Role of p16ink4a and bmi-1 in oxidative stress-induced premature senescence in human dental pulp stem cells
Las células madre son aquellas células que se dividen asimétricamente para producir una copia de sí mismas y una segunda célula que seguirá su camino hasta convertirse en una célula diferenciada y especializada. Así pues, las células madre que podemos encontrar en el organismo adulto comparten al menos dos características. En primer lugar, se pueden hacer copias idénticas de sí mismas durante largos períodos de tiempo; esta capacidad de proliferar se refiere como auto-renovación a largo plazo. Segundo, pueden dar lugar a tipos celulares maduros que tienen morfologías características y funciones especializadas. Las células madre mesenquimales humanas (CMM) tienen pues un potencial terapéutic…
Recent Approaches to Determine Static and Dynamic Redox State-Related Parameters
Oxidative stress refers to an imbalance between oxidant and antioxidant molecules, which is usually associated with oxidative damage to biomolecules and mitochondrial malfunction. Redox state-related parameters include (1) the direct measurement of ROS, (2) the assessment of the antioxidant defense status, and (3) the analysis of the resulting oxidative damage to molecules. Directly measuring ROS appears to be the preferred method among scientists, but most ROS are extremely unstable and difficult to measure. The processes of determining both the oxidative damage to biomolecules and the antioxidant system status, although both are indirect approaches, provide a reliable method to measure ox…
Relevance of Oxygen Concentration in Stem Cell Culture for Regenerative Medicine
The key hallmark of stem cells is their ability to self-renew while keeping a differentiation potential. Intrinsic and extrinsic cell factors may contribute to a decline in these stem cell properties, and this is of the most importance when culturing them. One of these factors is oxygen concentration, which has been closely linked to the maintenance of stemness. The widely used environmental 21% O2 concentration represents a hyperoxic non-physiological condition, which can impair stem cell behaviour by many mechanisms. The goal of this review is to understand these mechanisms underlying the oxygen signalling pathways and their negatively-associated consequences. This may provide a rationale…
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…
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…
Sex Differences in Age-Associated Type 2 Diabetes in Rats—Role of Estrogens and Oxidative Stress
Females live longer than males, and the estrogens are one of the reasons for this difference. We reported some years ago that estrogens are able to protect rats against oxidative stress, by inducing antioxidant genes. Type 2 diabetes is an age-associated disease in which oxidative stress is involved, and moreover, some studies show that the prevalence is higher in men than in women, and therefore there are sex-associated differences. Thus, the aim of this study was to evaluate the role of estrogens in protecting against oxidative stress in type 2 diabetic males and females. For this purpose, we used Goto-Kakizaki rats, which develop type 2 diabetes with age. We found that female diabetic ra…
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 …
Centenarians Overexpress Pluripotency-Related Genes.
Abstract Human mesenchymal cells can become pluripotent by the addition of Yamanaka factors OCT3/4, SOX2, c-MYC, KLF4. We have recently reported that centenarians overexpress BCL-xL, which has been shown to improve pluripotency; thus, we aimed to determine the expression of pluripotency-related genes in centenarians. We recruited 22 young, 32 octogenarian, and 47 centenarian individuals and determined the mRNA expression of Yamanaka factors and other stemness-related cell surface marker genes (VIM, BMP4, NCAM, BMPR2) in peripheral blood mononuclear cells by reverse transcription polymerase chain reaction. We found that centenarians overexpress OCT3/4, SOX2, c-MYC, VIM, BMP4, NCAM, and BMPR2…
Donkey Fascioliasis Within a One Health Control Action: Transmission Capacity, Field Epidemiology, and Reservoir Role in a Human Hyperendemic Area.
A One Health initiative has been implemented for fascioliasis control in a human hyperendemic area for the first time. The area selected for this multidisciplinary approach is the Northern Bolivian Altiplano, where the highest prevalences and intensities in humans have been reported. Within the strategic intervention axis of control activities concerning animal reservoirs, complete experimental studies, and field surveys have been performed to assess the fascioliasis transmission capacity and epidemiological role of the donkey for the first time. Laboratory studies with altiplanic donkey-infecting Fasciola hepatica and altiplanic Galba truncatula snail vector isolates demonstrate that the d…
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…
Small extracellular vesicles from young mice prevent frailty, improve healthspan and decrease epigenetic age in old mice
SummaryAging is associated with an increased risk of frailty, disability, comorbidities, institutionalization, falls, fractures, hospitalization, and mortality. Searching for strategies to delay the degenerative changes associated with aging and frailty is interesting. We treated old animals intravenously with small extracellular vesicles (sEVs) derived from adipose mesenchymal stem cells (ADSCs) of young animals, and we found an improvement of several functional parameters usually altered with aging, such as motor coordination, grip strength, fatigue resistance, fur regeneration, and renal function. Frailty index analysis showed that 40% of old control mice were frail, whereas none of the …
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 …
Relationship between diet, microbiota, and healthy aging
Este artículo se encuentra disponible en la siguiente URL: https://www.mdpi.com/2227-9059/8/8/287 Este artículo pertenece al número especial "Oxidative stress and inflammation: from mechanisms to therapeutic approaches". En este artículo también participan: Marta Inglés, Gloria Olaso, Juan Gambini y Cristina Mas-Bargues. Due to medical advances and lifestyle changes, population life expectancy has increased. For this reason, it is important to achieve healthy aging by reducing the risk factors causing damage and pathologies associated with age. Through nutrition, one of the pillars of health, we are able to modify these factors through modulation of the intestinal microbiota. The Mediterran…
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…
Role of p16INK4a and BMI-1 in oxidative stress-induced premature senescence in human dental pulp stem cells
Human dental pulp stem cells (hDPSCs) are a source for cell therapy. Before implantation, an in vitro expansion step is necessary, with the inconvenience that hDPSCs undergo senescence following a certain number of passages, loosing their stemness properties. Long-term in vitro culture of hDPSCs at 21% (ambient oxygen tension) compared with 3–6% oxygen tension (physiological oxygen tension) caused an oxidative stress-related premature senescence, as evidenced by increased β-galactosidase activity and increased lysil oxidase expression, which is mediated by p16INK4a pathway. Furthermore, hDPSCs cultured at 21% oxygen tension underwent a downregulation of OCT4, SOX2, KLF4 and c-MYC factors, w…
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.
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…
The Relationship between Diet and Frailty in Aging
The increase in lifespan in the 20th century entails an increase in the elderly population. This brings a new challenge for society, causing people to have physical and mental limitations caused by age-related diseases, such as frailty. Frailty is clinically characterized by multisystem pathophysiological processes, such as chronic inflammation, immune activation, dysregulation of the musculoskeletal and endocrine systems, oxidative stress, energy imbalances, mitochondrial dysfunction, and sarcopenia. The elderly should consume energy in amounts close to those in what is currently accepted as a balanced diet. However, an increase in protein intake may be recommended for elderly people as l…
BCL-xL, a Mitochondrial Protein Involved in Successful Aging: From C. elegans to Human Centenarians
B-Cell Lymphoma-extra-large (BCL-xL) is involved in longevity and successful aging, which indicates a role for BCL-xL in cell survival pathway regulation. Beyond its well described role as an inhibitor of apoptosis by preventing cytochrome c release, BCL-xL has also been related, indirectly, to autophagy and senescence pathways. Although in these latter cases, BCL-xL has dual roles, either activating or inhibiting, depending on the cell type and the specific conditions. Taken together, all these findings suggest a precise mechanism of action for BCL-xL, able to regulate the crosstalk between apoptosis, autophagy, and senescence, thus promoting cell survival or cell death. All three pathways…
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 …
Numerous Fasciola plasminogen-binding proteins may underlie blood-brain barrier leakage and explain neurological disorder complexity and heterogeneity in the acute and chronic phases of human fascioliasis
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Exploring New Kingdoms: The Role of Extracellular Vesicles in Oxi-Inflamm-Aging Related to Cardiorenal Syndrome
The incidence of age associated chronic diseases has increased in recent years. Although several diverse causes produce these phenomena, abundant evidence shows that oxidative stress plays a central role. In recent years, numerous studies have focused on elucidating the role of oxidative stress in the development and progression of both aging and chronic diseases, opening the door to the discovery of new underlying mechanisms and signaling pathways. Among them, senolytics and senomorphics, and extracellular vesicles offer new therapeutic strategies to slow the development of aging and its associated chronic diseases by decreasing oxidative stress. In this review, we aim to discuss the role …
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…
Lifelong soya consumption in males does not increase lifespan but increases health span under a metabolic stress such as type 2 diabetes mellitus.
Soya consumption can decrease oxidative stress in animal models. Moreover, phytoestrogens such as genistein, present in soya, can mimic some of the beneficial effects of estrogens and are devoid of significant side effects, such as cancer. In this study, we have performed a controlled lifelong study with male OF1 mice that consumed either a soya-free diet or a soya-rich diet. We show that, although we found an increase in the expression and activity of antioxidant enzymes in soya-consuming mice, it did not increase lifespan. We reasoned that the soya diet could not increase lifespan in a very healthy population, but perhaps it could extend health span in stressed animals such as type 2 diab…
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…
Identificación de polimorfismos de un solo nucleótido relacionados con la fragilidad
Resumen Introduccion La busqueda de biomarcadores que permitan la deteccion y el posible tratamiento precoz de la fragilidad se ha convertido en uno de los objetivos primordiales de la comunidad cientifica geriatrica. El objetivo del presente estudio fue identificar polimorfismos de un solo nucleotido ([SNP] del ingles single nucleotide polymorphisms) relacionados con la fragilidad. Material y metodos El estudio se llevo a cabo en 152 sujetos de la cohorte del Estudio de Toledo (de 65 a 95 anos de edad), clasificados como fragiles (n = 78), y no fragiles (n = 74), segun los criterios de Fried. Tras la extraccion de sangre se aislo y amplifico el ADN para el analisis de SNP mediante la tecno…
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…
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…
Protective Effects of Polyphenols Present in Mediterranean Diet on Endothelial Dysfunction
Endothelial dysfunction tends to be the initial indicator in proinflammatory state and macro- and microvascular complications, such as atherosclerosis and cardiovascular diseases. It has been shown that certain compounds in diet can generate beneficial effects on cardiovascular disease due to its interactions with endothelial cells. Thus, this review is aimed at investigating whether certain polyphenols present in the Mediterranean diet, specifically catechin, quercetin, resveratrol, and urolithin, could exert positive effects on endothelial dysfunction. After analysis of numerous papers, we found that polyphenols aiding endothelial function is beneficial not only for patients with cardiova…