Properties of Resveratrol:In VitroandIn VivoStudies about Metabolism, Bioavailability, and Biological Effects in Animal Models and Humans

Plants containing resveratrol have been used effectively in traditional medicine for over 2000 years. It can be found in some plants, fruits, and derivatives, such as red wine. Therefore, it can be administered by either consuming these natural products or intaking nutraceutical pills. Resveratrol exhibits a wide range of beneficial properties, and this may be due to its molecular structure, which endow resveratrol with the ability to bind to many biomolecules. Among these properties its activity as an anticancer agent, a platelet antiaggregation agent, and an antioxidant, as well as its antiaging, antifrailty, anti-inflammatory, antiallergenic, and so forth activities, is worth highlightin…

Response to Vidal and Colleagues

Higher oxidative stress in human dental pulp stem cells cultured at 21% O2 compared to 5% O2

Clearing Amyloid-β Through PPARγ/ApoE Activation by Genistein is an Experimental Treatment of Alzheimer's Disease

Amyloid-β (Aβ) clearance from brain, which is decreased in Alzheimer’s disease, is facilitated by apolipoprotein E. Apo E is up-regulated by activation of the retinoid X receptor moiety of the RXR/PPARγ dimeric receptor. Genistein, a non-toxic, well tested and inexpensive drug has a multifaceted protective effect: antioxidant (because it stimulates the expression of antioxidant genes), anit-inflammatory and stimulator of activates the PPARγ receptor, which results in increased expression of ApoE. Treatment of an Alzheimer’s mouse model with genistein results in a remarkable and rapid improvement in various parameters of cognition, such as hippocampal learning, recognition memory, implicit m…

Emergency Clinical Trials

Emergency clinical trials involve the administration of the study drug to healthy human volunteers or to patients under the supervision of a qualified investigator, usually a physician, pursuant to a reviewed protocol. Research in this field continues to grow because this department is often considered as a desirable place to conduct clinical research due to the broad and undifferentiated spectrum of acute conditions encountered. There are some specific aspects when studying emergency medicine that have to be taken into account. One of them is the emphasis on ultrarapid diagnosis and treatment to save the critically ill emergency patient. Keywords: emergency medicine; clinical trials; diagn…

Phytoestrogens Up-regulate Antioxidant Genes

Ursodeoxycholic acid protects against secondary biliary cirrhosis in rats by preventing mitochondrial oxidative stress

Ursodeoxycholic acid (UDCA) improves clinical and biochemical indices in primary biliary cirrhosis and prolongs survival free of liver transplantation. Recently, it was suggested that the cytoprotective mechanisms of UDCA may be mediated by protection against oxidative stress, which is involved in the development of cirrhosis induced by chronic cholestasis. The aims of the current study were 1) to identify the mechanisms involved in glutathione depletion, oxidative stress, and mitochondrial impairment during biliary cirrhosis induced by chronic cholestasis in rats; and 2) to determine the mechanisms associated with the protective effects of UDCA against secondary biliary cirrhosis. The find…

sj-docx-1-uix-10.1177_01617346211029656 – Supplemental material for Diagnostic Performance of Muscle Echo Intensity and Fractal Dimension for the Detection of Frailty Phenotype

Supplemental material, sj-docx-1-uix-10.1177_01617346211029656 for Diagnostic Performance of Muscle Echo Intensity and Fractal Dimension for the Detection of Frailty Phenotype by Rebeca Mirón Mombiela, Jelena Vucetic, Paloma Monllor, Jenny S. Cárdenas-Herrán, Paloma Taltavull de La Paz and Consuelo Borrás in Ultrasonic Imaging

Influence of partial O 2 pressure on the adhesion, proliferation, and osteogenic differentiation of human dental pulp stem cells on β-tricalcium phosphate scaffold

Our purpose was to analyse the influence of O2 pressure on the adhesion, proliferation, and osteogenic differentiation of human dental pulp stem cells (DPSC) on 3-tricalcium phosphate (3-TCP) scaffold. DPSC isolated from extracted third molars were seeded on 3-TCP and cultured under 3% or 21% O2 pressure. Cell adhesion, proliferation, and differentiation over the biomaterial were evaluated at 7, 13, 18, and 23 days of culture. Cell adhesion was determined by light microscopy, proliferation by DNA quantification, and osteogenic differentiation by alkaline phosphatase activity analysis. All DPSC adhered to 3-TCP with both O2 conditions. Cell proliferation values were higher at 3% O2 in each t…

Mitochondrial oxidant generation is involved in determining why females live longer than males

Females live longer than males in many mammalian species, including humans. This natural phenomenon can be explained on the basis of the mitochondrial theory of aging. Mitochondria are a major source of free radicals in cells. Mitochondria from female rats generate half the amount of hydrogen peroxide than those of males and have higher levels of mitochondrial reduced glutathione. The latter is due to females behaving as double transgenic in over-expressing antioxidant enzymes. Estrogens bind to the estrogen receptors and subsequently activate the mitogen activated protein (MAP) kinase and nuclear factor kappa B (NFkappaB) signalling pathways, resulting in an upregulation of antioxidant enz…

Women Live Longer than Men: Understanding Molecular Mechanisms Offers Opportunities to Intervene by Using Estrogenic Compounds

Abstract Women live longer than men. Moreover, females live longer than males in some, but not all, experimental animals. The differences in longevity between genders are related to free radical production. Indeed, females produce less radicals only in animal species in which they live longer than males. This is because estrogens upregulate antioxidant longevity-related genes. These considerations have led us to postulate an extended concept of antioxidant in biology: an antioxidant is any nutritional, physiological, or pharmacological manipulation that increases the expression and activity of antioxidant genes or proteins. Phytoestrogens or other selective estrogen receptor modulators lowe…

Targeting Alzheimer’s disease with multimodal polypeptide-based nanoconjugates

LRP1-targeted St-Cl–polyglutamate conjugates as multivalent neuroprotective/neurotrophic therapeutics for Alzheimer’s disease.

Chemical intervention in senescence-accelerated mice metabolism for modeling neurodegenerative diseases: an overview

Abstract SAMP1 is a line of inbred mice with a pronounced misbalance between generation and neutralization of reactive oxygen species (ROS) in brain and other tissues. This results in accumulation of molecular defects in lipids, proteins and DNA moieties. The metabolic disorders appear at a very early stage of ontogenic development and induce morphological and behavioral defects manifesting from the fourth month after birth. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment of these mice induced specific changes that closely resembled parkinsonian syndrome. Neuropeptide carnosine prevented toxic effects of MPTP and protected the animals against experimental parkinsonism.

Genistein effect on cognition in prodromal Alzheimer's disease patients : the GENIAL clinical trial

Background: Delaying the transition from minimal cognitive impairment to Alzheimer’s dementia is a major concern in Alzheimer’s disease (AD) therapeutics. Pathological signs of AD occur years before the onset of clinical dementia. Thus, long-term therapeutic approaches, with safe, minimally invasive, and yet efective substances are recommended. There is a need to develop new drugs to delay Alzheimer’s dementia. We have taken a nutritional supplement approach with genistein, a chemically defned polyphenol that acts by multimodal specifc mechanisms. Our group previously showed that genistein supplementation is efective to treat the double transgenic (APP/PS1) AD animal model. Methods: In this…

Additional file 1 of Genistein effect on cognition in prodromal Alzheimer’s disease patients. The GENIAL clinical trial

Additional file 1: Table S1. All possible comparisons of the values for the anterior cingulate gyrus before and after treatment with placebo or genistein.

Centenarian offspring: A model for understanding healthy aging

Centenarians exhibit extreme longevity showing a compression of morbidity. We showed previously that microRNA expression profiles and plasma protein carbonylation in centenarians and young people are similar, whereas they are very different from that found in old individuals. This suggests that centenarians have a better control of homeostasis and are protected against oxidative damage. In this study, we aimed to determine if such characteristic microRNA expression profile and lower protein oxidation status in centenarians may be inherited by their offspring. For this purpose, we collected plasma and peripheral blood mononuclear cells from 90 septuagenarians, 68 centenarians and 46 centenar…

Estradiol or genistein prevent Alzheimer's disease-associated inflammation correlating with an increase PPAR gamma expression in cultured astrocytes.

Inflammation has been implicated in neurodegenerative disorders such as Alzheimer's disease (AD). The main inflammatory players in AD are the glial cells which initiate the inflammatory response. One of the earliest neuropathological changes in AD is the accumulation of astrocytes at sites of A beta deposition. It is desirable to find methods of tipping the balance towards anti-inflammatory state. Estrogenic compounds have shown anti-inflammatory and also antioxidant activity. Astrocytes were pretreated with 17-beta estradiol or with genistein, and 48 h later treated with 5 microM amyloid beta (A beta) for 24 h. We found that A beta induces inflammatory mediators, such as cyclooxygenase 2 (…

Methionine transsulfuration pathway is upregulated in long-lived humans.

Available evidences point to methionine metabolism as a key target to study the molecular adaptive mechanisms underlying differences in longevity. The plasma methionine metabolic profile was determined using a LC-MS/MS platform to systematically define specific phenotypic patterns associated with genotypes of human extreme longevity (centenarians). Our findings demonstrate the presence of a specific plasma profile associated with human longevity characterized by an enhanced transsulfuration pathway and tricarboxylic acid (TCA) cycle intermediates, as well as a reduced content of specific amino acids. Furthermore, our work reveals that centenarians maintain a strongly correlated methionine m…

Resveratrol in Experimental Models and Humans

Abstract The search for natural compounds with beneficial activity for health has been one of the great challenges since men are aware of their survival. Many elixirs and ointments have been tested as the possible treatment or remedy for diseases or even death. In traditional medicine, compounds with biological activities have been used in humans. Among them, resveratrol (RSV) is, currently, one of the most studied natural compounds by modern science. To study this polyphenol we have a series of very useful tools that allow us to investigate from molecular targets, to signaling pathways in which it is involved, as well as effects on pathologies and even health and longevity. In this chapter…

La sobreexpresión de Fas en moscas aumenta su supervivencia

Brain-Derived Neurotrophic Factor as a Marker of Cognitive Frailty.

Antioxidant role of microvesicles, activated by genistein, in stem cells

Intercellular communication is an essential hallmark of multicellular organisms. Microvesicles (MVs), which are released from and taken up by most types of cells are involved in intercellular communication. The nutrients we ingest from food contact with immune cells in the bloodstream and can promote the formation of MVs. Some foods contain molecules with regulatory activity, such as genistein, a polyphenol found in soy. We aimed to study the effects of MVs released from genistein-treated immune cells on dental pulp stem cells (DPSC). We obtained peripheral blood mononuclear cells (PBMC) from 5 young women (aged 18–25). Cells were cultured and treated with 0.5 μM genistein or 0.01% DMSO as …

Fostering antioxidant defences: up-regulation of antioxidant genes or antioxidant supplementation?

Vitamins have traditionally been considered as food components that are required in the normal diet to prevent deficiencies. However, a newer concept of the function of vitamins in nutrition has taken them beyond simply prevention of deficiency symptoms. This concept considers that many vitamins, when taken in relatively larges doses, have important functions beyond preventing deficiencies. Linus Pauling was instrumental in putting forward this concept, particularly for vitamin C. Thus, relatively high intakes of vitamins, and in particular vitamins C and E which are antioxidants, are considered to be healthy for the human population. This may be true in some special situations such as, for…

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

The beneficial effects of moderate red wine consumption on cardiovascular health are well known. The composition of red wine includes several compounds, such as the phytoestrogen resveratrol, that exert these beneficial effects, although not all the mechanisms by which they act are known. Our aim was to study the effect of red wine consumption on longevity-related genes in controlled human populations, such as cloistered nuns. We found that the expression of catalase, manganese-superoxide dismutase, Sirt1, and p53 was increased in peripheral blood mononuclear cells after 14 days of moderate red wine consumption. This increase was accompanied by an enhanced metabolic wellness: fatty acids, c…

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 biomarke…

El resveratrol induce catabolismo lipídico en ratones C57Bl/6

Posibles mecanismos por los que las mujeres viven más ue los varones

Resumen Nuestro grupo ha estudiado el estres oxidativo mitocondrial en machos y hembras para tratar de dilucidar los mecanismos moleculares por los cuales las hembras son mas longevas que los machos. Las mitocondrias son la fuente principal generadora de radicales libres en las celulas. Las mitocondrias aisladas de ratas hembra producen aproximadamente la mitad de peroxidos en comparacion con las mitocondrias aisladas de sus congeneres machos. Sin embargo, la ovariectomia de las ratas conduce a una produccion de peroxidos comparable a la obtenida en los machos. La terapia sustitutiva con estrogenos previene el efecto causado por la ovariectomia. Ademas, los valores de glutation son mayores …

Importance of stem cell culture conditions for their derived extracellular vesicles therapeutic effect.

Stem cell-derived extracellular vesicles (EVs) could be enhanced by modifying specific in vitro parameters when culturing their originating stem cells. Controlling stem cell growth conditions with physical properties, oxygen tension and media preconditioning with soluble factors may influence EVs biogenesis and EVs biological function as well. Unfortunately, many misconceptions and methodological issues have hampered the progress in understanding the biological properties of EVs. In this review we will first discuss the major concerns involved in a suitable EVs production from stem cell culture. Then, we will describe the current techniques for EV isolation, focusing on their advantages and…

A free radical theory of frailty.

The free radical theory of ageing provided an intellectual framework for many laboratories working on ageing. However, experimental and clinical evidence showing that high doses of antioxidants do not have an effect on ageing or on age-associated diseases, cast doubts on the validity of this theory. Data from our own laboratory show that oxidative damage does not correlate with age, especially in the geriatric population, but rather with the frailty state. This has led us to postulate the free radical theory of frailty that proposes that oxidative damage is associated with frailty, but not with chronological age itself. Superoxide dismutase deficient mice are more frail than controls. But m…

Anti-aging activity of the Ink4/Arf locus.

The proteins encoded by the Ink4/Arf locus, p16Ink4a, p19Arf and p15Ink4b are major tumour suppressors that oppose aberrant mitogenic signals. The expression levels of the locus are progressively increased during aging and genome-wide association studies have linked the locus to a number of aging-associated diseases and frailty in humans. However, direct measurement of the global impact of the Ink4/Arf locus on organismal aging and longevity was lacking. In this work, we have examined the fertility, cancer susceptibility, aging and longevity of mice genetically modified to carry one (Ink4/Arf-tg) or two (Ink4/Arf-tg/tg) intact additional copies of the locus. First, increased gene dosage of …

sj-docx-1-uix-10.1177_01617346211029656 – Supplemental material for Diagnostic Performance of Muscle Echo Intensity and Fractal Dimension for the Detection of Frailty Phenotype

Supplemental material, sj-docx-1-uix-10.1177_01617346211029656 for Diagnostic Performance of Muscle Echo Intensity and Fractal Dimension for the Detection of Frailty Phenotype by Rebeca Mirón Mombiela, Jelena Vucetic, Paloma Monllor, Jenny S. Cárdenas-Herrán, Paloma Taltavull de La Paz and Consuelo Borrás in Ultrasonic Imaging

Los descendientes de centenarios como modelo de envejecimiento saludable

Direct antioxidant and protective effect of estradiol on isolated mitochondria

AbstractEstrogens have antioxidant properties which are due to their ability to bind to estrogen receptors and to up-regulate the expression of antioxidant enzymes via intracellular signalling pathways. Mitochondria are key organelles in the development of age-associated cellular damage. Recently, estrogen receptors were identified in mitochondria. The aim of this paper was to test whether estradiol directly affects mitochondria by preventing oxidative stress and protecting frail mitochondria. Incubation with estradiol at normal intracellular concentrations prevents the formation of reactive oxygen species by mitochondria in a saturable manner. Moreover, estradiol protects mitochondrial int…

Mitochondrial biogenesis in exercise and in ageing☆

Mitochondrial biogenesis is critical for the normal function of cells. It is well known that mitochondria are produced and eventually after normal functioning they are degraded. Thus, the actual level of mitochondria in cells is dependent both on the synthesis and the degradation. Ever since the proposal of the mitochondrial theory of ageing by Jaime Miquel in the 70's, it was appreciated that mitochondria, which are both a target and a source of radicals in cells, are most important organelles to understand ageing. Thus, a common feature between cell physiology of ageing and exercise is that in both situations mitochondria are critical for normal cell functioning. Mitochondrial synthesis i…

Ultrasonic Echo Intensity as a New Noninvasive In Vivo Biomarker of Frailty

Objectives To investigate whether muscle quality based on echo intensity (EI) is associated with muscle strength (MS) and correlates with risk of frailty in elderly outpatients. Design Cross-sectional, experimental study. Setting Outpatient clinic. Participants Individuals aged 20 to 90 (N = 112). Individuals aged 20 to 59 participated as controls. Those aged 60 and older participated in the experimental group and were subdivided into robust, prefrail, and frail according to the Fried frailty criteria. Measurements EI, muscle thickness (MT), and subcutaneous fat thickness (SFT) of the anterior compartment of the thigh were measured using ultrasound images. MS was quantified using a hand dyn…

Efecto antioxidante e hipolipemiante del pimentón ahumado en individuos sanos Antioxidant and hypolipidaemic effect of smoked paprika in healthy subjects

The healthy properties and antioxidant activity of smoked paprika in healthy male non-smoking students (age 20.6 ± 1.7 years), from Universidad de Extremadura (Spain), who consumed (2 g/day, 20 times, over 30 days) smoked (La Vera, Extremadura, Spain) or non-smoked (Novelda, Alicante, Spain) paprika were investigated. Anthropometric and cardiovascular measurements and blood and urine samples were taken from overnight fasted subjects for biochemical, hematological, and immunological measurements. The ingestion of smoked paprika increased the urinary excretion of 1-hydroxypyrene (from 38.6 ± 24.9 to 109.2 ± 85.6 nmol/mol; p < 0.05). Plasma triglyceride and total cholesterol levels were signif…

Adverse cutaneous reactions associated with the newest antiretroviral drugs in patients with human immunodeficiency virus infection.

HIV-infected patients have a higher risk of developing cutaneous reactions than the general population, which has a significant impact on patients' current and future care options. The severity of cutaneous adverse reactions varies greatly, and some may be difficult to manage. HIV-infected patients just at the beginning of antiretroviral treatment can frequently show a wide variety of adverse drug effects such as drug rashes, hyperpigmentation, hair loss, hypersensitivity reactions, injection site reaction, urticarial reaction, erythema multiforme, toxic epidermal necrolysis or Stevens-Johnson syndrome. The early detection and treatment of cutaneous adverse drug reactions, plus identificati…

Mitochondrial complex I impairment in leukocytes from type 2 diabetic patients.

Diabetes is associated with oxidative stress. This study evaluated the rates of oxidative stress and mitochondrial impairment in type 2 diabetes patients. The study population consisted of 182 diabetic patients and 50 body-composition- and age-matched controls. We assessed anthropometric and metabolic parameters and mitochondrial function by evaluating mitochondrial oxygen (O2) consumption, reactive oxygen species (ROS) production, glutathione (GSH) levels, GSH/GSSG ratio, mitochondrial membrane potential, and mitochondrial complex I activity in polymorphonuclear cells from diabetes type 2 patients. We found an increase in waist circumference and augmented serum levels of triglycerides, pro…

Sex Differences in Mitochondrial Antioxidant Gene Expression

Females live longer than males. This could be in part due to the higher levels of estrogens in females, which protect them against aging. Physiological concentrations of estrogens have antioxidant effects as they induce the expression of manganese superoxide dismutase and glutathione peroxidase by stimulating estrogen receptors and the mitogen-activated protein kinase and nuclear factor kappa B pathways. However, estrogens can have undesirable effects such as they are feminizing to males, so other alternatives need to be searched. Phytoestrogens are good candidates as they can also bind to estrogens receptors, and in fact, they are able to mimic the antioxidant properties of estrogens. It i…

Role of NAD+/NADH redox ratio in cell metabolism

Upregulation of microRNAs by centenarians

Pharmacological properties of physical exercise in the elderly.

Scientific evidence links physical activity to several benefits. Recently, we proposed the idea that exercise can be regarded as a drug. As with many drugs, dosage is of great importance. However, to issue a public recommendation of physical activity in aging is not an easy task. Exercise in the elderly needs to be carefully tailored and individualized with the specific objectives of the person or group in mind. The beneficial effects of exercise in two of the main age-related diseases, sarcopenia and Alzheimer's Disease, are dealt with at the beginning of this report. Subsequently, dosage of exercise and the molecular signaling pathways involved in its adaptations are discussed. Exercise a…

Validación de la carbonilación proteica como biomarcador de fragilidad

Extracellular Vesicles from Healthy Cells Improves Cell Function and Stemness in Premature Senescent Stem Cells by miR-302b and HIF-1α Activation.

Aging is accompanied by the accumulation of senescent cells that alter intercellular communication, thereby impairing tissue homeostasis and reducing organ regenerative potential. Recently, the administration of mesenchymal stem cells (MSC)-derived extracellular vesicles has proven to be more effective and less challenging than current stem cell-based therapies. Extracellular vesicles (EVs) contain a cell-specific cargo of proteins, lipids and nucleic acids that are released and taken up by probably all cell types, thereby inducing functional changes via the horizontal transfer of their cargo. Here, we describe the beneficial properties of extracellular vesicles derived from non-senescent M…

Bcl-xL as a Modulator of Senescence and Aging

Many features of aging result from the incapacity of cells to adapt to stress conditions. When cells are overwhelmed by stress, they can undergo senescence to avoid unrestricted growth of damaged cells. Recent findings have proven that cellular senescence is more than that. A specific grade of senescence promotes embryo development, tissue remodeling and wound healing. However, constant stresses and a weakening immune system can lead to senescence chronicity with aging. The accumulation of senescent cells is directly related to tissue dysfunction and age-related pathologies. Centenarians, the most aged individuals, should accumulate senescent cells and suffer from their deleterious effects,…

Therapeutic Potential of Extracellular Vesicles in Aging and Age-Related Diseases

Aging is associated with an alteration of intercellular communication. These changes in the extracellular environment contribute to the aging phenotype and have been linked to different aging-related diseases. Extracellular vesicles (EVs) are factors that mediate the transmission of signaling molecules between cells. In the aging field, these EVs have been shown to regulate important aging processes, such as oxidative stress or senescence, both in vivo and in vitro. EVs from healthy cells, particularly those coming from stem cells (SCs), have been described as potential effectors of the regenerative potential of SCs. Many studies with different animal models have shown promising results in …

Mitochondria and Ageing

Mitochondria are the major sites of oxygen utilisation for energy production in cells. Indeed, all the reactions of the Krebs’ Cycle take place in mitochondria and they produce NADH and succinate, which are then oxidised in the respiratory chain. Experiments dating back to the early part of the twentieth century seemed to indicate that at a high rate of oxygen consumption (referred to gram of body weight) was normally associated with a low maximum lifespan. Thus, it was thought that it was the rate of oxygen utilisation that was related to “the rate of living”. However, more recent data pointed out that birds are unique because they combine high rates of oxygen consumption with a high maxim…

Reductive stress in pathophysiology

Oxidative stress, as defined by Sies more than thirty years ago, has received much attention and has served as an important intellectual tool to understand the pathophysiology of many diseases and also of normal processes like ageing. However, recently the idea that the cells might suffer from reductive rather than oxidative stress and that such stress may be relevant in pathophysiology has gained momentum. Some time ago we defined reductive stress as a “as a pathophysiological situation in which the cell becomes more reduced than in the normal, resting state”. We postulated that reductive stress might be due, at least in part to a “small but persistent generation of oxidants that results i…

Centenarians maintain miRNA biogenesis pathway while it is impaired in octogenarians.

Centenarians but not octogenarians up regulate the expression of miRNAs, as we previously reported. We have looked into miRNA biogenesis. We show that RNA POL II, DROSHA, EXPORTIN 5 and DICER, are up-regulated in centenarians compared with octogenarians. Furthermore, factors involved in the control of these miRNAs biogenesis genes are also up-regulated in centenarians. Therefore, the up-regulation of miRNA expression in centenarians can be explained in part because miRNA biogenesis pathway is depressed in octogenarians (ordinary aging) while it is maintained in centenarians (extraordinary aging).

Role of mitochondrial oxidative stress to explain the different longevity between genders. Protective effect of estrogens

Females live longer than males. Work from our laboratory has shown that this may be due to the up-regulation of longevity-associated genes by estrogens. Estrogens bind to the estrogen receptors and subsequently activate the mitogen activated protein kinase and nuclear factor kappa B signalling pathways, resulting in an up-regulation of antioxidant enzymes. Estrogen administration, however, has serious undesirable effects and of course, cannot be administered to males because of its powerful feminizing effects. Thus, we tested the effect of genistein, a phytoestrogen of high nutritional importance whose structure is similar to estradiol, on the regulation of the expression of antioxidant, lo…

Identificación de polimorfismos de nucleótido simple en centenarios

Resumen Introduccion La longevidad viene determinada por la genetica propia de cada especie y por factores externos, tales como nutricionales, ambientales, sociales, etc. Sin embargo, los individuos mas longevos se caracterizan por presentar una mayor adaptacion al entorno condicionada predominantemente por su propia genetica. Dentro de una misma poblacion con relativa homogeneidad genotipica, podemos encontrar cambios sutiles en la secuencia de ADN que afectan unicamente a un nucleotido. Estos cambios denominados polimorfismos de nucleotido simple ( Single Nucleotide Polimorphisim [SNP]) se encuentran con una prevalencia mayor al 1-5% de la poblacion. Por ello, nos planteamos estudiar en i…

Delayed ageing through damage protection by the Arf/p53 pathway.

The tumour-suppressor pathway formed by the alternative reading frame protein of the Cdkn2a locus (Arf) and by p53 (also called Trp53) plays a central part in the detection and elimination of cellular damage, and this constitutes the basis of its potent cancer protection activity. Similar to cancer, ageing also results from the accumulation of damage and, therefore, we have reasoned that Arf/p53 could have anti-ageing activity by alleviating the load of age-associated damage. Here we show that genetically manipulated mice with increased, but otherwise normally regulated, levels of Arf and p53 present strong cancer resistance and have decreased levels of ageing-associated damage. These obser…

Oral administration of vitamin C decreases muscle mitochondrial biogenesis and hampers training-induced adaptations in endurance performance

Background Exercise practitioners often take vitamin C supplements because intense muscular contractile activity can result in oxidative stress, as indicated by altered muscle and blood glutathione concentrations and increases in protein, DNA, and lipid peroxidation. There is, however, considerable debate regarding the beneficial health effects of vitamin C supplementation. Objective This study was designed to study the effect of vitamin C on training efficiency in rats and in humans. Design The human study was double-blind and randomized. Fourteen men (27-36 y old) were trained for 8 wk. Five of the men were supplemented daily with an oral dose of 1 g vitamin C. In the animal study, 24 mal…

Drosophila melanogaster overexpression FAS live longer

FAS and FAS ligand is critical in the control of the extension of extrinsic pathway of apoptosis. In previous studies we have performed transcriptomics peripheral blood cells from centenarians, octogenarians and young persons and we found over expression in centenarians of the FAS receptor. To confirm the role of FAS ligand in longevity across animal species, we have generated Drosophila melanogaster that over expresses this gene using the GAL4-UAS technique. The results show that flies overexpressing FAS increase maximal longevity in twelve percent and average longevity in six percent. Therefore, we confirm that FAS is related to longevity flight.

A Stress-Resistant Lipidomic Signature Confers Extreme Longevity to Humans.

Plasma lipidomic profile is species specific and an optimized feature associated with animal longevity. In the present work, the use of mass spectrometry technologies allowed us to determine the plasma lipidomic profile and the fatty acid pattern of healthy humans with exceptional longevity. Here, we show that it is possible to define a lipidomic signature only using 20 lipid species to discriminate adult, aged and centenarian subjects obtaining an almost perfect accuracy (90%-100%). Furthermore, we propose specific lipid species belonging to ceramides, widely involved in cell-stress response, as biomarkers of extreme human longevity. In addition, we also show that extreme longevity present…

Extracellular vesicles and redox modulation in aging

Extracellular vesicles (EVs) are nowadays known to be mediators of cell-to-cell communication involved in physiological and pathological processes. The current expectation is their use as specific biomarkers and therapeutic tools due to their inner characteristics. However, several investigations still need to be done before we can use them in the clinic. First, their categorization is still under debate, although an accurate classification of EVs subtypes should be based on physical characteristics, biochemical composition or condition description of the cell of origin. Second, EVs carry lipids, proteins and nucleic acids that can induce epigenetic modifications on target cells. These carg…

Exceptional human longevity is associated with a specific plasma phenotype of ether lipids

A lipid profile resistant to oxidative damage is an inherent trait associated with animal lifespan. However, there is a lack of lipidomic studies on human longevity. Here we use mass spectrometry based technologies to detect and quantify 137 ether lipids to define a phenotype of healthy humans with exceptional lifespan. Ether lipids were chosen because of their antioxidant properties and ability to modulate oxidative stress. Our results demonstrate that a specific ether lipid signature can be obtained to define the centenarian state. This profile comprises higher level of alkyl forms derived from phosphatidylcholine with shorter number of carbon atoms and double bonds; and decreased content…

Influence of different types of pulp treatment during isolation in the obtention of human dental pulp stem cells

Background: Different methods have been used in order to isolate dental pulp stem cells. The aim of this study was to study the effect of different types of pulp treatment during isolation, under 3% O 2 conditions, in the time needed and the efficacy for obtaining dental pulp stem cells. Material and Methods: One hundred and twenty dental pulps were used to isolate dental pulp stem cells treating the pulp tissue during isolation using 9 different methods, using digestive, disgregation, or mechanical agents, or combining them. The cells were positive for CD133, Oct4, Nestin, Stro-1, CD34 markers, and negative for the hematopoietic cell marker CD-45, thus confirming the presence of mesenchyma…

Free [NADH]/[NAD+] regulates sirtuin expression

Sirtuins are deacetylases involved in metabolic regulation and longevity. Our aim was to test the hypothesis that they are subjected to redox regulation by the [NADH]/[NAD(+)] ratio. We used NIH3T3 fibroblasts in culture, Drosophila fed with or without ethanol and exercising rats. In all three models an increase in [NADH]/[NAD(+)] came up with an increased expression of sirtuin mRNA and protein. PGC-1α (a substrate of sirtuins) protein level was significantly increased in fibroblasts incubated with lactate and pyruvate but this effect was lost in fibroblasts obtained from sirtuin-deficient mice. We conclude that the expression of sirtuins is subject to tight redox regulation by the [NADH]/[…

Part of the Series: From Dietary Antioxidants to Regulators in Cellular Signalling and Gene ExpressionRole of reactive oxygen species and (phyto)oestrogens in the modulation of adaptive response to stress

There is increasing evidence that reactive oxygen species (ROS) are not only toxic but play an important role in cellular signalling and in the regulation of gene expression. We, here, discuss two examples of improved adaptive response to an altered cellular redox state. First, differences in longevity between males and females may be explained by a higher expression of antioxidant enzymes in females resulting in a lower yield of mitochondrial ROS. Oestrogens are made responsible for these phenomena. Oestradiol induces glutathione peroxidase-1 and MnSOD by processes requiring the cell surface oestrogen receptor (ER) and the activation of pathways usually involved in oxidative stress respons…

Human exceptional longevity: transcriptome from centenarians is distinct from septuagenarians and reveals a role of Bcl-xL in successful aging.

24 páginas, 7 figuras. Borras C, et al. Human exceptional longevity: transcriptome from centenarians is distinct from septuagenarians and reveals a role of Bcl-xL in successful aging. Aging (Albany NY). 2016 Oct 28;8(12):3185-3208. doi: 10.18632/aging.101078.

The mechanism of the antioxidant effect of smoked paprika from La Vera, Spain

This study aimed at further investigating the antioxidant effect of smoked paprika (Pimenton La Vera, Spain) in healthy subjects. Crossover study included male students (age 20.6 ± 1.7 years) who consumed smoked or non-smoked paprika (2 g/day, 20 times, over 30 days). After ingestion of smoked paprika, plasma malondialdehyde (MDA) levels were significantly (p < 0.01) reduced versus basal and non-smoked paprika ingestion values. Reduced glutathione (GSH) levels were increased and oxidised glutathione (GSSG) levels reduced significantly (p < 0.05) in paired subjects after consumption of smoked paprika. Smoked paprika significantly increased mRNA levels of glutathione peroxidase and cytochrome…

The dual role of p53: DNA protection and antioxidant.

The classical functions of p53 protein are those related to its role on DNA damage, cell growth arrest, senescence and apoptosis. For this reason it is called 'the guardian of the genome' and is considered one of the most important players in the development of cancer. However, more recently it has been show that p53 is not only involved in cancer, but also in ageing. p53 is stimulated by stress, which in turn results in the activation of a wide range of transcriptional targets. Low-intensity stress will activate p53 in a manner which results in antioxidant response, thus protecting against ageing because of its antioxidant function. On the contrary, high-intensity activation of p53 will re…

Effect of gender on mitochondrial toxicity of Alzheimer's Abeta peptide.

The aim of this article is to review the role of mitochondria in the pathogenesis of Alzheimer's disease. Additionally, the effect of gender on the incidence of Alzheimer's disease and the pathophysiological mechanisms involved will be discussed. Mitochondria, in the presence of Alzheimer's amyloid-beta peptide, increase the formation of reactive oxygen species which act both as damaging agents and also as signaling molecules. These radicals, in fact, unleash a mechanism involving the liberation of cytochrome c that leads to neuronal apoptosis. Notably, young females appear protected against the mitochondrial toxicity of amyloid-beta, likely due to the upregulation of antioxidant enzymes wh…

The Free Radical Theory of Aging Revisited: The Cell Signaling Disruption Theory of Aging

AbstractSignificance: The free radical theory of aging has provided a theoretical framework for an enormous amount of work leading to significant advances in our understanding of aging. Up to the turn of the century, the theory received abundant support from observations coming from fields as far apart as comparative physiology or molecular biology. Recent Advances: Work from many laboratories supports the theory, for instance showing that overexpression of antioxidant enzymes results in increases in life-span. But other labs have shown that in some cases, there is an increased oxidative stress and increased longevity. The discovery that free radicals can not only cause molecular damage to …

SOX2 expression diminishes with ageing in several tissues in mice and humans.

SOX2 (Sex-determining region Y box 2) is a transcription factor expressed in several foetal and adult tissues and its deregulated activity has been linked to chronic diseases associated with ageing. Nevertheless, the level of SOX2 expression in aged individuals at the tissue level has not previously been examined. In this work, we show that SOX2 expression decreases significantly in the brain with ageing, in both humans and rodents. The administration of resveratrol for 6 months in mice partly attenuated this reduction. We also identified an age-related decline in SOX2 mRNA and protein expression in several other organs, namely, the lung, heart, kidney, spleen and liver. Moreover, periphera…

Age-dependent changes in the transcription profile of long-lived Drosophila over-expressing glutamate cysteine ligase

Abstract In our prior studies ( Orr et al., 2005 ) we achieved a 30–50% increase in the life span of Drosophila by manipulating glutathione (GSH) production in neuronal tissues, through over-expression of glutamate-cysteine ligase (GCL), a key enzyme in glutathione biosynthesis. In the present study, we identified gene response patterns from which plausible mechanisms responsible for the observed effects on life span might be inferred. Functional clustering analysis of the transcriptome data revealed that biological processes affected by GCLc in young flies (10 days) were generally related to cell morphogenesis and differentiation, while those in older flies were associated with nucleosome …

Cellusim: Un simulador 3D en entorno videojuego para la docencia del laboratorio de cultivos celulares

[EN] Cell cultures allow the maintenance of living cells outside the body. This technique is fundamental to study the biological, biochemical and physiological properties of cells and can be used as an experimental model in vitro in the field of biomedical research. The teaching in the laboratory of this technique presents numerous difficulties at a practical, logistical and economic level. On the other hand, the learning of cell culture protocols is an important part of the student's training in Cell Biology. Based on the routine practices carried out within a cell culture laboratory, we have developed the virtual 3D simulator of a cell culture laboratory "Cellusim". In "Cellusim" you can …

Resveratrol shifts energy metabolism to increase lipid oxidation in healthy old mice.

Abstract Objectives The objective of this work was to determine the specific mechanisms by which resveratrol inhibits lipogenesis and stimulates lipolysis. Methods Twelve male mice were individually introduced into a metabolic cage for 24 h to measure basal metabolic rate, prior to intervention. They were randomly divided into two groups, resveratrol (RSV) and control (C), and administered resveratrol intraperitoneally or vehicle, respectively, for two consecutive days. After 24 h, the metabolic energy expenditure was again determined for 24 h, before mice were sacrificed. Protein and gene expression of different enzymes related to metabolism in the hepatic tissue, adipose tissue and gastro…

Females Live Longer than Males: Role of Oxidative Stress

One of the most significant achievements of the twentieth century is the increase in human lifespan. In any period studied, females live longer than males. We showed that mitochondrial oxidative stress is higher in males than females and that the higher levels of estrogens in females protect them against ageing, by up-regulating the expression of antioxidant, longevity-related genes. The chemical structure of estradiol confers antioxidant properties to the molecule. However, the low concentration of estrogens in females makes it unlikely that they exhibit significant antioxidant capacity in the organism. Therefore we studied the mechanisms enabling estradiol to be antioxidant at physiologic…

The importance of culturing primary cells under physiological conditions: proliferation, senescence, pluripotency

Mesenchymal stem cells (MSCs), such as human dental pulp stem cells (hDPSCs), are currently a source for cell therapy. However, cell therapy protocols require 10–400 million cells per treatment, and consequently, they need to be expanded in vitro before implantation, with the inconvenience that MSCs undergo senescence following a certain number of cell expansion passages, loosing their stem cell qualities. Ambient oxygen tension (21% pO2) is normally used for in vitro culture, but physiological levels in vivo range between 3% and 6% pO2. We previously demonstrated that hDPSC proliferation rate is significantly lowered at 21% pO2 due to enhanced oxidative stress, which led to the activation …

Molecular mechanisms involved in the hormonal prevention of aging in the rat.

Previous data from our group have provided support for the role of GH, melatonin and estrogens in the prevention of aging of several physiological parameters from bone, liver metabolism, vascular activity, the central nervous system (CNS), the immune system and the skin. In the present work data on the molecular mechanisms involved are presented. A total of 140 male and female rats have been submitted to different treatments over 10 weeks, between 22 and 24 months of age. Males have been treated with GH and melatonin. Females were divided in two groups: intact and castrated at 12 months of age. The first group was treated with GH and melatonin and the second with the two latter compounds an…

Application of mesenchymal stem cells in bone regenerative procedures in oral implantology. A literature review

Objective: The aim of this work was to review de literature about the role of mesenchymal stem cells in bone regenerative procedures in oral implantology, specifically, in the time require to promote bone regeneration. Study Design: A bibliographic search was carried out in PUBMED with a combination of different key words. Animal and human studies that assessed histomorphometrically the influence of mesenchymal stem cells on bone regeneration procedures in oral implantology surgeries were examined. Reults: - Alveolar regeneration: Different controlled histomorphometric animal studies showed that bone regeneration is faster using stem cells seeded in scaffolds than using scaffolds or platele…

Centenarians: An excellent example of resilience for successful ageing.

Centenarians are remarkable not only because of their prolonged life, but also because they compress morbidity until the very last moments of their lives, thus being proposed as a model of successful, extraordinary ageing. From the medical viewpoint, centenarians do not escape the physiological decline or the age-related diseases or syndromes (i.e. frailty), but the rate of such processes is slow enough to be counterbalanced by their increased intrinsic capacity to respond to minor stresses of daily life (i.e. resilience). These new concepts are reviewed in this paper. Allostatic stresses lead to a chronic low-grade inflammation that has led to the proposal of the "inflammaging" theory of a…

Redox lipidomics to better understand brain aging and function

Human prefrontal cortex (PFC) is a recently evolutionary emerged brain region involved in cognitive functions. Human cognitive abilities decline during aging. Yet the molecular mechanisms that sustain the preservation or deterioration of neurons and PFC functions are unknown. In this review, we focus on the role of lipids in human PFC aging. As the evolution of brain lipid concentrations is particularly accelerated in the human PFC, conferring a specific lipid profile, a brief approach to the lipidome of PFC was consider along with the relationship between lipids and lipoxidative damage, and the role of lipids in human PFC aging. In addition, the specific targets of lipoxidative damage in h…

Role of the aryl hydrocarbon receptor (AhR) signaling pathway in exceptional longevity in humans

Centenarians are the best example of successfully aging in humans. Thus, the characterization of the biological processes and pathways in this population is an excellent strategy to understand the lifespan extension. The aryl hydrocarbon receptor (AhR) is a ligand-activated-transcription factor historically known for regulating expression of several important drug-detoxifying proteins. But recently its role in the immune response and in cellular homeostasis has been recognized. Furthermore, AhR is activated in C. Elegans in extreme longevity due to a dietary restriction. We report here results of a whole transcriptome analysis of centenarians. The main biological process was the immune resp…

Mitochondria as sources and targets of damage in cellular aging.

Mitochondria are considered as the most important cellular sources and targets of free radicals. They are also a source of signalling molecules that regulate cell cycle, proliferation, and apoptosis. Denham Harman postulated the free radical theory of aging in 1956. Previously Rebecca Gershman showed that radiation toxicity could be attributed to free radical damage. Subsequently, Jaime Miquel formulated the mitochondrial free radical theory of aging. We have shown that mitochondrial size, membrane potential, inner membrane mass and peroxide production is altered inside cells in old animals. These result in an increase in the oxidative damage to mitochondrial DNA with aging that can be prev…

Estrogenic Modulation of Longevity by Induction of Antioxidant Enzymes

In many species including humans, females live longer than males. We and others have observed that mitochondria from females of Wistar rats and of OF1 mice produce half the amount of peroxide produced by males. We attributed this to a change in the expression of antioxidant, longevity-related genes. We have found that in those species in which females live longer than males, estrogens activate longevity-related genes, particularly antioxidant ones. It should be emphasized that estrogens do not act as antioxidants because of their phenolic ring but rather they act indirectly; that is, they behave as hormones and bind to estrogen receptors, which eventually leads to the upregulation of the ex…

Garcinoic acid prevents β-amyloid (Aβ) deposition in the mouse brain

Garcinoic acid (GA or δ-T3-13'COOH), is a natural vitamin E metabolite that has preliminarily been identified as a modulator of nuclear receptors involved in β-amyloid (Aβ) metabolism and progression of Alzheimer's disease (AD). In this study, we investigated GA's effects on Aβ oligomer formation and deposition. Specifically, we compared them with those of other vitamin E analogs and the soy isoflavone genistein, a natural agonist of peroxisome proliferator–activated receptor γ (PPARγ) that has therapeutic potential for managing AD. GA significantly reduced Aβ aggregation and accumulation in mouse cortical astrocytes. Similarly to genistein, GA up-regulated PPARγ expression and apolipoprote…

CENTENARIANS TRANSCRIPTOME IS UNIQUE AND REVEALS A ROLE OF BCL-XL IN SUCCESSFUL AGING

Centenarians not only enjoy an extraordinary aging, but also show a compression of morbidity. We identified 1721 mRNAs differentially expressed by PMBCs from centenarians when compared with septuagenarians and young people. Sub-network analysis led us to identify Bcl-xL as an important gene up-regulated in centenarians. We found that centenarians display lower plasma cytochrome C levels, higher mitochondrial membrane potential and also less cellular damage accumulation. Immune function is significantly impaired in septuagenarians compared with young people whereas centenarians maintain it. To further ascertain the functional role of Bcl-xL in cellular aging, we found in transduced lymphocyt…

The Challenge of Unlocking the Biological Secrets of Aging.

Oxidative stress is related to frailty, not to age or sex, in a geriatric population

Age-associated frailty is a geriatric syndrome. Frail individuals are vulnerable and lack capacity to manage external stressors. Frailty is associated with oxidative stress, but it has not been addressed in a large controlled human cohort. We aimed to ascertain whether indicators of oxidative damage to lipids and proteins are biomarkers of frailty, after adjusting for age, sex, and other possible confounders. We measured lipid and protein oxidation in the Toledo Study for Healthy Aging participants (N=742, aged 65–95), classified as frail, prefrail and nonfrail according to the Fried criteria. We found that age- and sex-adjusted levels of MDA and protein carbonylation in plasma proved to be…

Small extracellular vesicles from young adipose-derived stem cells prevent frailty, improve health span, and decrease epigenetic age in old mice.

Aging is associated with an increased risk of frailty, disability, and mortality. Strategies to delay the degenerative changes associated with aging and frailty are particularly interesting. We treated old animals with small extracellular vesicles (sEVs) derived from adipose mesenchymal stem cells (ADSCs) of young animals, and we found an improvement in several parameters usually altered with aging, such as motor coordination, grip strength, fatigue resistance, fur regeneration, and renal function, as well as an important decrease in frailty. ADSC-sEVs induced proregenerative effects and a decrease in oxidative stress, inflammation, and senescence markers in muscle and kidney. Moreover, pre…

Overweight, Obesity, and All-Cause Mortality

Dr Flegal and colleagues1 concluded that grade 1 obesity was not associated with higher all-cause mortality and that overweight was associated with significantly lower all-cause mortality. Other studies have shown that obesity in different populations, such as elderly people and patients with cardiovascular diseases, is also paradoxically not associated with a higher but rather with a lower mortality risk.2 This has been termed the obesity paradox

Clearing Amyloid-β through PPARγ/ApoE Activation by Genistein is a Treatment of Experimental Alzheimer’s Disease

Amyloid-b (Ab) clearance from brain, which is decreased in Alzheimer's disease, is facilitated by apolipoprotein E (ApoE). ApoE is upregulated by activation of the retinoid X receptor moiety of the RXR/PPAR dimeric receptor. As we have previously demonstrated, estrogenic compounds, such as genistein, have antioxidant activity, which can be evidenced by increased expression of manganese superoxide dismutase (MnSOD). Furthermore, genistein is a non-toxic, well-tested, and inexpensive drug that activates PPARg receptor. We isolated and cultured cortical astrocytes from dissected cerebral cortices of neonatal mice (C57BL/6 J). Preincubation with genistein (5 mM) for 24 hours, prior to the addit…

El envejecimiento y la ovariectomía causan una disminución del consumo cerebral de glucosa in vivo en ratas Wistar

Resumen Introduccion La esperanza de vida de la poblacion ha ido incrementandose en el siglo xx en ambos sexos. La supervivencia de las mujeres ha sido siempre mayor respecto a los hombres, aunque estas diferencias de longevidad se reproducen en otras especies animales, como las ratas. Debe existir alguna base biologica que sustente dichas diferencias entre sexos, las cuales pueden ser explicadas por la accion de los estrogenos, ya que la ovariectomia (OVX) anula las ventajas en el sexo femenino asemejandolo al masculino. Objetivos Nuestros objetivos fueron estudiar el consumo cerebral de glucosa in vivo en ratas hembras Wistar jovenes y viejas (V), ademas de evaluar el efecto de la OVX sob…