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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, predicted epigenetic age was lower in tissues of old mice treated with ADSC-sEVs and their metabolome changed to a youth-like pattern. Last, we gained some insight into the microRNAs contained in sEVs that might be responsible for the observed effects. We propose that young sEV treatment can promote healthy aging.

A species-specific lipidome profile is an inherent feature linked to longevity in the animal kingdom. However, there is a lack of lipidomic studies on human longevity. Here we use mass spectrometry based lipidomics to detect and quantify 151 sphingolipid molecular species and use these to define a phenotype of healthy humans with exceptional lifespan. Our results demonstrate that this profile specifically comprises a higher content of complex glycosphingolipids (hexosylceramides and gangliosides), and lower levels of ceramide species from the de novo pathway, sphingomyelin and sulfatide; while for ceramide-derived signaling compounds, their content remains unchanged. Our findings suggest that structural glycosphingolipids may be more relevant to achieve the centenarian condition than signaling sphingolipids. © The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America.

Hypomorphic Glucose 6-P dehydrogenase (G6PD) alleles, which cause G6PD deficiency, affect around one in twenty people worldwide. The high incidence of G6PD deficiency may reflect an evolutionary adaptation to the widespread prevalence of malaria, as G6PD-deficient red blood cells (RBCs) are hostile to the malaria parasites that infect humans. Although medical interest in this enzyme deficiency has been mainly focused on RBCs, more recent evidence suggests that there are broader implications for G6PD deficiency in health, including in skeletal muscle diseases. G6PD catalyzes the rate-limiting step in the pentose phosphate pathway (PPP), which provides the precursors of nucleotide synthesis for DNA replication as well as reduced nicotinamide adenine dinucleotide phosphate (NADPH). NADPH is involved in the detoxification of cellular reactive oxygen species (ROS) and de novo lipid synthesis. An association between increased PPP activity and the stimulation of cell growth has been reported in different tissues including the skeletal muscle, liver, and kidney. PPP activity is increased in skeletal muscle during embryogenesis, denervation, ischemia, mechanical overload, the injection of myonecrotic agents, and physical exercise. In fact, the highest relative increase in the activity of skeletal muscle enzymes after one bout of exhaustive exercise is that of G6PD, suggesting that the activation of the PPP occurs in skeletal muscle to provide substrates for muscle repair. The age-associated loss in muscle mass and strength leads to a decrease in G6PD activity and protein content in skeletal muscle. G6PD overexpression in Drosophila Melanogaster and mice protects against metabolic stress, oxidative damage, and age-associated functional decline, and results in an extended median lifespan. This review discusses whether the well-known positive effects of exercise training in skeletal muscle are mediated through an increase in G6PD.

INTRODUCTION: D-Glucosamine (GlcN) is one of the most widely consumed dietary supplements and complementary medicines in the world and has been traditionally used to attenuate osteoarthritis in humans. GlcN extends lifespan in different animal models. In humans, its supplementation has been strongly associated with decreased total mortality and improved vascular endothelial function. GlcN acts as a suppressor of inflammation and by inhibiting glycolysis, it can activate the metabolism of stored fat and mitochondrial respiration. METHODS: The conventional human GlcN dose is 1,500 mg x day-1 but extensive evidence indicates that much higher doses are well tolerated. GlcN is one of the supplements that has experienced a greater use in the last years in elite athletes mainly due to its potential chondroprotective effects that may promote cartilage health. However, the possibility of it being an ergogenic aid has not been explored. We aimed to study the potential beneficial effects of GlcN on mitochondrial content, on physical performance and oxidative stress in mice that were aerobically trained and supplemented with three different doses of glucosamine (250, 500, and 1,000 mg x Kg-1) for six weeks. We measured exercise performance (grip strength, motor coordination and running capacity) before and after the training period. Proteins involved in mitochondrial biogenesis (AMPK, PGC-1, NRF-1, SIRT-1, cytochrome c, citrate synthase), markers of oxidative stress (GSSG/GSH) or damage (MDA, carbonylated proteins), antioxidant enzymes (NRF-2, SOD1, SOD2, Catalase and PRDX6) and MAPKs (p38 and ERK ) were also determined in skeletal muscle. RESULTS AND CONCLUSIONS: Our results show that GlcN supplementation in aerobically trained mice, at doses equivalent to those conventionally used in humans, increases the protein levels of mitochondrial biogenesis markers, improves motor coordination and may have a synergistic effect with exercise training on running distance.

Geroprotection is defined as protection from the adverse effects of aging. The need for geroprotection implies changes towards individually tailored interventions that preserve an individual's independence, physical function, and cognition. Genistein, a phytoestrogen obtained from soya, has been reported to have beneficial properties on age-related diseases such as neurodegenerative and cardiovascular diseases or cancer. Indeed, genistein is a multimodal agent: it acts as a cancer protective agent, promoting apoptosis and cell cycle arrest, and inhibiting angiogenesis and metastasis, but it also acts as an antioxidant, anti-inflammatory, and anti-amyloid-beta and autophagy promoter. Altogether, these properties make genistein a possible treatment for the specific aspects of age-related diseases such as hypertension, metabolic diseases, Alzheimer's disease, and osteoporosis. Copyright © 2022. Published by Elsevier B.V.

Background: Ketogenic dietary therapies (KDT) are used as a treatment in childhood epilepsy. However, their mechanism has not yet been established. The main objective of this study was to determine the changes in the transcriptomic profile induced by KDT in children with epilepsy in order to shed light on its possible mechanisms. Methods: Eight children with refractory epilepsy were enrolled in the study. Peripheral blood mononuclear cells were obtained before and after the children were treated with KDT for a minimum of 6 months. RNA was extracted and mRNA and miRNA profiling were performed and analyzed. Results: Our intervention with KDT significantly reduced the seizure number in seven of the eight paediatric patients treated and caused important changes in their gene expression profile. Our study reveals modifications in the transcription of 4630 genes and 230 miRNAs. We found that the genes involved in the protection against epileptic crises were among those mainly changed. These genes collectively encode for ion channels, neurotransmitter receptors, and synapse structural proteins. Conclusions: Together our results explain the possible mechanisms of KDT and reinforce its clinical importance in the treatment of epilepsy. © 2022 The Author(s). Published by IMR Press.

Genistein is a phytoestrogen that, due to its structural similarity with estrogen, can both mimic and antagonize estrogen effects. Early analysis proved that at high concentrations, genistein inhibits breast cancer cell proliferation, thereby suggesting an anticancer activity. Since then, many discoveries have identified the genistein mechanism of action, including cell cycle arrest, apoptosis induction, as well as angiogenesis, and metastasis inhibition. In this review, we aim to discuss the multimodal action of genistein as an antioxidant, anti-inflammatory, anti-amyloid beta, and autophagy promoter, which could be responsible for the genistein beneficial effect on Alzheimer's. Furthermore, we pinpoint the main signal transduction pathways that are known to be modulated by genistein. Genistein has thus several beneficial effects in several diseases, many of them associated with age, such as the above mentioned Alzheimer disease. Indeed, the beneficial effects of genistein for health promotion depend on each multimodality. In the context of geroscience, genistein has promising beneficial effects due to its multimodal action to treat age associated-diseases. Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Dementia and cognitive disorders are major aging-associated pathologies. The prevalence and severity of these conditions are influenced by both genetic and environmental factors. Reflecting this, epigenetic alterations have been associated with each of these processes, especially at the level of DNA methylation, and such changes may help explain the observed inter-individual variability in the development of the two pathologies. However, the importance of epigenetic alterations in explaining their aetiology is unclear because little is known about the timing of when they appear. Here, using Illumina MethylationEPIC arrays, we have longitudinally analysed the peripheral blood methylomes of cognitively healthy older adults (> 70 yr), some of whom went on to develop dementia while others stayed healthy. We have characterized 34 individuals at the pre-diagnosis stage and at a 4-year follow-up in the post-diagnosis stage (total n = 68). Our results show multiple DNA methylation alterations linked to dementia status, particularly at the level of differentially methylated regions. These loci are associated with several dementia-related genes, including PON1, AP2A2, MAGI2, POT1, ITGAX, PACSIN1, SLC2A8 and EIF4E. We also provide validation of the previously reported epigenetic alteration of HOXB6 and PM20D1. Importantly, we show that most of these regions are already altered in the pre-diagnosis stage of individuals who go on to develop dementia. In conclusion, our observations suggest that dementia-associated epigenetic patterns that have specific biological features are already present before diagnosis, and thus may be important in the design of epigenetic biomarkers for disease detection based on peripheral tissues. © The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Hyperhomocysteinemia is an independent predictor of the risk for cognitive decline and may be a result of low levels of vitamins B-12, B-6, and folate. Previous findings suggest that adequate intake of these vitamins may reduce homocysteine levels. This review aimed to assess the effects of treatment with vitamins B-6,B- B-12, and/or folic acid in the homocysteine levels in patients with mild cognitive impairment (MCI). A systematic literature review was conducted in EMBASE, MEDLINE (R), PsycINFO, and Cochrane Central Register of Controlled Trials. The research question was formulated using the Population, Intervention, Comparison, and Outcome (PICO) framework: in patients with MCI (P); what is the efficacy of vitamins B-6, B-12, and/or folic acid intake (I); compared with baseline values, and/or compared with controls (C); in reducing homocysteine levels from baseline (O). A total of eight primary studies with a total of 1,140 participants were included in the review. Four were randomized controlled trials, one was a quasi-controlled trial, and three were observational studies. All studies included folic acid in their intervention, seven vitamin B-12, and four vitamin B-6. Mean (SD) length of the intervention period was 18.8 (19.3) months, ranging from 1 to 60 months. All studies showed a statistically significant decrease in homocysteine levels in groups treated with vitamins B-6,B- B-12, and/or folic acid compared to controls, with a mean decline of homocysteine concentration of 31.9% in the intervention arms whereas it increased by 0.7% in the control arm. This review identified evidence of a reduction of plasma homocysteine levels in MCI patients taking vitamins B-6,B- B-12, and/or folic acid supplements, with statistically significant declines being observed after 1 month of supplementation. Findings support that supplementation with these vitamins might be an option to reduce homocysteine levels in people with MCI and elevated plasma homocysteine.

Centenarians exhibit extreme longevity and compression of morbidity and display a unique genetic signature. Centenarians' offspring seem to inherit centenarians' compression of morbidity, as measured by lower rates of age-related pathologies. We aimed to ascertain whether centenarians' offspring are less frail and whether they are endowed with a "centenarian genetic footprint" in a case-control study, matched 1:1 for gender, age ±5 years, and place of birth and residence. Cases must have a living parent aged 97 years or older, aged 65-80 years, community-dwelling, not suffering from a terminal illness, or less than 6 months of life expectancy. Controls had to meet the same criteria as cases except for the age of death of their parents (not older than 89 years). Centenarians were individuals 97 years or older. Frailty phenotype was determined by Fried's Criteria. We collected plasma and peripheral blood mononuclear cells from 63 centenarians, 88 centenarians' offspring, and 88 non-centenarians' offspring. miRNA expression and mRNA profiles were performed by the GeneChip miRNA 4.0 Array (Thermo Fisher Scientific) and GeneChip Clariom S Human Array (Thermo Fisher Scientific), respectively. We found a lower incidence of frailty among centenarians' offspring when compared to their contemporaries' non- centenarians' offspring (p

Previous research in rodents suggests that the long-term neurobehavioral disturbances induced by chronic ethanol (EtOH) exposure could be due to endocannabinoid system (ECS) alterations. Moreover, ECS failure has been proposed to mediate the cognitive impairment and beta-amyloid production in Alzheimer disease (AD). Thus, in the present study, we evaluated the effects of adolescent EtOH binge drinking on the cognitive disturbances, hippocampal beta-amyloid levels, and in the ECS expression on a transgenic mouse model (APP/PSEN, AZ) of AD. We exposed AZ and wild-type mice to a binge-drinking treatment during adolescence. At 6 and 12 months of age, we evaluated hippocampal-dependent learning and memory: beta-amyloid concentrations and RNA and protein levels of cannabinoid type-2 receptors (CB2), diacylglycerol lipase-alpha (DAGL alpha), and monoacylglycerol lipase (MAGL) in the hippocampus. The results showed that binge-EtOH treatment worsens cognitive function and increases beta-amyloid levels in AZ. At 6 months, EtOH heightens CB2 (RNA and protein) and DAGL alpha (RNA) expression in wild type but not in AZ. On the contrary, EtOH enhances MAGL RNA expression only in AZ. At 12 months, AZ displays increased levels of CB2 (RNA and protein) and DAGL alpha (protein) compared with control. Similar to what happens at 6 months, EtOH induces an increase in CB2 gene expression in wild type but not in AZ; however, it augments CB2 and DAGL alpha protein levels in both genotypes. Therefore, we propose that adolescent binge drinking accelerates cognitive deficits associated with aging and AD. It also accelerates hippocampal beta-amyloid accumulation in AZ and affects differently the ECS response in wild type and AZ.

Background Frailty is a major age-associated syndrome leading to disability. Oxidative damage plays a significant role in the promotion of frailty. The cellular antioxidant system relies on reduced nicotinamide adenine dinucleotide phosphate (NADPH) that is highly dependent on glucose 6-P dehydrogenase (G6PD). The G6PD-overexpressing mouse (G6PD-Tg) is protected against metabolic stresses. Our aim was to examine whether this protection delays frailty. Methods Old wild-type (WT) and G6PD-Tg mice were evaluated longitudinally in terms of frailty. Indirect calorimetry, transcriptomic profile, and different skeletal muscle quality markers and muscle regenerative capacity were also investigated. Results The percentage of frail mice was significantly lower in the G6PD-Tg than in the WT genotype, especially in 26-month-old mice where 50% of the WT were frail vs. only 13% of the Tg ones (P < 0.001). Skeletal muscle transcriptomic analysis showed an up-regulation of respiratory chain and oxidative phosphorylation (P = 0.009) as well as glutathione metabolism (P = 0.035) pathways in the G6PD-Tg mice. Accordingly, the Tg animals exhibited an increase in reduced glutathione (34.5%, P < 0.01) and a decrease on its oxidized form (-69%, P < 0.05) and in lipid peroxidation (4-HNE: -20.5%, P < 0.05). The G6PD-Tg mice also showed reduced apoptosis (BAX/Bcl2: -25.5%, P < 0.05; and Bcl-xL: -20.5%, P < 0.05), lower levels of the intramuscular adipocyte marker FABP4 (-54.7%, P < 0.05), and increased markers of mitochondrial content (COX IV: 89.7%, P < 0.05; Grp75: 37.8%, P < 0.05) and mitochondrial OXPHOS complexes (CII: 81.25%, P < 0.01; CIII: 52.5%, P < 0.01; and CV: 37.2%, P < 0.05). Energy expenditure (-4.29%, P < 0.001) and the respiratory exchange ratio were lower (-13.4%, P < 0.0001) while the locomotor activity was higher (43.4%, P < 0.0001) in the 20-month-old Tg, indicating a major energetic advantage in these mice. Short-term exercise training in young C57BL76J mice induced a robust activation of G6PD in skeletal muscle (203.4%, P < 0.05), similar to that achieved in the G6PD-Tg mice (142.3%, P < 0.01). Conclusions Glucose 6-P dehydrogenase deficiency can be an underestimated risk factor for several human pathologies and even frailty. By overexpressing G6PD, we provide the first molecular model of robustness. Because G6PD is regulated by pharmacological and physiological interventions like exercise, our results provide molecular bases for interventions that by increasing G6PD will delay the onset of frailty.

NAD(P)H donates electrons for reductive biosynthesis and antioxidant defense across all forms of life. Glucose-6-phosphate dehydrogenase (G6PD) is a critical enzyme to provide NADPH. G6PD deficiency is present in more than 400 million people worldwide. This enzymopathy provides protection against malaria but sensitizes cells to oxidative stressors. Oxidative stress has been involved in the pathogenesis of the diabetic complications and several studies have provided evidences of a link between G6PD deficiency and type 2 diabetes (T2D). We hypothesized that a moderate overexpression of G6PD (G6PD-Tg) could protect beta-cells from age-associated oxidative stress thus reducing the risk of developing T2D. Here we report, that G6PD-Tg mice show an improved glucose tolerance and insulin sensitivity when compared to old age-matched Wild Type (WT) ones. This is accompanied by a decrease in oxidative damage and stress markers in the pancreas of the old Tg animals (20-24month-old). Pancreatic beta-cells progress physiologically towards a state of reduced responsiveness to glucose. In pancreatic islets isolated from G6PD-Tg and WT animals at different ages, and using electrophysiological techniques, we demonstrate a wider range of response to glucose in the G6PD-Tg cells that may explain the improvements in glucose tolerance and insulin sensitivity. Together, our results show that overexpression of G6PD maintains pancreatic beta-cells from old mice in a "juvenile-like" state and points to the G6PD dependent generation of NADPH as an important factor to improve the natural history of diabetes.

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, cholesterol, branched chain amino acids (isoleucine and leucine), ketone bodies (acetoacetate), bacterial co-metabolites (trimethylamine), and cellular antioxidants (taurine) contributed to a change in metabolic profile after moderate red wine consumption by the nuns. No serious unwanted side effects were observed. Finally, we tested the effect of moderate red wine consumption on longevity in a controlled animal population, such as D. melanogaster, and found that it increased average life span by 7%. In conclusion, moderate red wine consumption increases the expression of key longevity-related genes and improves metabolic health in humans and increases longevity in flies.

Research in redox biology of exercise has made considerable advances in the last 70 years. Since the seminal study of George Pake?s group calculating the content of free radicals in skeletal muscle in resting conditions in 1954, many discoveries have been made in the field. The first section of this review is devoted to highlight the main research findings and fundamental changes in the exercise redox biology discipline. It includes: i) the first steps in free radical research, ii) the relation between exercise and oxidative damage, iii) the redox regulation of muscle fatigue, iv) the sources of free radicals during muscle contractions, and v) the role of reactive oxygen species as regulators of gene transcription and adaptations in skeletal muscle. In the second section of the manuscript, we review the available biomarkers for assessing health, performance, recovery during exercise training and overtraining in the sport population. Among the set of biomarkers that could be determined in exercise studies we deepen on the four categories of redox biomarkers: i) oxidants, ii) antioxidants, iii) oxidation products (markers of oxidative damage), and iv) measurements of the redox balance (markers of oxidative stress). The main drawbacks, strengths, weaknesses, and methodological considerations of every biomarker are also discussed.

The main epigenetic features in aging are: reduced bulk levels of core histones, altered pattern of histone post-translational modifications, changes in the pattern of DNA methylation, replacement of canonical histones with histone variants, and altered expression of non-coding RNA. The identification of epigenetic mechanisms may contribute to the early detection of age-associated subclinical changes or deficits at the molecular and/or cellular level, to predict the development of frailty, or even more interestingly, to improve health trajectories in older adults. Frailty reflects a state of increased vulnerability to stressors as a result of decreased physiologic reserves, and even dysregulation of multiple physiologic systems leading to adverse health outcomes for individuals of the same chronological age. A key approach to overcome the challenges of frailty is the development of biomarkers to improve early diagnostic accuracy and to predict trajectories in older individuals. The identification of epigenetic biomarkers of frailty could provide important support for the clinical diagnosis of frailty, or more specifically, to the evaluation of its associated risks. Interventional studies aimed at delaying the onset of frailty and the functional alterations associated with it, would also undoubtedly benefit from the identification of frailty biomarkers. Specific to the article yet reasonably common within the subject discipline.

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 diabetic Goto Kakizaki (GK) rats. Indeed, this was the case: we found that male GK rats consuming a soya-rich diet developed the disease at a lower rate and, therefore, lived longer than soya-free dietconsuming rats.

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, however, they enjoy a compression of morbidity. We have shown that they overexpress B-cell lymphoma-extra large (Bcl-xL). Bcl-xL could avoid an excessive burden of senescent cells through the regulation of intrinsic apoptosis, mitochondrial bioenergetics and oxidative stress. On the other hand, Bcl-xL maintains a fully functional immune system that ensures an efficient clearance of senescent cells. Moreover, there is a paradox, as inhibitors of Bcl-xL have been employed as senolytic agents, which have been shown to protect from aging in animal models. In this review, we aim to discuss how Bcl-xL could modulate senescence-associated harmful effects in centenarians, protecting them from the burden of accumulation of senescent cells.

BACKGROUND: Alzheimer's disease (AD) is characterized by the accumulation of the amyloid-beta peptide in the brain, leading to early oxidative stress and neurotoxicity. It has been suggested that physical exercise could be beneficial in preventing AD, but studies with multicomponent training are scanty.; OBJECTIVE: Verify the effects of multicomponent exercise training to prevent deficits in recognition memory related to Abeta neurotoxicity.; METHODS: We subjected Wistar rats to multicomponent training (including aerobic and anaerobic physical exercise and cognitive exercise) and then infused amyloid-beta peptide into their hippocampus.; RESULTS: We show that long-term multicomponent training prevents the amyloid-beta-associated neurotoxicity in the hippocampus. It reduces hippocampal lipid peroxidation, restores antioxidant capacity, and increases glutathione levels, finally preventing recognition memory deficits.; CONCLUSION: Multicomponent training avoids memory deficits related to amyloid-beta neurotoxicity on an animal model.

BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia and biomarkers are essential to help in the diagnosis of this disease. Image techniques and cerebrospinal fluid (CSF) biomarkers are limited in their use because they are expensive or invasive. Thus, the search for blood-borne biomarkers is becoming central to the medical community. OBJECTIVE: The main objective of this study is the evaluation of three serum proteins as possible biomarkers in AD patients. METHODS: We recruited 27 healthy controls, 19 mild cognitive impairment patients, and 17 AD patients. Using the recent A/T/N classification we split our population into two groups (AD and control). We used ELISA kits to determine Abeta42, tau, and p-tau in CSF and clusterin, PKR, and RAGE in serum. RESULTS: The levels of serum clusterin, PKR, and RAGE were statistically different in the AD group compared to controls. These proteins showed a statistically significant correlation with CSF Abeta42. So, they were selected to generate an AD detection model showing an AUC-ROC of 0.971 (CI 95%, 0.931-0.998). CONCLUSION: The developed model based on serum biomarkers and other co-variates could reflect the AD core pathology. So far, not one single blood-biomarker has been described, with effectiveness offering high sensitivity and specificity. We propose that the complexity of AD pathology could be reflected in a set of biomarkers also including clinical features of the patients.

Free radicals and oxidants are involved in physiological signaling pathways, although an imbalance between pro-oxidant and anti-oxidant systems in favor of the former leads to major biomolecular damage. This is the so-called oxidative stress, a complex process that affects us all and is responsible for the development of many diseases. Lipids are very sensitive to oxidant attack and to-date, malondialdehyde (MDA), 4-hydroxy-2-nonenal (4-HNE) and F2-isoprostane are the main biomarkers for lipid peroxidation assessment. They all derive from polyunsaturated fatty acids (PUFAs) either by enzyme-catalyzed reactions (physiological) or by non-enzyme reactions (pathological). The profile of PUFAs present in the tissue will determine the proportion of each biomarker. In this review we aim to discuss the proper method for MDA determination using HPLC. We also offer reference MDA values in humans in physiological and pathological conditions. Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

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 can be both beneficial or detrimental depending on the circumstances. Thus, targeting BCL-xL would in turn be a "double-edge sword" and therefore, additional studies are needed to better comprehend this dual and apparently contradictory role of BCL-XL in longevity.

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 ageing and frailty. The biology of centenarians, described in this review, provides us with clues for intervention to promote healthy ageing in the general population. One of the major reasons for this healthy ageing has to do with the genetic signature that is specific for centenarians and certainly different from octogenarians who do not enjoy the extraordinary qualities of centenarians.

Garcinoic acid (GA or delta-T3-13'COOH), is a natural vitamin E metabolite that has preliminarily been identified as a modulator of nuclear receptors involved in beta-amyloid (Abeta) metabolism and progression of Alzheimer's disease (AD). In this study, we investigated GA's effects on Abeta 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 gamma (PPARgamma) that has therapeutic potential for managing AD. GA significantly reduced Abeta aggregation and accumulation in mouse cortical astrocytes. Similarly to genistein, GA up-regulated PPARgamma expression and apolipoprotein E (ApoE) efflux in these cells with an efficacy that was comparable to that of its metabolic precursor delta-tocotrienol and higher than those of alpha-tocopherol metabolites. Unlike for genistein and the other vitamin E compounds, the GA-induced restoration of ApoE efflux was not affected by pharmacological inhibition of PPARgamma activity, and specific activation of pregnane X receptor (PXR) was observed together with ApoE and multidrug resistance protein 1 (MDR1) membrane transporter up-regulation in both the mouse astrocytes and brain tissue. These effects of GA were associated with reduced Abeta deposition in the brain of TgCRND8 mice, a transgenic AD model. In conclusion, GA holds potential for preventing Abeta oligomerization and deposition in the brain. The mechanistic aspects of GA's properties appear to be distinct from those of other vitamin E metabolites and of genistein. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

Dementia is one of the greatest global challenges for health and social care in the 21st century. Alzheimer's disease (AD), the most common type of dementia, is by no means an inevitable consequence of growing old. Several lifestyle factors may increase, or reduce, an individual's risk of developing AD. Much has been written overthe ages about the benefits of exercise and physical activity. Among the risk factors associated with AD is a low level of physical activity. The relationship between physical and mental health was established several years ago. In this review, we discuss the role of exercise (aerobic and resistance) training as a therapeutic strategy for the treatment and prevention of AD. Older adults who exercise are more likely to maintain cognition. We address the main protective mechanism on brain function modulated by physical exercise by examining both human and animal studies. We will pay especial attention to the potential role of exercise in the modulation of amyloid beta turnover, inflammation, synthesis and release of neurotrophins, and improvements in cerebral blood flow. Promoting changes in lifestyle in presymptomatic and predementia disease stages may have the potential for delaying one-third of dementias worldwide. Multimodal interventions that include the adoption of an active lifestyle should be recommended for older populations. Copyright © 2020. Production and hosting by Elsevier B.V.

Recent Advances: This review discusses the importance of the modulation of the oxidant levels through physiological strategies such as physical exercise or genetic manipulations such as the overexpression of antioxidant enzymes, in the promotion of healthy aging. Critical Issues: We have divided the review into five different sections. In the first two sections of the article "Oxidants are signals" and "Exercise training is an antioxidant," we discuss the main sources of free radicals during muscle contraction and their role, as hormetic substances, in the regulation of two main muscle adaptations to exercise in skeletal muscle; that is, mitochondrial biogenesis and the endogenous antioxidant defense. In the third section of the review, we deal with "the energy collapse in aging." The increased rate of reactive oxygen species (ROS) production and the low rate of mitochondria biosynthesis in the old cells are examined. Finally, in the fourth and fifth sections entitled "Overexpression of antioxidants enzymes in healthy aging" and "Exercise, longevity, and frailty," we consider the importance of the potentiation of the cellular defenses in health span and in life span. Future Directions: A correct manipulation of the ROS generation, directing these species to their physiological signaling role and preventing their deleterious effects, would allow the promotion of healthy 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 cargos, as well as EVs biogenesis, shedding and uptake is both ageing and redox sensitive. More specifically, senescence and oxidative stress increase EVs release, and their altered content can trigger antioxidant but also prooxidant responses in target cells thereby modulating the redox status. Further analysis would help to asses EVs role in the development and progression of oxidative stress-related pathologies. In this review we aimed to summarize the current knowledge on EVs and their involvement in redox modulation on age-related pathologies. We also discuss future directions and prospective that could be performed to improve EVs usage as biomarkers or therapeutic tools. Copyright © 2019. Published by Elsevier Inc.

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 MSC, cultured in a low physiological oxygen tension (3%) microenvironment into prematurely senescent MSC, cultured in a hyperoxic ambient (usual oxygen culture conditions, i.e., 21%). We observed that senescent MCS, treated with EVs from non-senescent MCS, showed reduced SA-beta-galactosidase activity levels and pluripotency factor (OCT4, SOX2, KLF4 and cMYC, or OSKM) overexpression and increased glycolysis, as well as reduced oxidative phosphorylation (OXPHOS). Moreover, these EVs' cargo induced the upregulation of miR-302b and HIF-1alpha levels in the target cells. We propose that miR-302b triggered HIF-1alpha upregulation, which in turn activated different pathways to delay premature senescence, improve stemness and switch energetic metabolism towards glycolysis. Taken together, we suggest that EVs could be a powerful tool to restore altered intercellular communication and improve stem cell function and stemness, thus delaying stem cell exhaustion in aging.

Scoliosis is defined as the three-dimensional (3D) structural deformity of the spine with a radiological lateral Cobb angle (a measure of spinal curvature) of =10° that can be caused by congenital, developmental or degenerative problems. However, those cases whose etiology is still unknown, and affect healthy children and adolescents during growth, are the commonest form of spinal deformity, known as adolescent idiopathic scoliosis (AIS). In AIS management, early diagnosis and the accurate prediction of curve progression are most important because they can decrease negative long-term effects of AIS treatment, such as unnecessary bracing, frequent exposure to radiation, as well as saving the high costs of AIS treatment. Despite efforts made to identify a method or technique capable of predicting AIS progression, this challenge still remains unresolved. Genetics and epigenetics, and the application of machine learning and artificial intelligence technologies, open up new avenues to not only clarify AIS etiology, but to also identify potential biomarkers that can substantially improve the clinical management of these patients. This review presents the most relevant biomarkers to help explain the etiopathogenesis of AIS and provide new potential biomarkers to be validated in large clinical trials so they can be finally implemented into clinical settings. Copyright © 2020. Published by Elsevier Inc.

The vast majority of the literature on the aryl hydrocarbon receptor is concerned with its functions in xenobiotic detoxification. However, in the course of evolution, this receptor had to have physiological (rather than toxicological) functions. Our aim was to review the aryl hydrocarbon receptor's role in the physiological functions involved in aging. This study was performed by searching the MEDLINE and Google Academic databases. A total of 34 articles were selected that focused specifically on the aryl hydrocarbon receptor and aging, the aryl hydrocarbon receptor and physiological functions, and the combination of both. This receptor's main physiological functions (mediated by the modulation of gene expression) were cell regeneration, the immune reaction, intestinal homeostasis, and cell proliferation. Furthermore, it was shown that the loss of this receptor led to premature aging. This process may be caused by the dysregulation of hematopoietic stem cells, loss of glucose and lipid homeostasis, increase in inflammation, and deterioration of the brain. We conclude that the aryl hydrocarbon receptor, apart from its well-established role in xenobiotic detoxication, plays an important role in physiological functions and in the aging process. Modulation of the signaling pathway of this receptor could be a therapeutic target of interest in aging.

Vitamin A (all-trans-retinol), its active derivatives retinal and retinoic acid, and their synthetic analogues constitute the group of retinoids. It is obtained from diet either as preformed vitamin A or as carotenoids. Retinal plays a biological role in vision, but most of the effects of vitamin A are exerted by retinoic acid, which binds to nuclear receptors and regulates gene transcription. Vitamin A deficiency is an important nutritional problem, particularly in the developing world. Retinol and carotenoids from diet during pregnancy and lactation influence their concentration in breast milk, which is important in the long term, not only for the offspring, but also for maternal health. In this study, we review the role of vitamin A in mammary gland metabolism, where retinoid signaling is required not only for morphogenesis and development of the gland and for adequate milk production, but also during the weaning process, when epithelial cell death is coupled with tissue remodeling.

In the 2015 Ageing Report, the European Commission (EC) and the Economic Policy Committee stated that coping with the challenge posed by an ageing population will require determined policy action in Europe, particularly in reforming pension, health care and long-term care systems. The concern for this situation motivated the EC, the Parliament and many of the Member States (MS) to co-fund, in the 2015 call of the Third European Health Programme of the European Union 2014-2020, the first Joint Action (JA) on the prevention of frailty. ADVANTAGE JA brings together 33 partners from 22 MSs for 3 years. It aims to build a common understanding on frailty to be used in the MSs by policy makers and other stakeholders involved in the management, both at individual and population level, of older people who are frail or at risk for developing frailty throughout the European Union (EU). It is a formidable challenge but also a great opportunity for concerted action resulting in fostering effective and successful policies in frailty prevention and management in the participating MS. The Consortium has 2 years of hard work ahead to contribute to the needed change for frailty related disability free Europe. The first practical step towards this aim was the preparation of a document: the State of the Art on Frailty Report to support an overview of evidence of what works and what does not work on frailty prevention and management. Subsequently, this will be reflected in the advice that the JA will give to policy makers at MS level. Overall, these messages intend to be an instrument of added value to advocate for policy driven decisions on frailty prevention and management in the JA participating MSs and subsequently towards a frailty related disability free older population in Europe. The aim of this paper is to describe ADVANTAGE JA general structure, approach and recommendations towards a European health and social policy which will support frailty prevention in the participating MS.

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 did not have an effect on ageing or on age-associated diseases, cast doubts on the validity of this theory. Data from our own laboratory showed that oxidative stress 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 in which frailty is associated with oxidative stress, but age itself is not. Superoxide dismutase deficient mice are more frail than controls. But more importantly, we observed that animals overexpressing glucose-6-phosphate dehydrogenase that are protected against oxidative stress, delay frailty and are more vigorous than controls. We will describe experiments from both experimental animals and human cohorts that provide support to the free radical theory of frailty.