evaluated paediatricians should be improved. Paediatricians had difficulties in identifying early caries lesions and enamel defects. Nevertheless, a higher level of knowledge and positive attitudes towards dental caries has been detected among paediatricians with fewer years of professional experience.

Developmental Dental Defects in Permanent Teeth Resulting from Trauma in Primary Dentition: A Systematic Review.

The objective was to determine whether trauma in primary dentition causes alterations in the development of permanent dentition. Searches were made in May 2020 using PubMed, MEDLINE, MEDES, Scopus, Lilacs, and Embase. Papers in English, German, and Spanish, without restrictions in the year of publication, were included. The quality of the studies was analyzed using the NOS Scale. The search retrieved 537 references, and seven studies were included for a qualitative analysis. The results showed that trauma to a deciduous tooth can damage the bud of the permanent tooth. Enamel discoloration and/or hypoplasia were the most common sequelae in the permanent teeth after trauma to the primary predecessor. The type and severity of sequelae in the permanent tooth are associated with the development phase of the bud. Children with trauma of their primary teeth should receive checkups until the eruption of the permanent teeth for the early diagnosis and treatment of possible sequelae. Intrusion of the primary tooth was the trauma that caused the most damage and enamel alterations the most frequent sequelae.

Effect of Colchicine vs Usual Care Alone on Intubation and 28-Day Mortality in Patients Hospitalized With COVID-19: A Randomized Clinical Trial.

Importance: Hospitalized patients with COVID-19 pneumonia have high rates of morbidity and mortality. Objective: To assess the efficacy of colchicine in hospitalized patients with COVID-19 pneumonia. Design, Setting, and Participants: The Estudios Clínicos Latino América (ECLA) Population Health Research Institute (PHRI) COLCOVID trial was a multicenter, open-label, randomized clinical trial performed from April 17, 2020, to March 28, 2021, in adults with confirmed or suspected SARS-CoV-2 infection followed for up to 28 days. Participants received colchicine vs usual care if they were hospitalized with COVID-19 symptoms and had severe acute respiratory syndrome or oxygen desaturation. The main exclusion criteria were clear indications or contraindications for colchicine, chronic kidney disease, and negative results on a reverse transcription-polymerase chain reaction test for SARS-CoV-2 before randomization. Data were analyzed from June 20 to July 25, 2021. Interventions: Patients were assigned in a 1:1 ratio to usual care or usual care plus colchicine. Colchicine was administered orally in a loading dose of 1.5 mg immediately after randomization, followed by 0.5 mg orally within 2 hours of the initial dose and 0.5 mg orally twice a day for 14 days or discharge, whichever occurred first. Main Outcomes and Measures: The first coprimary outcome was the composite of a new requirement for mechanical ventilation or death evaluated at 28 days. The second coprimary outcome was death at 28 days. Results: A total of 1279 hospitalized patients (mean [SD] age, 61.8 [14.6] years; 449 [35.1%] women and 830 [64.9%] men) were randomized, including 639 patients in the usual care group and 640 patients in the colchicine group. Corticosteroids were used in 1171 patients (91.5%). The coprimary outcome of mechanical ventilation or 28-day death occurred in 160 patients (25.0%) in the colchicine group and 184 patients (28.8%) in the usual care group (hazard ratio [HR], 0.83; 95% CI, 0.67-1.02; P = .08). The second coprimary outcome, 28-day death, occurred in 131 patients (20.5%) in the colchicine group and 142 patients (22.2%) in the usual care group (HR, 0.88; 95% CI, 0.70-1.12). Diarrhea was the most frequent adverse effect of colchicine, reported in 68 patients (11.3%). Conclusions and Relevance: This randomized clinical trial found that compared with usual care, colchicine did not significantly reduce mechanical ventilation or 28-day mortality in patients hospitalized with COVID-19 pneumonia. Trial Registration: ClinicalTrials.gov Identifier: NCT04328480.

Effects of Fluoride and Calcium Phosphate-Based Varnishes in Children at High Risk of Tooth Decay: A Randomized Clinical Trial.

BACKGROUND: The aim of this study was to investigate the effect of the application of two varnishes-MI Varnish (5% sodium fluoride with CPP-ACP) and Clinpro White Varnish (5% sodium fluoride with fTCP)-applied every three months in children with high caries risk for 12 months on plaque indexes, salivary pH, salivary lactic acid and chemical elements concentrations. METHODS: We included 58 children aged 4-12 years, assigned to control (placebo), Clinpro and MI groups. Baseline and three-month saliva samples were taken. We assessed changes in pH, lactic acid concentrations and chemical elements in saliva. RESULTS: At 12 months, all groups showed a nonsignificant increase in pH levels and a reduction in lactic acid, which was greatest in the placebo group. There was a significant reduction in 24Mg (p = <0.001), 31P (p = 0.033) and 66Zn (p = 0.005) levels in the placebo group (p ≤ 0.05), but not in the other elements studied: 23Na, 27Al, 39K, 44Ca, 52Cr, 55Mn, 57Fe, 59Co, 63Cu, 75As, 111Cd, 137Ba, 208Pb and 19F. CONCLUSIONS: Neither pH, lactic acid concentrations or most salivary chemical elements were useful in defining patients at high risk of caries or in monitoring the effect of MI Varnish and Clinpro White Varnish after three-month application for 12 months. However, the appearance of new cavities was stopped, and the hygiene index improved, probably due to hygienic and dietary measures and the use of fluoridated toothpaste. TRIAL REGISTRATION: ISRCTN registry, ISRCTN13681286.

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.

Cost and healthcare utilization analysis of culturally sensitive, shared medical appointment model for Latino children with type 1 diabetes.

OBJECTIVE: This study evaluated costs and healthcare utilization associated with a culturally-sensitive, medical and education program for pediatric Latino patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: Program participants included Latino children ages 1-20 years old diagnosed with type 1 diabetes (n = 57). Control subjects with type 1 diabetes were matched by age, sex, and zip code to intervention participants from the Colorado All Payer Claims Database. Data included emergency department (ED) visits, hospitalizations, demographic information, and health insurance claims data 180 days prior to program start/index date through 1 year after program start/index date. We tracked program staff time and estimated costs for healthcare utilization using data from the scientific literature. Generalized Estimating Equation (GEE) models with logit link were used to estimate group differences in probabilities of ED visits and hospitalizations over 6-month periods pre/post-study, accounting for correlation of within-subject data across time points. Sensitivity analyses modeled longer-term cost differences under different assumptions. RESULTS: The intervention group had fewer hospitalizations, 2% versus 12% of controls (p = 0.047,OR = 0.13;95%CI: 0.02-0.97) for 6 months following start date. The intervention group had fewer ED visits, 19% versus 32% in controls (n.s.; p = 0.079,OR = 0.52;95%CI:0.25-1.08) and significantly fewer hospitalizations, 4% versus 15% of controls (p = 0.039,OR = 0.21;95%CI: 0.05-0.93) 6-12 months post-start date. One-year per-patient program costs of $633 and healthcare cost savings of $2710 yielded total per-patient savings of $2077, or a 5-year cost savings of $14,106. CONCLUSION: This unique type 1 diabetes management program altered health service utilization of program participants, reducing major healthcare cost drivers, ED visits, and hospitalizations.

Fasting ameliorates oxidative stress: A review of physiological strategies across life history events in wild vertebrates.

Fasting is a component of many species' life history due to environmental factors or behavioral patterns that limit access to food. Despite metabolic and physiological challenges associated with these life history stages, fasting-adapted wild vertebrates exhibit few if any signs of oxidative stress, suggesting that fasting promotes redox homeostasis. Here we review mammalian, avian, reptilian, amphibian, and piscine examples of animals undergoing fasting during prolonged metabolic suppression (e.g. hibernation and estivation) or energetically demanding processes (e.g. migration and breeding) to better understand the mechanisms underlying fasting tolerance in wild vertebrates. These studies largely show beneficial effects of fasting on redox balance via limited oxidative damage. Though some species exhibit signs of oxidative stress due to energetically or metabolically extreme processes, fasting wild vertebrates largely buffer themselves from the negative consequences of oxidative damage through specific strategies such as elevating antioxidants, selectively maintaining redox balance in critical tissues, or modifying behavioral patterns. We conclude with suggestions for future research to better elucidate the protective effects of fasting on oxidative stress as well as disentangle the impacts from other life history stages. Further research in these areas will facilitate our understanding of the mechanisms wild vertebrates use to mitigate the negative impacts associated with metabolically-extreme life history stages as well as potential translation into therapeutic interventions in non-fasting-adapted species including humans.

Perception, knowledge, and attitudes towards molar incisor hypomineralization among Spanish dentists: a cross-sectional study.

BACKGROUND: Molar incisor hypomineralization (MIH) is a growing health problem, and its treatment is a challenge. The purpose of the present study was to evaluate and compare the perceptions, knowledge, and clinical experiences of MIH in general dental practitioners (GDPs) and paediatric dentists (PDs) in Spain. METHODS: All dentists belonging to the College of Dentists of the Region of Murcia, in the South-East of Spain, were invited to participate in a cross-sectional survey. They were asked to complete a two-part questionnaire including sociodemographic profiles and knowledge, experience, and perceptions of MIH. Data were analysed using Pearson's chi-square test, Fisher's exact test and Cramer's V test. RESULTS: The overall response rate was 18.6% (214/1147). Most respondents were aged 31-40 years (44.86%), with more than 15 years of professional experience (39.72%). They worked mainly in the private sector (84.58%) and were licensed in dentistry (74.30%): 95.45% of PDs had detected an increase in the incidence of MIH in recent years (p <  0.001). Only 23.80% of GDPs claimed to have made a training course on MIH. With respect to the aetiology, chronic medical conditions (p = 0.029) and environmental pollutants (p = 0.008) were the only factors that showed significant between-group differences. Durability (p = 0.009) and remineralization potential (p = 0.018) were the factors where there was a between-group difference in the choice of the restoration material. In the case of post-eruptive fractures and opacities, the preferred material for both groups was resin-modified glass ionomer (RMGIC). However, in incisor lesions, composite was the material of choice for both groups, with significant differences (p = 0.032) in the use of glass ionomer. Most respondents expressed a need for continuing education on MIH. CONCLUSION: Spanish dentists perceived an increase in the incidence of MIH. The material of choice was RMGIC for non-aesthetic sectors and composite for incisors. Dentists believe it is difficult or very difficult to manage MIH, since the long-term success of restorations of MIH lesions is compromised because resin adhesion is not good. Both GDPs and PDs believe they need more training on the aetiology, diagnosis, and treatment of MIH.

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.

Early reductive stress and late onset overexpression of antioxidant enzymes in experimental myocardial infarction.

Reductive stress is defined as a pathophysiological situation in which the cell becomes more reduced than in the normal, resting state. It represents a disturbance in the redox state that is harmful to biological systems. Our aim was to study the occurrence of reductive stress in the early phases of experimental myocardial infarction and to determine the mechanisms leading to such stress using a swine model. During the ischemic period, we found a decrease in the oxidized to reduced glutathione ratio (GSSG/GSH) (0.7-0.3), in the lactate to pyruvate ratio (42.7-132.4), in protein glutathionylation (111.8-96.1), and in p38 phosphorylation (0.9-0.4). This was accompanied by a significant increase in the expression of Thioredoxin (TXN) (0.6-1.9) and peroxiredoxin (PRDX6) (0.6-1.6) in different left ventricle areas. After reperfusion, there was a massive increase in oxidative damage markers including lipid peroxidation (0.2-0.4), protein carbonylation (144.9-462.8), and glutathionylation (111.8-176.8). Concomitantly, we found an activation of nuclear factor erythroid 2-related factor 2 (Nrf2) (1.2-6.1) and of a set of antioxidant enzymes including TXN, PRDX6, glutathione peroxidase (GPX1), glutathione reductase (GSR), and glucose 6 phosphate dehydrogenase (G6PD). We describe an early reductive, followed by a late onset oxidative stress (1 week and 1 month after reperfusion) in a swine myocardial infarction model. The occurrence of an early reductive phase may explain the lack of effectiveness of antioxidant therapies when administered in the early phases after reperfusion of ischemic hearts.

Novel, culturally sensitive, shared medical appointment model for Hispanic pediatric type 1 diabetes patients.

BACKGROUND/OBJECTIVE: Latino patients with type 1 diabetes (T1D) face cultural and language barriers leading to poor outcomes. Shared medical appointments (SMAs) are recognized as effective models of care. Our aim is to develop a culturally sensitive, cost effective SMA program for Latino T1D. SUBJECTS: Spanish speaking Latinos 1 to 20 years with T1D (n = 88) and their families. METHODS: Routine care alternating with SMAs that included group education was provided. Teens, ages >11 received the SMA separate from parents. Younger children were seen together. Hemoglobin A1c (HbA1c), behavioral questionnaires, and use of diabetes technology were measured at baseline and every 3 to 6 months. RESULTS: 57.7% of children and 77.27% of teens completed the 2 years of the Program. There was a significant association between age and change in HbA1c from baseline to year 1 (P = .001) and baseline to year 2 (P = <.0001). For participants <12 years, there was a significant improvement in HbA1c from baseline to year 1 (P = .0146) and from year 1 to year 2 (P = .0069). Participants ≥12 years, had an increase in HbA1c from year 1 to year 2 (P = .0082). Technology use increased significantly from baseline to year 2 for participants <12 years of age (19%-60%, P = .0455) and for participants who were ≥12 years of age (10%-23%, P = .0027). Participants reported a 98% satisfaction rate. CONCLUSIONS: The culturally sensitive SMA proved to be an appreciated, feasible, and effective alternative to care for Latinos with T1D.

Reactivación de hepatitis B en paciente con hepatitis crónica C tratado con antivirales de acción directa / Hepatitis B reactivation in a patient with chronic hepatitis C treated with direct-acting antivirals

No disponible

Overexpression of CYB5R3 and NQO1, two NAD+ -producing enzymes, mimics aspects of caloric restriction.

Calorie restriction (CR) is one of the most robust means to improve health and survival in model organisms. CR imposes a metabolic program that leads to increased stress resistance and delayed onset of chronic diseases, including cancer. In rodents, CR induces the upregulation of two NADH-dehydrogenases, namely NAD(P)H:quinone oxidoreductase 1 (Nqo1) and cytochrome b5 reductase 3 (Cyb5r3), which provide electrons for energy metabolism. It has been proposed that this upregulation may be responsible for some of the beneficial effects of CR, and defects in their activity are linked to aging and several age-associated diseases. However, it is unclear whether changes in metabolic homeostasis solely through upregulation of these NADH-dehydrogenases have a positive impact on health and survival. We generated a mouse that overexpresses both metabolic enzymes leading to phenotypes that resemble aspects of CR including a modest increase in lifespan, greater physical performance, a decrease in chronic inflammation, and, importantly, protection against carcinogenesis, one of the main hallmarks of CR. Furthermore, these animals showed an enhancement of metabolic flexibility and a significant upregulation of the NAD+ /sirtuin pathway. The results highlight the importance of these NAD+ producers for the promotion of health and extended lifespan.

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.

Biology of frailty: Modulation of ageing genes and its importance to prevent age-associated loss of function.

Frailty is associated with loss of functional reserve as well as with the prediction of adverse events in the old population. The traditional criteria of frailty are based on five physical determinations described in the Cardiovascular Health Study. We propose that biological and genetic markers of frailty should be used to increase the predictive capacity of the established clinical indeces. In recent times, research for biological markers of frailty has gained impetus. Finding a biological markers with diagnostic and prognostic capacity would be a major milestone to identify frailty risk, and also pre-frailty status. In the first section of the manuscript, we review the available biomarkers that help to monitor and prevent the evolution and the efficacy of interventions to delay the onset of frailty and to prevent its progression to incapacity. We also discuss the contribution of genetics to frailty. There are scientific bases that support that genetics influences frailty, although environmental factors probably will have the highest contribution. We review the known SNPs of the genes associated with frailty and classify them, taking into account the pathway in which they are involved. We also highlight the importance of longevity genes and their possible relation with frailty, citing centenarians who reach a very old age as an example of successful ageing. Finally, the reversibility of frailty is discussed. It can potentially be treated with nutritional or pharmacological interventions. However, physical exercise seems to be the most effective strategy to treat and prevent frailty. The last section of the manuscript is devoted to explaining the recommendations on the appropriate design of an exercise protocol to maximize its beneficial effects in a population of frail individuals.