Muscle Hypertrophy Is Linked to Changes in the Oxidative and Proteolytic Systems during Early Tenderization of the Spanish Breed "Asturiana de los Valles".

For fresh meat consumers, eating satisfaction is of utmost importance and tenderness is one of the most important characteristics in this regard. Our study examined beef of different animal biotypes of the autochthonous breed "Asturiana de los Valles" (AV) to determine if early postmortem oxidative and proteolytic processes may influence the final tenderness of the product. This meat-specialized breed shows different biotypes depending on the frequency of a myostatin mutation "mh" that induces double-muscling or muscular hypertrophy (mh/mh, mh/+, +/+). Samples from the longissimus dorsi muscles of yearling bulls were analyzed during the first 24 h postmortem. Changes in the redox balance of muscle cells were significant in the first hours after slaughter; total antioxidant activity was higher in the mh/mh biotype and it followed the shortening of the sarcomeres, a key parameter in understanding meat tenderness. The two proteolytic systems studied (proteasome and lysosome) followed distinct patterns. Proteasome activity was higher in the (mh/+) biotype, which correlated with higher protein damage. Lysosome proteolysis was increased in the more tender biotypes (mh genotypes). Autophagic activation showed significant differences between the biotypes, with (mh/mh) showing more intense basal autophagy at the beginning of the postmortem period that decreased gradually (p < 0.001), while in the normal biotype (+/+), it was slightly delayed and then increased progressively (p < 0.001). These results suggest that this type of catalytic process and antioxidant activity could contribute to the earlier disintegration of the myofibers, particularly in the mh/mh biotypes, and influence the conversion of muscle into meat.

Melatonin Alleviates the Impairment of Muscle Bioenergetics and Protein Quality Control Systems in Leptin-Deficiency-Induced Obesity.

Leptin is critically compromised in the major common forms of obesity. Skeletal muscle is the main effector tissue for energy modification that occurs as a result of the effect of endocrine axes, such as leptin signaling. Our study was carried out using skeletal muscle from a leptin-deficient animal model, in order to ascertain the importance of this hormone and to identify the major skeletal muscle mechanisms affected. We also examined the therapeutic role of melatonin against leptin-induced muscle wasting. Here, we report that leptin deficiency stimulates fatty acid ß-oxidation, which results in mitochondrial uncoupling and the suppression of mitochondrial oxidative damage; however, it increases cytosolic oxidative damage. Thus, different nutrient-sensing pathways are disrupted, impairing proteostasis and promoting lipid anabolism, which induces myofiber degeneration and drives oxidative type I fiber conversion. Melatonin treatment plays a significant role in reducing cellular oxidative damage and regulating energy homeostasis and fuel utilization. Melatonin is able to improve both glucose and mitochondrial metabolism and partially restore proteostasis. Taken together, our study demonstrates melatonin to be a decisive mitochondrial function-fate regulator in skeletal muscle, with implications for resembling physiological energy requirements and targeting glycolytic type II fiber recovery.

Dissecting the functions of cancer-associated fibroblasts to therapeutically target head and neck cancer microenvironment.

Head and neck cancers (HNC) are a diverse group of aggressive malignancies with high morbidity and mortality, leading to almost half-million deaths annually worldwide. A better understanding of the molecular processes governing tumor formation and progression is crucial to improve current diagnostic and prognostic tools as well as to develop more personalized treatment strategies. Tumors are highly complex and heterogeneous structures in which growth and dissemination is not only governed by the cancer cells intrinsic mechanisms, but also by the surrounding tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) emerge as predominant TME components and key players in the generation of permissive conditions that ultimately impact in tumor progression and metastatic dissemination. Although CAFs were initially considered a consequence of tumor development, it is now well established that they actively contribute to numerous cancer hallmarks i.e., tumor cell growth, migration and invasion, cancer cell stemness, angiogenesis, metabolic reprograming, inflammation, and immune system modulation. In this scenario, therapeutic strategies targeting CAF functions could potentially have a major impact in cancer therapeutics, providing avenues for new treatment options or for improving efficacy in established approaches. This review is focused on thoroughly dissecting existing evidences supporting the contribution of CAFs in HNC biology with an emphasis on current knowledge of the key molecules and pathways involved in CAF-tumor crosstalk, and their potential as novel biomarkers and/or therapeutic targets to effectively interfere the tumor-stroma crosstalk for HNC patients benefit. involved in CAF-tumor crosstalk, and their potential as novel biomarkers and/or therapeutic targets to effec- tively interfere the tumor-stroma crosstalk for HNC patients benefit.

Suppression of Endothelial Cell FAK Expression Reduces Pancreatic Ductal Adenocarcinoma Metastasis after Gemcitabine Treatment.

Despite substantial advances in the treatment of solid cancers, resistance to therapy remains a major obstacle to prolonged progression-free survival. Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, with a high level of liver metastasis. Primary PDAC is highly hypoxic, and metastases are resistant to first-line treatment, including gemcitabine. Recent studies have indicated that endothelial cell (EC) focal adhesion kinase (FAK) regulates DNA-damaging therapy-induced angiocrine factors and chemosensitivity in primary tumor models. Here, we show that inducible loss of EC-FAK in both orthotopic and spontaneous mouse models of PDAC is not sufficient to affect primary tumor growth but reduces liver and lung metastasis load and improves survival rates in gemcitabine-treated, but not untreated, mice. EC-FAK loss did not affect primary tumor angiogenesis, tumor blood vessel leakage, or early events in metastasis, including the numbers of circulating tumor cells, tumor cell homing, or metastatic seeding. Phosphoproteomics analysis showed a downregulation of the MAPK, RAF, and PAK signaling pathways in gemcitabine-treated FAK-depleted ECs compared with gemcitabine-treated wild-type ECs. Moreover, low levels of EC-FAK correlated with increased survival and reduced relapse in gemcitabine-treated patients with PDAC, supporting the clinical relevance of these findings. Altogether, we have identified a new role of EC-FAK in regulating PDAC metastasis upon gemcitabine treatment that impacts outcome. SIGNIFICANCE: These findings establish the potential utility of combinatorial endothelial cell FAK targeting together with gemcitabine in future clinical applications to control metastasis in patients with pancreatic ductal adenocarcinoma.

Elucidating the role of the kinase activity of endothelial cell focal adhesion kinase in angiocrine signalling and tumour growth.

A common limitation of cancer treatments is chemotherapy resistance. We have previously identified that endothelial cell (EC)-specific deletion of focal adhesion kinase (FAK) sensitises tumour cells to DNA-damaging therapies, reducing tumour growth in mice. The present study addressed the kinase activity dependency of EC FAK sensitisation to the DNA-damaging chemotherapeutic drug, doxorubicin. FAK is recognised as a therapeutic target in tumour cells, leading to the development of a range of inhibitors, the majority being ATP competitive kinase inhibitors. We demonstrate that inactivation of EC FAK kinase domain (kinase dead; EC FAK-KD) in established subcutaneous B16F0 tumours improves melanoma cell sensitisation to doxorubicin. Doxorubicin treatment in EC FAK-KD mice reduced the percentage change in exponential B16F0 tumour growth further than in wild-type mice. There was no difference in tumour blood vessel numbers, vessel perfusion or doxorubicin delivery between genotypes, suggesting a possible angiocrine effect on the regulation of tumour growth. Doxorubicin reduced perivascular malignant cell proliferation, while enhancing perivascular tumour cell apoptosis and DNA damage in tumours grown in EC FAK-KD mice 48 h after doxorubicin injection. Human pulmonary microvascular ECs treated with the pharmacological FAK kinase inhibitors defactinib, PF-562,271 or PF-573,228 in combination with doxorubicin also reduced cytokine expression levels. Together, these data suggest that targeting EC FAK kinase activity may alter angiocrine signals that correlate with improved acute tumour cell chemosensitisation. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Inhibition of Mitochondrial Dynamics Preferentially Targets Pancreatic Cancer Cells with Enhanced Tumorigenic and Invasive Potential.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest tumors, partly due to its intrinsic aggressiveness, metastatic potential, and chemoresistance of the contained cancer stem cells (CSCs). Pancreatic CSCs strongly rely on mitochondrial metabolism to maintain their stemness, therefore representing a putative target for their elimination. Since mitochondrial homeostasis depends on the tightly controlled balance between fusion and fission processes, namely mitochondrial dynamics, we aim to study this mechanism in the context of stemness. In human PDAC tissues, the mitochondrial fission gene DNM1L (DRP1) was overexpressed and positively correlated with the stemness signature. Moreover, we observe that primary human CSCs display smaller mitochondria and a higher DRP1/MFN2 expression ratio, indicating the activation of the mitochondrial fission. Interestingly, treatment with the DRP1 inhibitor mDivi-1 induced dose-dependent apoptosis, especially in CD133+ CSCs, due to the accumulation of dysfunctional mitochondria and the subsequent energy crisis in this subpopulation. Mechanistically, mDivi-1 inhibited stemness-related features, such as self-renewal, tumorigenicity, and invasiveness and chemosensitized the cells to the cytotoxic effects of Gemcitabine. In summary, mitochondrial fission is an essential process for pancreatic CSCs and represents an attractive target for designing novel multimodal treatments that will more efficiently eliminate cells with high tumorigenic potential.

Cancer Burden Is Controlled by Mural Cell-ß3-Integrin Regulated Crosstalk with Tumor Cells.

Enhanced blood vessel (BV) formation is thought to drive tumor growth through elevated nutrient delivery. However, this observation has overlooked potential roles for mural cells in directly affecting tumor growth independent of BV function. Here we provide clinical data correlating high percentages of mural-ß3-integrin-negative tumor BVs with increased tumor sizes but no effect on BV numbers. Mural-ß3-integrin loss also enhances tumor growth in implanted and autochthonous mouse tumor models with no detectable effects on BV numbers or function. At a molecular level, mural-cell ß3-integrin loss enhances signaling via FAK-p-HGFR-p-Akt-p-p65, driving CXCL1, CCL2, and TIMP-1 production. In particular, mural-cell-derived CCL2 stimulates tumor cell MEK1-ERK1/2-ROCK2-dependent signaling and enhances tumor cell survival and tumor growth. Overall, our data indicate that mural cells can control tumor growth via paracrine signals regulated by ß3-integrin, providing a previously unrecognized mechanism of cancer growth control.

Cancer associated fibroblast FAK regulates malignant cell metabolism.

Emerging evidence suggests that cancer cell metabolism can be regulated by cancer-associated fibroblasts (CAFs), but the mechanisms are poorly defined. Here we show that CAFs regulate malignant cell metabolism through pathways under the control of FAK. In breast and pancreatic cancer patients we find that low FAK expression, specifically in the stromal compartment, predicts reduced overall survival. In mice, depletion of FAK in a subpopulation of CAFs regulates paracrine signals that increase malignant cell glycolysis and tumour growth. Proteomic and phosphoproteomic analysis in our mouse model identifies metabolic alterations which are reflected at the transcriptomic level in patients with low stromal FAK. Mechanistically we demonstrate that FAK-depletion in CAFs increases chemokine production, which via CCR1/CCR2 on cancer cells, activate protein kinase A, leading to enhanced malignant cell glycolysis. Our data uncover mechanisms whereby stromal fibroblasts regulate cancer cell metabolism independent of genetic mutations in cancer cells.

Selective autophagy, lipophagy and mitophagy, in the Harderian gland along the oestrous cycle: a potential retrieval effect of melatonin.

Sexual dimorphism has been reported in many processes. However, sexual bias in favour of the use of males is very present in science. One of the main reasons is that the impact of hormones in diverse pathways and processes such as autophagy have not been properly addressed in vivo. The Harderian gland is a perfect model to study autophagic modulation as it exhibits important changes during the oestrous cycle. The aim of this study is to identify the main processes behind Harderian gland differences under oestrous cycle and their modulator. In the present study we show that redox-sensitive transcription factors have an essential role: NF-κB may activate SQSTM1/p62 in oestrus, promoting selective types of autophagy: mitophagy and lipophagy. Nrf2 activation in dioestrus, leads the retrieval phase and restoration of mitochondrial homeostasis. Melatonin's receptors show higher expression in dioestrus, leading to decreases in pro-inflammatory mediators and enhanced Nrf2 expression. Consequently, autophagy is blocked, and porphyrin release is reduced. All these results point to melatonin as one of the main modulators of the changes in autophagy during the oestrous cycle.

Metabolism-Based Therapeutic Strategies Targeting Cancer Stem Cells.

Cancer heterogeneity constitutes the major source of disease progression and therapy failure. Tumors comprise functionally diverse subpopulations, with cancer stem cells (CSCs) as the source of this heterogeneity. Since these cells bear in vivo tumorigenicity and metastatic potential, survive chemotherapy and drive relapse, its elimination may be the only way to achieve long-term survival in patients. Thanks to the great advances in the field over the last few years, we know now that cellular metabolism and stemness are highly intertwined in normal development and cancer. Indeed, CSCs show distinct metabolic features as compared with their more differentiated progenies, though their dominant metabolic phenotype varies across tumor entities, patients and even subclones within a tumor. Following initial works focused on glucose metabolism, current studies have unveiled particularities of CSC metabolism in terms of redox state, lipid metabolism and use of alternative fuels, such as amino acids or ketone bodies. In this review, we describe the different metabolic phenotypes attributed to CSCs with special focus on metabolism-based therapeutic strategies tested in preclinical and clinical settings.

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.

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.

Overweight in elderly people induces impaired autophagy in skeletal muscle.

Sarcopenia is the gradual loss of skeletal muscle mass, strength and quality associated with aging. Changes in body composition, especially in skeletal muscle and fat mass are crucial steps in the development of chronic diseases. We studied the effect of overweight on skeletal muscle tissue in elderly people without reaching obesity to prevent this extreme situation. Overweight induces a progressive protein breakdown reflected as a progressive withdrawal of anabolism against the promoted catabolic state leading to muscle wasting. Protein turnover is regulated by a network of signaling pathways. Muscle damage derived from overweight displayed by oxidative and endoplasmic reticulum (ER) stress induces inflammation and insulin resistance and forces the muscle to increase requirements from autophagy mechanisms. Our findings showed that failure of autophagy in the elderly deprives it to deal with the cell damage caused by overweight. This insufficiently efficient autophagy leads to an accumulation of p62 and NBR1, which are robust markers of protein aggregations. This impaired autophagy affects myogenesis activity. Depletion of myogenic regulatory factors (MRFs) without links to variations in myostatin levels in overweight patients suggest a possible reduction of satellite cells in muscle tissue, which contributes to declined muscle quality. This discovery has important implications that improve the understanding of aged-related atrophy caused by overweight and demonstrates how impaired autophagy is one of the main responsible mechanisms that aggravate muscle wasting. Therefore, autophagy could be an interesting target for therapeutic interventions in humans against muscle impairment diseases.

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.

Melatonin administration decreases adipogenesis in the liver of ob/ob mice through autophagy modulation.

Despite efforts to curb the incidence of obesity and its comorbidities, this condition remains the fifth leading cause of death worldwide. To identify ways to reduce this global effect, we investigated the actions of daily melatonin administration on oxidative stress parameters and autophagic processes as a possible treatment of obesity in ob/ob mice. The involvement of melatonin in many physiological functions, such as the regulation of seasonal body weight variation, glucose uptake, or adiposity, and the role of this indoleamine as an essential antioxidant, has become the focus of numerous anti-obesity studies. Here, we examined the oxidative status in the livers of obese melatonin-treated and untreated mice, observing a decrease in the oxidative stress levels through elevated catalase activity. ROS-mediated autophagy was downregulated in the liver of melatonin-treated animals and was accompanied by significant accumulation of p62. Autophagy is closely associated with adipogenesis; in this study, we report that melatonin-treated obese mice also showed reduced adiposity, as demonstrated by diminished body weight and reduced peroxisome proliferator-activated receptor gamma expression. Based on these factors, it is reasonable to assume that oxidative stress and autophagy play important roles in obesity, and therefore, melatonin could be an interesting target molecule for the development of a potential therapeutic agent to curb body weight.

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.

Chronic inflammation as predictor of 1-year hospitalization and mortality in elderly population.

BACKGROUND: Systemic low-grade inflammation is thought to be associated with an increased risk of adverse clinical outcomes in elderly population. We tested this notion with the goal of identifying useful potential biomarkers of 1-year hospitalization and mortality in the elderly population. DESIGN: A total of 120 institutionalized older subjects were enrolled as participants in this study, including 90 women and 30 men (ranging in age from 68 to 105 years), selected from Santa Teresa nursing home (Oviedo, Spain). We studied functional status, morbidity, socio-demographic characteristics and several inflammation and inflammation-related markers. RESULTS: The study included 95 non-hospitalized participants and 23 participants with at least one hospitalization during 1 year (19% of subjects). The study also included 100 survivors and 19 participants who died during the 1-year study (16% of subjects). In logistic regression models adjusted by age, sex, anti-inflammatory drug use and morbid conditions, high levels of interleukin 1 receptor antagonist (IL-1ra) and red blood cell distribution width (RDW) were associated with hospitalization and death at 1 year. Elevated levels of tumour necrosis factor α (TNF-α) were also associated with an increased risk of death at 1 year after adjusting for the same potential confounders. Multivariate logistic regression models showed that elevated serum levels of IL-1ra were intimately associated with 1-year subsequent hospitalization and mortality in aged subjects after adjusting for age, sex, anti-inflammatory drug use and morbid conditions. CONCLUSIONS: Current data suggest that IL-1ra is a predictor of 1-year hospitalization and mortality in the elderly population.

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.

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.