The hMTH1 paradox: antioxidants recommended in cancer?

Summary Activated Ras GTPase signalling is a critical driver of oncogenic transformation and malignant disease. Cellular models of RAS-dependent cancers have been used to identify experimental small-molecules, such as SCH51344, but their molecular mechanism of action remains generally enigmatic. Here, using a chemical proteomic approach we identify the target of SCH51344 as the human mutT homologue MTH1, a nucleotide pool sanitising enzyme. Loss-of-function of MTH1 impaired growth of KRAS tumour cells whereas MTH1 overexpression mitigated sensitivity toward SCH51344. Searching for more drug-like inhibitors, we identified the kinase inhibitor crizotinib as a nanomolar suppressor of MTH1 acti…

p16INK4a, NAD+, and Sestrins: New Targets for Combating Aging-Related Chronic Illness?

Aging-related chronic illness is a price we have to pay to live longer. Prevalent among the oldest old, the condition limits their functional independence and also aggravates the course of several age-related chronic diseases. Thus, the search is on for efficient therapies that will mitigate age-related pathologies. In this article, we point out the potential clinical implications of recent provocative basic research in the field. New possible targets have been recently discovered, are clearly involved in age-related pathologies and might benefit the treatment of other age-related conditions, particularly metabolic diseases.

Topical application of the Wnt/β-catenin activator methyl vanillate increases hair count and hair mass index in women with androgenetic alopecia

Activation of the WNT/β-catenin pathway has emerged as a potential therapeutic target in androgenetic alopecia (AGA). Methyl vanillate (MV) - a safe plant-derived ingredient - has been recently shown to activate the WNT/β-catenin signaling. Objectives Two distinct substudies were conducted. First, we designed a 6-month, uncontrolled, open-label clinical study to investigate whether topically applied MV may increase hair count and hair mass index (HMI) in female AGA. Second, we conducted a molecular study on the effect of MV on WNT10B mRNA expression in scalp biopsies of women with AGA. A total of 20 Caucasian women (age range: 25-57 years) with AGA (Sinclair grade 1-2) were included. The re…

Trace elements levels in centenarian ‘dodgers’

Trace element bioavailability can play a role in several metabolic and physiological pathways known to be altered during the aging process. We aimed to explore the association of trace elements with increased lifespan by analyzing the circulating levels of seven trace elements (Cr, Cu, Fe, Mn, Mo, Se and Zn) in a cohort of healthy centenarians or ‘dodgers’ (≥100 years, free of major age-related diseases) in comparison with sex-matched younger elderly controls. Centenarians showed significant lower Cu (783.7 (76.7, 1608.9) vs 962.5 (676.3, 2064.4) μg/mL, P < 0.001), but higher Fe (1.3 (0.4, 4.7) vs 1.1 (0.5, 8.4) μg/mL, P = 0.003) and Se (85.7 (43.0, 256.7) vs 77.8 (24.3, 143.8) ng/mL, P = 0…

Protective effect of trehalose-loaded liposomes against UVB-induced photodamage in human keratinocytes

Trehalose, a naturally occurring non-reducing disaccharide, is known to act as a major protein stabilizer that can reduce ultraviolet B (UVB)-induced corneal damage when topically applied to the eye. However, due to the low skin permeability of trehalose, which makes the development of topical formulations difficult, its use as a skin photoprotective agent has been limited. Previous findings demonstrated that liposomes may significantly improve the intracellular delivery of trehalose. Therefore, the present study aimed to assess the protective effects of trehalose-loaded liposomes against UVB-induced photodamage using the immortalized human keratinocyte cell line, HaCaT. The effects were al…

Exome sequencing of three cases of familial exceptional longevity

Exceptional longevity (EL) is a rare phenotype that can cluster in families, and co-segregation of genetic variation in these families may point to candidate genes that could contribute to extended lifespan. In this study, for the first time, we have sequenced a total of seven exomes from exceptionally long-lived siblings (probands ≥ 103 years and at least one sibling ≥ 97 years) that come from three separate families. We have focused on rare functional variants (RFVs) which have ≤ 1% minor allele frequency according to databases and that are likely to alter gene product function. Based on this, we have identified one candidate longevity gene carrying RFVs in all three families, APOB. Inter…

Implications of obesity in exceptional longevity.

Except for the world’s poorest regions, it is estimated that global obesity [body mass index (BMI) >30 kg/m 2 ] prevalence will reach 18% (men) and >21% (women) by 2025 (1). Recent nationally representative surveys in the US for the 2013–2014 period indicate age-adjusted obesity prevalence of 35.0% and 40.4% among adult men and women, respectively (2) and of 17.0% for children and adolescents aged 2–19 years (3).

Benefits of skeletal-muscle exercise training in pulmonary arterial hypertension: The WHOLEi + 12 trial

Pulmonary arterial hypertension is often associated with skeletal-muscle weakness. The purpose of this randomized controlled trial was to determine the effects of an 8-week intervention combining muscle resistance, aerobic and inspiratory pressure-load exercises on upper/lower-body muscle power and other functional variables in patients with this disease. Participants were allocated to a control (standard care) or intervention (exercise) group (n = 20 each, 45 ± 12 and 46 ± 11 years, 60% women and 10% patients with chronic thromboembolic pulmonary hypertension per group). The intervention included five, three and six supervised (inhospital) sessions/week of aerobic, resistance and inspirato…

No evidence of adverse cardiac remodeling in former elite endurance athletes

Background: The impact of high exercise loads on a previously healthy heart remains controversial. We examined the consequences of decades of strenuous endurance exercise at the highest competition level on heart dimensions and volumes as well as on serum biomarkers of cardiac fibrosis/remodeling. Methods and results: We compared echocardiographic measurements and serum biomarkers of cardiac fibrosis/remodeling [troponin I, galectin-3, matrix metallopeptidase-2 and -9, N-terminal pro-brain natriuretic peptide, carboxy-terminal propeptide of type I procollagen, and soluble suppressor of tumorigenicity-2 (sST-2)/interleukin(IL)-1R4] in 53 male athletes [11 former professional ('elite') and 42…

The role of mitochondrial derived peptides (MDPs) in metabolism

The mitochondrial‐derived peptide MOTS ‐c: a player in exceptional longevity?

Mitochondrial-derived peptides (MDP) are encoded by functional short open reading frames in the mitochondrial DNA (mtDNA). These include humanin, and the recently discovered mitochondrial open reading frame of the 12S rRNA-c (MOTS-c). Although more research is needed, we suggest that the m.1382A>C polymorphism located in the MOTS-c encoding mtDNA, which is specific for the Northeast Asian population, may be among the putative biological mechanisms explaining the high longevity of Japanese people. 5.760 JCR (2015) Q1, 36/187 Cell biology, 3/49 Geriatrics & gerontology UEM

Methodological considerations to determine the effect of exercise on brain-derived neurotrophic factor levels.

Objectives: Physical exercise up-regulates brain-derived neurotrophic factor (BDNF) in the brain and blood. However, there is yet no consensus about the adequate blood processing conditions to standardize its assessment. We aimed to find a reliable blood sample processing method to determine changes in BDNF due to exercise. Design and methods: Twelve healthy university students performed an incremental cycling test to exhaustion. At baseline, immediately after exercise, and 30 and 60 min of recovery, venous blood was drawn and processed under different conditions, i.e. whole blood, serum coagulated for 10 min and 24 h, total plasma, and platelet-free plasma. BDNF concentration was measured …

Physical inactivity and low fitness deserve more attention to alter cancer risk and prognosis.

Abstract Sedentary lifestyle is associated with elevated cancer risk whereas regular physical activity (PA) and high cardiorespiratory fitness (CRF) have the opposite effect, with several biologic mechanisms mediating such associations. There is a need for lifestyle interventions aimed at increasing the PA levels and CRF of the general population and particularly cancer survivors. Furthermore, provocative data suggest a dose-dependent benefit of increasing levels of PA and/or CRF against cancer risk or mortality. Thus, current PA guidelines (≥150 min/wk of moderate-to-vigorous PA) may not be sufficiently rigorous for preventing cancer nor for extending cancer survivorship. Research targetin…

Strenuous exercise and the heart: are we not seeing the wood for the trees?

The health benefits of regular moderate-intensity physical activity (e.g. brisk walking, jogging) are well established and include, among others, a lower risk of all-cause mortality and cardiovascular disease (CVD). Yet whether such benefits, especially with regard to CVD, are also conferred by higher exercise levels is a matter of growing controversy in the medical literature. For instance, Guash and Mont recently expressed understandable concern about the link between regular strenuous endurance exercise. 4.036 JCR (2014) Q1, 29/123 Cardiac and cardiovascular systems UEM

Effects of progressive resistance exercise in akinetic-rigid Parkinson's disease patients: a randomized controlled trial.

Progressive resistance exercise (PRE) can have a positive effect in individuals with Parkinson’s disease (PD). However, the effect of PRE may vary with the clinical subtype of PD. To date, no study has assessed the effects of PRE in the different subtypes of PD. AIM: The aim of the present study was to assess the effects of PRE in PD patients with akinesia and rigidity (AR-subtype). DESIGN: A randomized controlled trial was conducted. SETTING: Outpatients clinics of the Bierzo Parkinson Association (Ponferrada, Spain) and the Asturias Parkinson Association (Oviedo, Spain). POPULATION: Twenty-eight patients with AR-subtype PD were randomized into an Experimental Group (EG, N.=13) and Control…

Anti-gout drugs as potential therapy for atrial fibrillation.

Atrial fibrillation (AF) is an important cardiovascular disease in theelderly [1]. Noticeably, it has been increasingly demonstrated thatserum uric acid (UA) is associated with AF [2–9]. In a recent meta-analysis performed by Tamariz and coworkers, the authors concludedthat high levels of UA and AF are clearly associated [10]. Interestingly,serum UA has been linked to AF in obstructive sleep apnea patients[11], whereas it has been also associated with thromboembolic risk inpatients with nonvalvular AF [12].The treatment of gout, a metabolic disorder caused by chronic hyper-uricemia, is based on administration of colchicine, xanthine oxidase (XO)competitive inhibitors such as allopurinol, and…

Effects of Exercise on the Immune Function of Pediatric Patients With Solid Tumors

The purpose of this study was to assess the effects of an in-hospital exercise intervention during neoadjuvant chemotherapy on the inflammatory profile and immune cell subpopulation in 20 children with solid tumors (control [n = 11] and exercise group [n = 9]). Although no significant interaction (group × time) effect was found with an analysis of variance test, we found a trend toward an interaction effect for natural killer cells expressing the immunoglobulin-like receptor KIR2DS4, with their numbers remaining stable in the exercise group but increasing in controls. Our data support that exercise interventions are safe in pediatric cancer patients with solid tumors during chemotherapy tre…

Serum irisin levels, precocious myocardial infarction, and healthy exceptional longevity.

Abstract Background Skeletal muscles produce irisin. Growing controversy exists on the association between this myokine and chronic disease risk. On the basis of the potential protective effects that irisin could exert on both vascular function and skeletal muscle mass, we hypothesized that an elevated level of this molecule may contribute to successful aging. Methods Serum irisin levels were measured using enzyme-linked immunosorbent assay in disease-free centenarians, young healthy controls, and patients with precocious acute myocardial infarction. Results We found the highest levels of serum irisin in disease-free centenarians (35.3 ± 5.5 ng/mL) compared with young healthy controls (20.7…

PTK2 rs7460 and rs7843014 polymorphisms and exceptional longevity: a functional replication study

Focal adhesion is critical for cell survival. The focal adhesion kinase (FAK, or PTK2) is an important component of the human interactome and thus is a potential longevity-related protein. Here we studied the association between two PTK2 gene single-nucleotide polymorphisms (SNPs) (rs7843014, rs7460) and exceptional longevity (EL). In addition to gaining insight into their functionality by determining luciferase gene reporter activity, we studied the genotype/allele frequency of these two SNPs among three different cohorts: (1) Spanish centenarians (n=175, 100–111 years, 144 women) and healthy controls (n=355, 20–50 years, 284 women); (2) Italian centenarians (n=79, 100–104 years, 40 women)…

Scientific discovery and its role in sports science

Scientific discovery is about a search for the Truth, for the consistent and predictable in how the universe works. Using a particular method of inquiry, the scientific method, and with acknowledgement of the inherently self-correcting nature of science, scientific inquiry moves forward incrementally to ever closer approximations of the Truth. This paper reviews the history of scientific inquiry, the methodology of the scientific method, including the necessity for hypothesis testing and development of the probability that a particular answer is a closer approximation of the Truth than previous answers have been. It also discusses some of the pitfalls of scientific inquiry, and areas in whi…

Exercise as the master polypill of the 21st century for the prevention of cardiovascular disease

To the Editor,The growing pandemic of cardiovascular diseases (CVD) has para-doxically paralleled advances in pharmacology, and CVD remains theleading cause of death worldwide. Therapeutic strategies aiming atcontrolling several CVD risk factors simultaneously in individualswithout evidence of CVD are expensive and difficult to implement.Thus, the development of fixed-dose drug combinations of antiplatelettogether with blood pressure (BP) and cholesterol-lowering drugs,i.e., polypills, is gaining attention to prevent CVD [1,2] and all-causemortality [3], even after an acute coronary syndrome [4]. Despite thepotential of polypills to increase adherence at a lower cost [5], peoplerandomized to …

New Molecular Targets and Lifestyle Interventions to Delay Aging Sarcopenia

The term sarcopenia was originally created to refer age-related loss of muscle mass with consequent loss of strength (Morley et al., 2001). There are now four international definitions of sarcopenia (Cruz-Jentoft et al., 2010; Muscaritoli et al., 2010; Morley et al., 2011). In essence they all agree, requiring a measure of walking capability [either low gait speed or a limited endurance (distance) in a 6-min walk], together with an appendicular lean mass of <2 SDs of a sex and ethnically corrected normal level for individuals 20–30 years old. Sarcopenia is a prevalent health problem among the elderly. On average, 5–13 and 11–50% of people aged 60−70 years and ≥80 years, respectively suffer …

Antidepressant Effects of Exercise: A Role for the Adiponectin-PGC-1α-kynurenine Triad?

It is well-recognized that exercise improves mental health, e.g., by decreasing depressive behaviors, improving hippocampal-dependent learning and neurogenesis, and increasing dendritic plasticity. Yet how exercise influences the brain at the molecular level is not clearly understood. Yau et al recently reported that the antidepressant effects of physical exercise are mainly mediated by adiponectin, an adipocyte-secreted hormone ('adipocytokine') with neuroprotective effects at the central nervous system level (Yau et al., 2014). 4.155 JCR (2015) Q1, 12/83 Physiology; Q2, 63/187 Cell biology UEM

Does midlife obesity really lower dementia risk?

Letter about: Qizilbash, N., Gregson, J., & Pocock, S. (2015). Does midlife obesity really lower dementia risk? The Lancet Diabetes & Endocrinology, 3(7), 501-502. 16.320 JCR (2015) Q1, 2/131 Endocrinology & metabolism UEM

Strenuous endurance exercise and right ventricular systolic function: no evidence of long-term sequelae.

a Faculty of Medicine, Department of Physiology, University of Valencia, Valencia, Spain b Fundacion de Investigacion del Hospital Clinico Universitario Valencia (FIHCUV-INCLIVA), Valencia, Spain c Faculty of Health and Sport Science, University of Zaragoza, Huesca, Spain d Hospital Universitario 12 de Octubre, Research Institute (i + 12), Madrid, Spain e HospitalUniversitario Miguel Servet, Zaragoza, Spain f Cardiology Service, Hospital Universitario Miguel Servet, Zaragoza, Spain g European University of Madrid, Madrid, Spain h Faculty of Medicine, Physical Education and Sports Section, University of Zaragoza, Zaragoza, Spain

Elite athletes live longer than the general population: a meta-analysis

OBJECTIVE: To perform a meta-analysis of cohort studies aimed at providing an accurate overview of mortality in elite athletes. PATIENTS AND METHODS: We reviewed English-language scientific articles available in Medline and Web of Science databases following the recommendations of the Meta-analyses Of Observational Studies in Epidemiology group. We searched for publications on longevity and professional or elite athletes (with no restriction on the starting date and up to March 31, 2014). RESULTS: Ten studies, including data from a total of 42,807 athletes (707 women), met all inclusion criteria. The all-cause pooled standard mortality ratio (SMR) was 0.67 (95% CI, 0.55-0.81; P<.001) with n…

Vitamin D, precocious acute myocardial infarction, and exceptional longevity

Recent studies have reported low circulating levels of 25-hydroxyvitamin D (25(OH)D), the biologically active form of vitamin D, in patients with cardiovascular disease (CVD) [1], hypertension [2], carotid atherosclerosis [3], atrial fibrillation [4], and heart failure [5]. Moreover, vitamin D deficiency has been associated with all-cause mortality [6,7] and predicts adverse cardiac events in patients with established CVD [8] or after acute myocardial infarction (AMI) [9]. In turn, vitamin D supplementation improves the modulation of autonomic tone [10]. 4.638 JCR (2015) Q1, 24/124 Cardiac and cardiovascular systems UEM

Blood and urinary abnormalities induced during and after 24-hour continuous running: A case report

In this reported clinical case, a healthy and well-trained male subject [aged 37 years, maximal oxygen uptake (V[Combining Dot Above]O2max) 64 mL·kg·min] ran for 23 hours and 35 minutes covering 160 km (6.7 km/h average running speed). The analysis of hematological and biochemical parameters 3 days before the event, just after termination of exercise, and after 24 and 48 hours of recovery revealed important changes on muscle and liver function, and hemolysis. The analysis of urine sediments showed an increment of red and white blood cells filtrations, compatible with transient nephritis. After 48 hours, most of these alterations were recovered. Physicians and health professionals who monito…

'Olympic' centenarians: are they just biologically exceptional?

4.036 JCR (2014) Q1, 29/123 Cardiac and sardiovascular systems UEM

Muscle-Related Polymorphisms (MSTN rs1805086 and ACTN3 rs1815739) Are Not Associated with Exceptional Longevity in Japanese Centenarians

Myostatin (MSTN) and α-actinin-3 (ACTN3) genes are potentially associated with preservation of muscle mass and oxidative capacity, respectively. To explore the possible role of these genes in exceptional longevity (EL), the allele/genotype frequency distribution of two polymorphisms in MSTN (rs1805086, K153R) and ACTN3 (rs1815739, R577X) was studied in Japanese centenarians of both sexes (n = 742) and healthy controls (n = 814). The rs1805086 R-allele (theoretically associated with muscle mass preservation at the expense of oxidative capacity) was virtually absent in the two groups, where genotype distributions were virtually identical. Likewise, no differences in allele (p = 0.838 (women);…

Atrial fibrillation in highly trained endurance athletes — Description of a syndrome

Atrial fibrillation (AF) is the most common heart arrhythmia, the risk of which typically increases with age. This condition is commonly associated with major cardiovascular diseases and structural heart damage, while it is rarely observed in healthy young people. However, increasing evidence indicates that paroxysmal AF can also onset in young or middle-aged and otherwise healthy endurance athletes (e.g., cyclists, runners and cross-country skiers). Here we review the topic of AF associated with strenuous endurance exercise (SEE), for example cycling, running and cross-country skiing, especially at a competitive level, and we propose the definition of a new syndrome based on the accumulati…

Slackline Training in Children with Spastic Cerebral Palsy: A Randomized Clinical Trial

Objective: To assess whether a slackline intervention program improves postural control in children/adolescents with spastic cerebral palsy (CP). Design: Randomized controlled trial. Setting: Patients&rsquo