Melatonin reduces endoplasmic reticulum stress and autophagy in liver of leptin-deficient mice.

The sedentary lifestyle of modern society along with the high intake of energetic food has made obesity a current worldwide health problem. Despite great efforts to study the obesity and its related diseases, the mechanisms underlying the development of these diseases are not well understood. Therefore, identifying novel strategies to slow the progression of these diseases is urgently needed. Experimental observations indicate that melatonin has an important role in energy metabolism and cell signalling; thus, the use of this molecule may counteract the pathologies of obesity. In this study, wild-type and obese (ob/ob) mice received daily intraperitoneal injections of melatonin at a dose of 500 µg/kg body weight for 4 weeks, and the livers of these mice were used to evaluate the oxidative stress status, proteolytic (autophagy and proteasome) activity, unfolded protein response, inflammation and insulin signalling. Our results show, for the first time, that melatonin could significantly reduce endoplasmic reticulum stress in leptin-deficient obese animals and ameliorate several symptoms that characterize this disease. Our study supports the potential of melatonin as a therapeutic treatment for the most common type of obesity and its liver-associated disorders.

Interleukin 6, soluble tumor necrosis factor receptor I and red blood cell distribution width as biological markers of functional dependence in an elderly population: a translational approach.

In the present investigation we have analyzed the association between functional dependence and inflammatory biomarkers using the Barthel Index (BI) and the Katz Index (KI). This analysis may contribute to translational medicine by incorporating the clinical and laboratory data to better understand the relationship between chronic inflammation and functional dependence in the elderly population. The ultimate goal of this study was to identify possible useful biomarkers of functional dependence in the elderly. Participants in this study consisted of 120 older subjects (90 women and 30 men; range 68-105 years) who were selected from the Santa Teresa nursing home (Oviedo, Spain). We studied functional status using the following tools to diagnose the functional dependence by clinicians: BI and KI for activities of daily living. We analyzed morbidity, sociodemographic characteristics and a panel of inflammatory and inflammatory-related markers. In linear regression models adjusted by age, sex, anti-inflammatory drug use and morbid conditions high levels of interleukin 6 (IL-6) and soluble TNF receptor-I (sTNF-RI) were associated with functional dependence as measured using BI and KI. Elevated levels of red blood cell distribution width (RDW) were also associated with functional dependence measured using the KI after adjusting for the same potential confounders. The current results suggest that high IL-6, sTNF-RI and RDW levels are associated with the functional dependence in the elderly population. The results are consistent with the presumed underlying biological mechanism, in which the up-regulation of inflammatory mediators is associated with functional dependence in elderly subjects.

Prognostic networks for unraveling the biological mechanisms of Sarcopenia.

Sarcopenia is an age-related multifactorial process that involved several biological mechanisms, whose specific contribution and interplay is still unknown. The present study proposes prognostic networks based on machine learning approaches to unravel the interplay among those biological mechanisms mainly involved in the development of Sarcopenia. After analyzing 114 biological and clinical variables in adults older than 70 years, and using all the biological prognostic networks detected by machine learning with accuracy higher than 82%, we designed a consensus classifier based on majority vote that improve the predictive accuracy of Sarcopenia up to 91%. Additionally, we applied logistic regression analysis to propose the interplay among the most discriminative biological variables of Sarcopenia: anthropometry, body composition, functional performance of lower limbs, systemic oxidative stress, presence of depression and medication for the digestive system based on proton-pump inhibitors. Our data also demonstrate that besides a loss of muscle mass, impairments on functional performance of lower limbs are more relevant for develop Sarcopenia than those affecting the muscle strength.

Melatonin Prevents the Harmful Effects of Obesity on the Brain, Including at the Behavioral Level.

Obesity is a health problem caused by a diet rich in energy and the sedentary lifestyle of modern societies. A leptin deficiency is one of the worst causes of obesity, since it results in morbid obesity, a chronic disease without a cure. Leptin is an adipokine secreted in a manner dependent on the circadian rhythm that ultimately reduces food intake. We studied cellular alterations in brain of leptin-deficient obese animals and tested whether these alterations are reflected in abnormal behaviors. Obesity induced increases in oxidative stress and the unfolded protein response caused by endoplasmic reticulum stress. However, the subsequent signaling cascade was disrupted, blocking possible systemic improvements and increasing the production of misfolded proteins that trigger autophagy. Up-regulated autophagy was not indefinitely maintained and misfolded proteins accumulated in obese animals, which led to aggresome formation. Finally, neurodegenerative markers together with anxiety and stress-induced behaviors were observed in leptin-deficient mice. As oxidative stress has an essential role in the development of these harmful effects of obesity, melatonin, a powerful antioxidant, might counteract these effects on the brain. Following treatment with melatonin, the animals' antioxidant defenses were improved and misfolded protein, proteasome activity, and autophagy decreased. Aggresome formation was reduced due to the reduction in the levels of misfolded proteins and the reduction in tubulin expression, a key element in aggresome development. The levels of neurodegenerative markers were reduced and the behaviors recovered. The data support the use of melatonin in therapeutic interventions to reduce brain damage induced by leptin deficiency-dependent obesity.

High-Fructose Consumption Impairs the Redox System and Protein Quality Control in the Brain of Syrian Hamsters: Therapeutic Effects of Melatonin.

Although numerous studies have demonstrated the harmful effect of excessive fructose consumption at the systemic level, there is little information on its effects in the central nervous system. The purpose of the present work was to study the cellular alterations related to oxidative stress and protein quality control systems induced by a high-fructose diet in the brain of Syrian hamsters and their possible attenuation by exogenous melatonin. High-fructose intake induced type II diabetes together with oxidative damage, led to alterations of the unfolded protein response by activating the eIF2α branch, and impaired the macroautophagic machinery in the brain, favoring the accumulation of aggregates labeled for selective degradation and neurodegeneration markers such as ß-amyloid (1-42), tau-p-S199, and tau-p-S404. Melatonin attenuated the manifestation of type II diabetes and reduced oxidative stress, deactivated eIF2α, and decreased tau-p-S404 levels in the brain of animals fed a high-fructose diet.

Potential early biomarkers of sarcopenia among independent older adults.

OBJECTIVES: There are no tools or biomarkers for a quantitative analysis of sarcopenia. STUDY DESIGN: Cross-sectional study of the diagnosis of sarcopenia in 200 independent adults aged 70 years or over. MAIN OUTCOME MEASURES: Sarcopenia was defined as loss of muscle mass together with low strength and/or loss of physical performance. We considered different clinical parameters and assayed potential blood biomarkers (cell energetic metabolism, muscle performance, inflammation, infection and oxidative stress). RESULTS: The prevalence of sarcopenia was 35.3% in women and 13.1% in men, and it was significantly associated with advanced age, a low functional performance in the lower extremities, deficient weekly consumption of kilocalories, risk of malnutrition, and drug use for the digestive system. A close relationship was found between sarcopenia, pre-frailty and depressed mood. With these confounding variables, we observed that products of lipid peroxidation were closely associated with sarcopenia in independent older adults (frail participants and those with severe dependence had been excluded from the sample). The best multivariate model proposed was able to predict 67.6% of the variance in sarcopenia, with a power of discrimination of 93.5%. Additional analyses considering lipid levels, fat mass, dyslipidemia, use of lipid-lowering drugs and hypertension confirmed this close association between lipid peroxidation and sarcopenia. CONCLUSIONS: Given the difficulty in the diagnosis of sarcopenia in clinical practice, we suggest the use of blood circulating products of lipid peroxidation as potential biomarkers for an early diagnosis of sarcopenia in independent older adults.

Associations of the antioxidant capacity and hemoglobin levels with functional physical performance of the upper and lower body limbs.

Herein we considered the role of oxidative stress on deficiencies of functional physical performance that could affect a future pre-frailty condition. Using principal component analyses (PCA), we created new variables to better describe the functionality regarding the physical performance of the upper and lower body limbs. Gait speed and the Short Physical Performance Battery (SPPB) score were classified by PCA to describe functional performance of the lower body limbs. Variables describing the general physical status, including weekly consumption of kilocalories and the musculoskeletal index, were classified together with grip strength of the dominant hand as indicators of functional performance of the upper body limbs. An intimate association between the functional physical performance of the upper body limbs and the total antioxidant capacity was observed in older subjects. Low levels of total antioxidant capacity were found in women 76 years or younger with deficiencies in the physical performance of both upper and lower body limbs. Similarly, we observed a close association between the functional physical performance of the lower body limbs and the levels of hemoglobin. In particular, low levels of hemoglobin were mostly found in men older than 76 years of age, showing impaired functional physical performance. In addition, the physical performance of the lower body limbs was shown to be more important than that of the upper body limbs in the statistical association with pre-frailty in the elderly. Therefore, specific low levels of hemoglobin and deficient oxidative defense in the elderly could significantly affect the functional physical performance and future outcomes of pre-frailty.

Chronic training increases blood oxidative damage but promotes health in elderly men.

The objective of the present study was to investigate a large panel of oxidative stress biomarkers in long-term trained elderly men to analyse the effects of chronic training on an aged population. We collected blood samples from two groups of male volunteers older than 65 years who maintain a measure of functional independence: one group of sedentary subjects without a history of regular physical activity and the other of subjects who have sustained training, starting during middle age (mean training time=49 ± 8 years). We studied morbidity and polypharmacy, as well as haematological parameters including red cell count, haemoglobin concentration, haematocrit, mean corpuscular volume, red cell distribution width and several oxidative biomarkers including protein carbonyl content and lipid peroxidation in plasma and erythrocytes, red blood cell H2O2-induced haemolysis test, plasma total antioxidant activity and the main antioxidant enzymes of erythrocytes: superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione-S-transferase. After adjusting for confounding factors, we observed an increase in all oxidative damage biomarkers in the plasma and erythrocytes of the long-term exercise group. However, we reported a decrease in the number of diseases per subject with statistical differences nearly significant (p=0.061), reduced intake of medications per subject and lower levels of red cell distribution width in the chronic exercise group. These results indicate that chronic exercise from middle age to old age increases oxidative damage; however, chronic exercise appears to be an effective strategy to attenuate the age-related decline in the elderly.

Oxidative protein damage is associated with severe functional dependence among the elderly population: a principal component analysis approach.

BACKGROUND: Studies of the role of oxidative stress in functional dependence among the aging population are limited. In this report, we address this situation through an analysis of a large panel of blood oxidative biomarkers in elderly population. Because the analysis of multiple biomarkers increases the complexity of data interpretation, this investigation has utilized both an analysis of single biomarkers in addition to employment of the statistical data reduction tool principal component analysis that might allow for a clearer description of redox status as compared with a single measure alone. METHODS: We studied three groups of participants older than 65 years based on their Barthel Index: an independent group (100-95), a moderately dependent group (94-60), and a severely dependent group (59-0). RESULTS: We observed a significant increase in circulating protein carbonyl levels in the severely dependent group as compared with the independent and moderately dependent groups. Using principal component analysis, we found at least three factors (an erythrocyte-related component, a protein damage-related component, and a plasma-related component) that could be used to assess the different oxidative parameters in our population. We discovered a significant association of higher levels of the protein damage-related component with the severely dependent group. CONCLUSIONS: Protein damage levels could be assessed in clinical use as a biomarker of severe dependence. Furthermore, our results support the hypothesis that functional decline could be associated in part due to oxidative stress. Finally, we show that principal component analysis could be a useful statistical tool in the analysis of age-related decline.

Long-term training induces a healthy inflammatory and endocrine emergent biomarker profile in elderly men.

The objective of the present study was to investigate the changes in a large panel of emergent geriatric biomarkers in long-term trained elderly men to analyze the effects of long-term exercise on an aged population. We collected blood samples from two groups of male volunteers older than 65 years who maintain a measure of functional independence: one group of sedentary subjects without a history of regular physical activity and the other of subjects who have sustained training, starting during adulthood (mean training time = 49 ± 8 years). We studied morbidity, polypharmacy, cellular and serological inflammatory parameters, and endocrine mediators. After adjusting for confounding factors, we observed reduced medication intake per subject and lower number of diseases per subject with statistical differences nearly significant in the long-term exercise group. We showed that long-term training was associated with lower levels of white blood cell counts, neutrophil counts, interleukin-6, interleukin-10, interleukin-1 receptor antagonist, and soluble TNF receptor-I. Furthermore, we noted an increase in the concentrations of insulin-like growth factor-1 and dehydroepiandrosterone in the long-term training group. We concluded that long-term exercise training from adulthood to old age is clearly associated with a healthy profile of emergent geriatric biomarkers. Long-term training could improve the inflammatory-endocrine imbalance associated with disease, frailty, functional decline, and mortality in elderly men. Our results point to the benefits of prolonged exercise from adulthood to old age.

Defective adaption of erythrocytes during acute hypoxia injury in an elderly population.

The present study investigated the changes in several erythrocyte oxidative stress biomarkers in hypoxic elderly individuals to analyze the deleterious effects of low oxyhemoglobin saturation in an elderly population. We collected blood samples from one normoxic middle-aged group and two groups composed of individuals older than 75 years of age: one normoxic group and one hypoxic group. Aging appeared to provoke a defective erythrocyte antioxidant defense associated with increased oxidative damage in the elderly population. Acute hypoxia activated an insufficient antioxidant defense response as suggested by the oxidative damage observed. The oxidative imbalance presented in older participants and increased in hypoxia participants had a direct effect on glyceraldehyde-3-phosphate dehydrogenase cell distribution. Oxidative stress levels altered Band 3 protein and mediated caspase-3 activation in erythrocyte from the aged group although it was not extended to hypoxic individuals. Therefore, aged participants appeared to activate an insufficient antioxidant response against hypoxia-related oxidative stress.

Differential inflammatory responses in aging and disease: TNF-alpha and IL-6 as possible biomarkers.

Oxidative stress has been reported to increase during aging and conditions of hypoxia. Although low oxygen saturation has a key role in the development of several age-related diseases, the underlying mechanisms are still unknown. We analyzed the relationship between aging and hypoxia by examining oxidative stress and inflammation-related cytokines. We collected blood samples from three volunteer experimental groups, consisting of one group of normoxic middle-aged people and two groups of individuals older than 75 years, which comprised a subgroup of normoxic subjects and another with oxyhemoglobin saturation lower than 95% (hypoxic). Our results showed a fall in antioxidant defenses in older people with hypoxia. TNF-alpha, the first element in the cytokine cascade, was significantly increased in the aged population, implying that aging is accompanied by a gradual increase in this inflammatory biomarker. IL-6 was not associated with aging, but it was highly elevated under hypoxia conditions in elderly subjects. Thus, these parameters could be used as biological markers of different inflammatory processes triggered by oxidative stress induced by a decrease in antioxidant defenses in the elderly population, with TNF-alpha as an indicator of chronic processes, such as aging, and IL-6 as a marker for acute responses, such as hypoxia.