Development Of Age-related Diseases Research Articles

Geropathology. An inside view of biological aging.

The geropathology concept assumes all age-related lesions are relevant, which allows the ability to grade each lesion in an organ with a severity score resulting in a quantitative value. Because aging pet cats have similar age-related diseases as older humans, knowledge of histopathology occurring during aging would be invaluable to determine how age-related lesions progress with increasing age and the connection with comorbidities. The ability to use the severity of specific organ geropathology to predict biological aging would provide new approaches to study pathways of aging and their role in the development of age-related diseases in animal models.

Effect of oxidative stress on telomere maintenance in aortic smooth muscle cells

Reactive oxygen species (ROS) and telomere dysfunction are both associated with aging and the development of age-related diseases. Although there is evidence for a direct relationship between ROS and telomere dysfunction as well as an independent association of oxidative stress and telomere attrition with age-related disorders, there has not been sufficient exploration of how the interaction between oxidative stress and telomere function may contribute to the pathophysiology of cardiovascular diseases (CVD). To better understand the complex relationships between oxidative stress, telomerase biology and pathophysiology, we examined the telomere biology of aortic smooth muscle cells (ASMCs) isolated from mutant mouse models of oxidative stress. We discovered that telomere lengths were significantly shorter in ASMCs isolated from superoxide dismutase 2 heterozygous (Sod2+/−) mice, which exhibit increased arterial stiffness with aging, and the observed telomere attrition occurred over time. Furthermore, the telomere erosion occurred even though telomerase activity increased. In contrast, telomeres remained stable in wild-type and superoxide dismutase 1 heterozygous (Sod1+/−) mice, which do not exhibit CVD phenotypes. The data indicate that mitochondrial oxidative stress, in particular elevated superoxide levels and decreased hydrogen peroxide levels, induces telomere erosion in the ASMCs of the Sod2+/− mice. This reduction in telomere length occurs despite an increase in telomerase activity and correlates with the onset of disease phenotype. Our results suggest that the oxidative stress caused by imbalance in mitochondrial ROS, from deficient SOD2 activity as a model for mitochondrial dysfunction results in telomere dysfunction, which may contribute to pathogenesis of CVD.

Oxidative Stress and 4-hydroxy-2-nonenal (4-HNE): Implications in the Pathogenesis and Treatment of Aging-related Diseases.

Oxidative stress plays an important role in the development of aging-related diseases by accelerating the lipid peroxidation of polyunsaturated fatty acids in the cell membrane, resulting in the production of aldehydes, such as malondialdehyde and 4-hydroxy-2-nonenal (4-HNE) and other toxic substances. The compound 4-HNE forms adducts with DNA or proteins, disrupting many cell signaling pathways including the regulation of apoptosis signal transduction pathways. The binding of proteins to 4-HNE (4-HNE-protein) acts as an important marker of lipid peroxidation, and its increasing concentration in brain tissues and fluids because of aging, ultimately gives rise to some hallmark disorders, such as neurodegenerative diseases (Alzheimer's and Parkinson's diseases), ophthalmic diseases (dry eye, macular degeneration), hearing loss, and cancer. This review aims to describe the physiological origin of 4-HNE, elucidate its toxicity in aging-related diseases, and discuss the detoxifying effect of aldehyde dehydrogenase and glutathione in 4-HNE-driven aging-related diseases.

The in vitro Evaluation of Protective Effect of Rutin on Acrylamide Induced Oxidative Aging in NIH3T3 Cells

Background: Aging is one of the important factor in the development of age-related diseases. Acrylamide (ACR) can be produced during rich-carbohydrate foods preparing at high temperature. Recently, studies showed that ACR can induce cellular aging. Furthermore, Rutin is a natural flavonoid, which possesses a potent antioxidant activity. Objective: In this study, ptotective effect of Rutin (a potent antioxidant) on oxidative-induced aging after ACR exposure was evaluated. Materials and Methods: NIH3T3 mouse embryonic fibroblast cells were used for this study, which treated by different concentrations of ACR and H2O2. Oxidative stress was assessed by measuring of malondialdehyde and glutathion concentrations. To evaluate of the aging process, β-galactosidase activity was evaluated by enzyme staining and β-galactosidase activity assay kit. MTT assay was used to evaluate the viability of the cells. Results: Exposure of cells to ACR and H2O2 significantly decreased the cell viability and using of rutin significantly improved cell viability in cells treated by ACR (P<0.05). Rutin increased glutathion level in cells treated by ACR and H2O2 (P<0.05). Also, the rate of lipid peroxidation was significantly lower in the group treated with rutin and H2O2 than in the H2O2 group (P<0.05).The β -galactosidase activity was increased in H2O2 and ACR groups. The using of rutin with acrylamide significantly reduced the activity of β-galactosidase enzyme compared to acrylamide group (P<0.05). Conclusion: Based on this study, oxidative stress may be presented as an important mechanism in ACR induced-aging in NIH3T3 cells. On the other hand, Rutin, as a potent antioxidant, decresead aging by inhibition of oxidative damage.

Pharmacological Depletion of Microglia Leads to a Dose-Dependent Reduction in Inflammation and Senescence in the Aged Murine Brain

Chronic macrophage activation was implicated as one of the main culprits for chronical, low-grade inflammation which significantly contributes to development of age-related diseases. Microglia as the brain macrophages have been recently implicated as key players in neuroinflammation and neurodegeneration in the aged brain. Microglial cell functions are indispensable in early development, however, activation or senescence of microglia in aging cells may be detrimental. Depletion of microglia using genetical or pharmacological approaches leads to opposite results regarding effects on brain cognition. In this study we pharmacologically depleted microglia using orally delivered low and high doses of the CSF1R inhibitor PLX5622 and assessed the expression levels of known inflammation markers (TNF-α, IL1-β, IL-6, IL-10), glia markers (Iba-1 and Gfap) and specific senescence marker p16Ink4a in the aged murine brain. Our results indicate that treatment with low and high doses of PLX5622 leads to a dose-dependent depletion of microglial cells with similar levels in young and aged mice. We also show that treatment with low and high PLX5622 differentially affected cytokine levels in young and old brains. By using low doses we could achieve reduction in inflammation circumventing the astrocyte activation. Removal of microglia cells led to decreased expression of the senescence marker p16Ink4a in the aged brain, indicating a relevant contribution of these cells to the expression of this marker and their senescent status in the healthy aging brain. Our results indicate that increased and detrimental brain inflammation in aged murine brain can be impaired by selectively reducing the microglial cell population.

A mutation in transmembrane protein 135 impairs lipid metabolism in mouse eyecups

Aging is a significant factor in the development of age-related diseases but how aging disrupts cellular homeostasis to cause age-related retinal disease is unknown. Here, we further our studies on transmembrane protein 135 (Tmem135), a gene involved in retinal aging, by examining the transcriptomic profiles of wild-type, heterozygous and homozygous Tmem135 mutant posterior eyecup samples through RNA sequencing (RNA-Seq). We found significant gene expression changes in both heterozygous and homozygous Tmem135 mutant mouse eyecups that correlate with visual function deficits. Further analysis revealed that expression of many genes involved in lipid metabolism are changed due to the Tmem135 mutation. Consistent with these changes, we found increased lipid accumulation in mutant Tmem135 eyecup samples. Since mutant Tmem135 mice have similar ocular pathologies as human age-related macular degeneration (AMD) eyes, we compared our homozygous Tmem135 mutant eyecup RNA-Seq dataset with transcriptomic datasets of human AMD donor eyes. We found similar changes in genes involved in lipid metabolism between the homozygous Tmem135 mutant eyecups and AMD donor eyes. Our study suggests that the Tmem135 mutation affects lipid metabolism as similarly observed in human AMD eyes, thus Tmem135 mutant mice can serve as a good model for the role of dysregulated lipid metabolism in AMD.

Effect of polyphenol secondary metabolites on oxidative stress and inflammatory responses associated with aging diseases

Several mechanisms are responsible for regulating the process of aging. A rise in reactive oxygen species (ROS) and oxidative stress is usually linked to the development of age-related diseases. Evidence indicates that prolonged oxidative stress can predispose to frequent diseases such as chronic inflammation, cancer and heart diseases. Polyphenols are naturally occurring substances found in numerous fruits, vegetables, cereals, etc. They considered as one of the most abundant and widely distributed secondary metabolites of the plant kingdom. Long-term consumption of polyphenol-rich diets was confirmed for protection from as shown by earlier. Additionally, polyphenol-rich foods and beverages offer protection against certain chronic diseases, particularly type 2 diabetes and heart disease. Certain polyphenols, such as quercetin, have anti-inflammatory properties and they were also associated with lower levels of biomarkers of muscle injury and inflammation. Flavonoids were shown to slow memory problems and the progression of Alzheimer’s disease. Antioxidants such as plant polyphenols have been proposed for cancer prevention and/or treatment. Dietary benefits are attributed in part to polyphenols, which have antitumor properties in both animal models and humans. Resveratrol (RV), a polyphenol found in blueberries, cranberries, wine almonds, and red grapes, has anti-inflammatory and anti-cancer properties and was shown to reduce cancer cell glycolytic metabolism and reduce intracellular ROS levels.

Creation of a collection of different biological sample types from elderly patients to study the relationship of clinical, systemic, tissue and cellular biomarkers of accumulation of senescent cells during aging

With aging, tissue homeostasis and their effective recovery after damage is violated. It has been shown that this may be due to the excessive accumulation of senescent (SC) cells in various tissues, which leads to the activation of chronic sterile inflammation, tissue dysfunction and, as a result, to the development of age-related diseases. To assess the contribution of SC cells to human body aging and pathogenesis of such diseases, relevant biomarkers are studied. For successful translation into clinical practice of approaches aimed at regulating the SC cell content in various tissues, it is necessary to study the relationship between the established clinical biomarkers of aging and age-related diseases, systemic aging parameters, and SC biomarkers at the tissue and cellular levels.Aim. To develop and describe action algorithms for creating a biobank of samples obtained from patients aged >65 years in order to study biomarkers of SC cell accumulation.Material and methods. To collect samples, an interaction system was built between several research, clinical and infrastructure departments of a multidisciplinary medical center. At the stage of preanalytical training, regulatory legal acts were developed, including informed consent for patients, as well as protocols for each stage of the study.Results. A roadmap was formed with action algorithms for all participants in the study, as well as with a convenient and accessible system of annotations and storage of biological samples. To date, the collection includes biological samples of 7 different types (peripheral blood serum, formalin-fixed tissue samples and formalin fixed paraffin embedded tissue specimens, samples of different cells isolated from peripheral blood, skin and adipose tissue, samples of deoxyribonucleic and ribonucleic acids, cell secretome conditioned media) obtained from 82 patients. We accumulated relevant anamnestic, clinical and laboratory data, as well as the results of experimental studies to assess the SC cell biomarkers. Using the collection, the relationship between clinical, tissue and cellular biomarkers of SC cell accumulation was studied.Conclusion. The creation of a collection of biological samples at the molecular, cellular, tissue and organism levels from one patient provides great opportunities for research in the field of personalized medicine and the study of age-related disease pathogenesis.

Stem Cell-derived Exosomal MicroRNA as Therapy for Vascular Age-related Diseases.

Vascular age-related diseases describe a group of age-related chronic diseases that result in a considerable healthcare burden to society. Vascular aging includes structural changes and dysfunctions of endothelial cells (ECs) and smooth muscle cells (SMCs) in blood vessels. Compared with conventional treatment for vascular age-related diseases, stem cell (SC) therapy elicits better anti-aging effects viathe inhibition/delay ECs and SMCs from entering senescence. Exosomal noncoding RNA (ncRNAs) in vascular aging and stem cell-derived exosomal microRNAs (SCEV-miRNAs), especially in mesenchymal stem cells, have an important role in the development of age-related diseases. This review summarizes SCEV-miRNAs of diverse origins that may play a vital role in treating subclinical and clinical stages of vascular age-related disorders. We further explored possible age-related pathways and molecular targets of SCEV-miRNA, which are associated with dysfunctions of ECs and SMCs in the senescent stage. Moreover, the perspectives and difficulties of SCEV-miRNA clinical translation are discussed. This review aims to provide greater understanding of the biology of vascular aging and to identify critical therapeutic targets for SCEV-miRNAs. Though still in its infancy, the potential value of SCEV-miRNAs for vascular age-related diseases is clear.

Higher habitual intake of dietary dicarbonyls is associated with higher corresponding plasma dicarbonyl concentrations and skin autofluorescence: the Maastricht Study

Dicarbonyls are highly reactive compounds and major precursors of advanced glycation end products (AGEs). Both dicarbonyls and AGEs are associated with development of age-related diseases. Dicarbonyls are formed endogenously but also during food processing. To what extent dicarbonyls from the diet contribute to circulating dicarbonyls and AGEs in tissues is unknown. To examine cross-sectional associations of dietary dicarbonyl intake with plasma dicarbonyl concentrations and skin AGEs. In 2566 individuals of the population-based Maastricht Study (age: 60±8 y, 50% males, 26% with type 2 diabetes), we estimated habitual intake of the dicarbonyls methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG) by combining FFQs with our dietary dicarbonyl database of MGO, GO, and 3-DG concentrations in>200 commonly consumed food products. Fasting plasma concentrations of MGO, GO, and 3-DG were measured by ultra-performance liquid chromatography-tandem mass spectrometry. Skin AGEs were measured as skin autofluorescence (SAF), using the AGE Reader. Associations of dietary dicarbonyl intake with their respective plasma concentrations and SAF (all standardized) were examined using linear regression models, adjusted for age, sex, potential confounders related to cardiometabolic risk factors, and lifestyle. Median intake of MGO, GO, and 3-DG was 3.6, 3.5, and 17mg/d, respectively. Coffee was the main dietary source of MGO, whereas this was bread for GO and 3-DG. In the fully adjusted models, dietary MGO was associated with plasma MGO (β: 0.08; 95% CI: 0.02, 0.13) and SAF (β: 0.12; 95% CI: 0.07, 0.17). Dietary GO was associated with plasma GO (β: 0.10; 95% CI: 0.04, 0.16) but not with SAF. 3-DG was not significantly associated with either plasma 3-DG or SAF. Higher habitual intake of dietary MGO and GO, but not 3-DG, was associated with higher corresponding plasma concentrations. Higher intake of MGO was also associated with higher SAF. These results suggest dietary absorption of MGO and GO. Biological implications of dietary absorption of MGO and GO need to be determined. The study has been approved by the institutional medical ethical committee (NL31329.068.10) and the Minister of Health, Welfare and Sports of the Netherlands (Permit 131088-105234-PG).

The impact of metabolic disorders on ageing rates in patients with moderate cardiovascular risk

Introduction. Prediction of cardiovascular risk (CVR) and the effectiveness of prevention of metabolic-associated diseases (MAD) is a serious challenge of modern medicine. Recently, for this purpose, it has been proposed to estimate the biological age (BA) of a person for the timely determination of premature aging. Calendar age (CA) is an important risk factor for the development of age-related diseases, including cardiovascular disease (CVD). Biological age (BA) may be more accurate for assessing CVR and predicting early vascular ageing and the development of atherosclerosis. The available data allow us to testify about the relationship between premature aging and the most significant pathogenetic factors of MAD. Purpose: to assess the impact of metabolic disorders on biological age in patients with moderate cardiovascular risk and the significance for the development of premature ageing. Materials and methods. 120 patients with moderate CVR (by SCORE) aged from 32 to 59 years (women n=65, 54.17%) were involved in the examination. They were divided into the main group (n= 67) who additionally had metabolic disorders (overweight/obesity, insulin resistance, dyslipidemia) and a comparison group (n=53) without metabolic disorders. All included patients underwent anthropometric studies with calculation of body mass index (BMI), studies of indicators of carbohydrate metabolism and lipid metabolism. Determination of biological age was carried out according to the methods of A.G. Gorelkin and B.B. Pinkhasov and P.V. Voytenko. Telomere length (TL) of blood leukocytes and buccal epithelium was determined by real-time PCR. Statistical data processing was performed using the Statistica program package, version 10.0. Results and discussion. The BA of normal-weight patients not only did not exceed the CA, but was also lower in both the main group and the comparison group. At the same time, in the overweight patients BA did not differ from CA in both groups, and the presence of obesity led to an acceleration of the rate of ageing in patients of the main group. It was determined that an increase in BMI and waist circumference (WC), hyperinsulinemia, hyperuricemia, and high levels of proatherogenic lipids are associated with an increase in BA regardless of the presence of metabolic disorders and may influence the ageing rate. Also, the presence of overweight and obesity is associated with a decrease in TL and an increase in BA. Conclusions. Assessment of premature ageing allows to identify persons with a high risk of developing age-related diseases at a time when there are no clinical symptoms yet, and to develop measures for timely and effective prevention.

Senescent Cells in Cancer: Wanted or Unwanted Citizens.

Over recent decades, the field of cellular senescence has attracted considerable attention due to its association with aging, the development of age-related diseases and cancer. Senescent cells are unable to proliferate, as the pathways responsible for initiating the cell cycle are irreversibly inhibited. Nevertheless, senescent cells accumulate in tissues and develop a pro-inflammatory secretome, known as the senescence-associated secretory phenotype (SASP), which can have serious deleterious effects if not properly regulated. There is increasing evidence suggesting senescent cells contribute to different stages of carcinogenesis in different anatomical sites, mainly due to the paracrine effects of the SASP. Thus, a new therapeutic field, known as senotherapeutics, has developed. In this review, we aim to discuss the molecular mechanisms underlying the senescence response and its relationship with cancer development, focusing on the link between senescence-related inflammation and cancer. We will also discuss different approaches to target senescent cells that might be of use for cancer treatment.

Hallmarks of Testicular Aging: The Challenge of Anti-Inflammatory and Antioxidant Therapies Using Natural and/or Pharmacological Compounds to Improve the Physiopathological Status of the Aged Male Gonad.

The evolutionary theory of aging supports a trade-off relationship between reproduction and aging. Aging of the male reproductive system primarily affects the testes, leading to a decrease in the levels of sexual hormones, alterations in sperm quality and production, and a decline in fertility that does not necessarily involve a complete cessation of spermatogenesis. Inflammation, oxidation, and apoptosis are events considered as predictors of pathogenesis and the development of age-related diseases that are frequently observed in aged testes. Although the molecular mechanisms are still poorly understood, accumulating evidence points toward pro-inflammatory molecules and reactive oxygen species as primary contributing factors for testicular aging. However, the real impact of aging-related testicular alterations on fertility, reproductive health, and life span is far from being fully revealed. This work discusses the current knowledge on the impact of aging in the testis, particularly of aging-related dysregulated inflammation and oxidative damage on the functioning of its different cell populations. More interestingly, this review covers the potential benefits of anti-aging interventions and therapies using either pharmacological compounds (such as non-selective non-steroidal anti-inflammatory medication) or more natural alternatives (such as various nutraceuticals or even probiotics) that exhibit anti-inflammatory, antioxidant, and anti-apoptotic properties. Some of these are currently being investigated or are already in clinical use to delay or prevent testicular aging.

Effect of Caloric Restriction on Aging: Fixing the Problems of Nutrient Sensing in Postmitotic Cells?

The review discusses the role of metabolic disorders (in particular, insulin resistance) in the development of age-related diseases and normal aging with special emphasis on the changes in postmitotic cells of higher organisms. Caloric restriction helps to prevent such metabolic disorders, which could probably explain its ability to prolong the lifespan of laboratory animals. Maintaining metabolic homeostasis is especially important for the highly differentiated long-lived body cells, whose lifespan is comparable to the lifespan of the organism itself. Normal functioning of these cells can be ensured only upon correct functioning of the cytoplasm clean-up system and availability of all required nutrients and energy sources. One of the central problems in gerontology is the age-related disruption of glucose metabolism leading to obesity, diabetes, metabolic syndrome, and other related pathologies. Along with the adipose tissue, skeletal muscles are the main consumers of insulin; hence the physical activity of muscles, which supports their energy metabolism, delays the onset of insulin resistance. Insulin resistance disrupts the metabolism of cardiomyocytes, so that they fail to utilize the nutrients to perform their functions even being surrounded by a nutrient-rich environment, which contributes to the development of age-related cardiovascular diseases. Metabolic pathologies also alter the nutrient sensitivity of neurons, thus disrupting the action of insulin in the central nervous system. In addition, there is evidence that neurons can develop insulin resistance as well. It has been suggested that affecting nutritional sensors (e.g., AMPK) in postmitotic cells might improve the state of the entire multicellular organism, slow down its aging, and increase the lifespan.

Estimation of calendar age based on autonomic cardiovascular function by applying machine learning techniques

Abstract Aging is accompanied by changes in the cardiovascular physiology that promote the development of age-related diseases. This paper presents a modern approach to quantify the physiological effects of age on the cardiovascular system by applying modern machine learning techniques to several indicators of autonomic cardiovascular function. In 885 healthy subjects, 33 different indices were calculated on resting state electrocardiogram and continuous blood pressure recordings. Based on those parameters, five different approaches were applied in order to reconstruct the calendar age of healthy subjects, i.e., linear regression (LR), neural network (NN), Gaussian process regression (GPR), support vector regression (SVR), and relevance vector regression (RVR). Hyper parameters of machine learning methods were optimized via grid search. After 20 repetitions of a five-fold cross-validation, the mean absolute error (MAE) was computed between the calendar and estimated age to assess the accuracy of each method. The results show that the lowest error for age estimation was achieved using SVR with a MAE of 5.49 years. GPR performed comparably well to SVR with a MAE of 5.55 years, while NN led to a MAE of 5.72 years. RVR and LR revealed MAE of more than six years (6.21 and 6.34 years). The error of age estimation could be further reduced by applying outlier correction to the input data leading to a minimum MAE of 4.53 years with GPR. In conclusion, our results suggest that machine learning can be used to quantify the effects of healthy aging on cardio-vascular function.

Extracellular vesicles derived from inflammatory-educated stem cells reverse brain inflammation—implication of miRNAs

Inflammation plays a key role in the development of age-related diseases. In Alzheimer's disease, neuronal cell death is attributed to amyloidbeta oligomers that trigger microglial activation. Stem cells have shown promise as therapies for inflammatory diseases- because of their paracrine activity combined with their ability to respond to the inflammatory environment. However, the mechanisms underlying stem cell-promoted neurological recovery are poorly understood. To elucidate these mechanisms, we first primed stem cells with the secretome of lipopolysaccharide- or amyloidbeta-activated microglia. Then, we compared the immunomodulatory effects of extracellular vesicles (EVs) secreted from primed and non-primed stem cells. Our results demonstrate that EVs from primed cells are more effective in inhibiting microglia and astrocyte activation, amyloid deposition, demyelination, memory loss and motor and anxiety-like behavioral dysfunction, compared to EVs from non-primed cells. MicroRNA (miRNA) profiling revealed the upregulation of at least 19 miRNAs on primed-stem cell EVs. The miRNA targets were identified, and KEGG pathway analysis showed that the overexpressed miRNAs target key genes on the toll-like receptor-4 (TLR4) signaling pathway. Overall, our results demonstrate that priming mesenchymal stem cells (MSCs) with the secretome of activated microglia results in the release of miRNAs from EVs with enhanced immune regulatory potential able to fight neuroinflammation.

Role of NF-κB in Ageing and Age-Related Diseases: Lessons from Genetically Modified Mouse Models.

Ageing is a complex process, induced by multifaceted interaction of genetic, epigenetic, and environmental factors. It is manifested by a decline in the physiological functions of organisms and associated to the development of age-related chronic diseases and cancer development. It is considered that ageing follows a strictly-regulated program, in which some signaling pathways critically contribute to the establishment and maintenance of the aged state. Chronic inflammation is a major mechanism that promotes the biological ageing process and comorbidity, with the transcription factor NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) as a crucial mediator of inflammatory responses. This, together with the finding that the activation or inhibition of NF-κB can induce or reverse respectively the main features of aged organisms, has brought it under consideration as a key transcription factor that acts as a driver of ageing. In this review, we focused on the data obtained entirely through the generation of knockout and transgenic mouse models of either protein involved in the NF-κB signaling pathway that have provided relevant information about the intricate processes or molecular mechanisms that control ageing. We have reviewed the relationship of NF-κB and premature ageing; the development of cancer associated with ageing and the implication of NF-κB activation in the development of age-related diseases, some of which greatly increase the risk of developing cancer.

The Glyoxalase System in Age-Related Diseases: Nutritional Intervention as Anti-Ageing Strategy.

The glyoxalase system is critical for the detoxification of advanced glycation end-products (AGEs). AGEs are toxic compounds resulting from the non-enzymatic modification of biomolecules by sugars or their metabolites through a process called glycation. AGEs have adverse effects on many tissues, playing a pathogenic role in the progression of molecular and cellular aging. Due to the age-related decline in different anti-AGE mechanisms, including detoxifying mechanisms and proteolytic capacities, glycated biomolecules are accumulated during normal aging in our body in a tissue-dependent manner. Viewed in this way, anti-AGE detoxifying systems are proposed as therapeutic targets to fight pathological dysfunction associated with AGE accumulation and cytotoxicity. Here, we summarize the current state of knowledge related to the protective mechanisms against glycative stress, with a special emphasis on the glyoxalase system as the primary mechanism for detoxifying the reactive intermediates of glycation. This review focuses on glyoxalase 1 (GLO1), the first enzyme of the glyoxalase system, and the rate-limiting enzyme of this catalytic process. Although GLO1 is ubiquitously expressed, protein levels and activities are regulated in a tissue-dependent manner. We provide a comparative analysis of GLO1 protein in different tissues. Our findings indicate a role for the glyoxalase system in homeostasis in the eye retina, a highly oxygenated tissue with rapid protein turnover. We also describe modulation of the glyoxalase system as a therapeutic target to delay the development of age-related diseases and summarize the literature that describes the current knowledge about nutritional compounds with properties to modulate the glyoxalase system.

THE ROLE OF INFLAMMATION IN AGE-RELATED DISEASES

The risk of developing of the diseases such as Alzheimer's disease, atherosclerosis, osteoporosis, arthritis, type 2 diabetes and cancer increases with age. This is why these diseases are also referred to as age-related diseases. There is evidence that the development of age-related diseases significantly contributes to the so-called. Immune aging, in particular, age-related changes in the immune system, one of the manifestations of which is a low level systemic chronic inflammation. The term "inflammatory aging" (Inflamm-aging) well describes the close relationship between low-grade chronic inflammation and aging. At the present stage of the development of medicine, the mechanisms associated with the development of age-related, low-level, chronic inflammatory processes and the ways of their evaluation require further in-depth, multidisciplinary studies. Clearly, inflammatory aging is a predictor of many age-related disease development and high risk of death. Clinical studies have confirmed the view that inhibition of certain mediators of inflammation may reduce the incidence of age-related diseases. However, similar studies focusing on anti-inflammatory drugs are few in number and the results are ambiguous. Further fundamental and translational studies in this direction hope that in the future we will be able to regulate inflammatory processes in a way that ensures a healthy and long-lasting aging of the population.

Beneficial Effects of Exogenous Ketogenic Supplements on Aging Processes and Age-Related Neurodegenerative Diseases.

Life expectancy of humans has increased continuously up to the present days, but their health status (healthspan) was not enhanced by similar extent. To decrease enormous medical, economical and psychological burden that arise from this discrepancy, improvement of healthspan is needed that leads to delaying both aging processes and development of age-related diseases, thereby extending lifespan. Thus, development of new therapeutic tools to alleviate aging processes and related diseases and to increase life expectancy is a topic of increasing interest. It is widely accepted that ketosis (increased blood ketone body levels, e.g., β-hydroxybutyrate) can generate neuroprotective effects. Ketosis-evoked neuroprotective effects may lead to improvement in health status and delay both aging and the development of related diseases through improving mitochondrial function, antioxidant and anti-inflammatory effects, histone and non-histone acetylation, β-hydroxybutyrylation of histones, modulation of neurotransmitter systems and RNA functions. Administration of exogenous ketogenic supplements was proven to be an effective method to induce and maintain a healthy state of nutritional ketosis. Consequently, exogenous ketogenic supplements, such as ketone salts and ketone esters, may mitigate aging processes, delay the onset of age-associated diseases and extend lifespan through ketosis. The aim of this review is to summarize the main hallmarks of aging processes and certain signaling pathways in association with (putative) beneficial influences of exogenous ketogenic supplements-evoked ketosis on lifespan, aging processes, the most common age-related neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis), as well as impaired learning and memory functions.