Search

Hormesis is any kind of biphasic dose-response when low doses of some agents are beneficial while higher doses are detrimental. Radiation hormesis is the most thoroughly investigated among all hormesis-like phenomena, in particular in biogerontology. In this review, we aimed to summarize research evidence supporting hormesis through exposure to low-dose ionizing radiation (LDIR). Radiation-induced longevity hormesis has been repeatedly reported in invertebrate models such as C. elegans, Drosophila and flour beetles and in vertebrate models including guinea pigs, mice and rabbits. On the contrary, suppressing natural background radiation was repeatedly found to cause detrimental effects in protozoa, bacteria and flies. We also discussed here the possibility of clinical use of LDIR, predominantly for age-related disorders, e.g., Alzheimer's disease, for which no remedies are available. There is accumulating evidence that LDIR, such as those commonly used in X-ray imaging including computer tomography, might act as a hormetin. Of course, caution should be exercised when introducing new medical practices, and LDIR therapy is no exception. However, due to the low average residual life expectancy in old patients, the short-term benefits of such interventions (e.g., potential therapeutic effect against dementia) may outweigh their hypothetical delayed risks (e.g., cancer). We argue here that assessment and clinical trials of LDIR treatments should be given priority bearing in mind the enormous economic, social and ethical implications of potentially-treatable, age-related disorders.

The steady rise in life expectancy occurred across all developed countries during the last century. This demographic trend is, however, not accompanied by the same healthspan extension. This is since aging is the main risk factor for all age-associated pathological conditions. Therefore, slowing the rate of aging is suggested to be more efficient in preventing or delaying age-related diseases than treat them one by one, which is the common approach in a current pharmacological disease-oriented paradigm. To date, a variety of medications designed to treat particular pathological conditions have been shown to exhibit pro-longevity effects in different experimental models. Among them, there are many commonly used prescription and over-the-counter pharmaceuticals such as metformin, rapamycin, aspirin, statins, melatonin, vitamin antioxidants, etc. All of them are being increasingly investigated in preclinical and clinical trials with the aim of determine whether they have potential for extension of human healthspan. The results from these trials are frequently inconclusive and fall short of initial expectations, suggesting that innovative research ideas and additional translational steps are required to overcome obstacles for implementation of such approaches in clinical practice. In this review, recent advances and challenges in the field of repurposing widely used conventional pharmaceuticals to target the aging process are summarized and discussed.

In many human populations, especially those living in regions with pronounced climatic differences between seasons, the most sensitive (prenatal and neonatal) developmental stages occur in contrasting conditions depending on the season of conception. The difference in prenatal and postnatal environments may be a factor significantly affecting human development and risk for later life chronic diseases. Factors potentially contributing to this kind of developmental programming include nutrition, outdoor temperature, infectious exposures, duration of sunlight, vitamin D synthesis, etc. Month of birth is commonly used as a proxy for exposures which vary seasonally around the perinatal period. Season-of-birth patterns have been identified for many chronic health outcomes. In this review, the research evidence for the seasonality of birth in adult-life disorders is provided and potential mechanisms underlying the phenomenon of early life seasonal programming of chronic disease and longevity are discussed.

Cardio-metabolic disorders, including type 2 diabetes, are known to be associated with accelerated attrition of telomeres, recognized as genetic and biological markers of aging. Some common genetic characteristics were found regarding the presence of shorter telomeres and the development of type 2 diabetes. However, there are conflicting epidemiological reports regarding the association of leukocyte telomeres lengths with type 2 diabetes: not only the causality of such a link remains unclear, but not all researchers acknowledge its existence. The link between current trends in life expectancy of people with type 2 diabetes and the increase in the number of people with type 2 diabetes raises interest in the question of the possibility of drug or life-style-related modification of leukocyte telomeres length. To address the question how leukocyte telomeres lengths are associated with glucose levels in hyperglycemic categories, we examined the correlations between leukocyte telomeres length and fasting plasma glucose and 2 h post-load plasma glucose levels (2hPG). Our data indicate that leukocyte telomeres length is negatively related to 2hPG and the relationship with increasing of fasting plasma glucose may be non-linear. Remarkably, the negative association between leukocyte telomeres length and age was demonstrated in our research only for individuals with normal fasting plasma glucose levels, but not for those with high fasting plasma glucose levels. The nonlinear nature of interactions between age and 2hPG level has been demonstrated by artificial neural networks modeling when investigating the links between leukocyte telomeres length and metabolic syndrome. Thus, it can be assumed that relationships between leukocyte telomeres length and FPG/2hPG levels are not the same, and this distinction can potentially be used in categorization of metabolic disorders. It is possible that these data along with reports of the possibility of modifying leukocyte telomeres length can improve the understanding of present-day epidemiological trends in type 2 diabetes incidence and mortality. Impact statement Metabolic disorders are known to be associated with accelerated telomere attrition. Their pathophysiological heterogeneity suggests the importance of multiple tests in examining these associations. However, oral glucose tolerance test (OGTT) has rarely been performed in such studies to date. There are few studies aimed at determining leukocyte telomere length (LTL) in different categories of impaired glucose tolerance (IGT), and those that do exist do not take into account the impaired fasting glucose (IFG)/IGT categorization. Therefore, we believe our study, when the OGTT was used, is important to the field. This testing made it possible to determine whether LTLs are associated with glucose levels in different hyperglycemic categories. Our data indicate that relationships between LTLs and IFG/IGT levels are not the same. This distinction can potentially be used in categorization of metabolic disorders and in determining the effectiveness of interventions aimed at treating diabetes and other metabolic abnormalities.

Stem cell therapy (SCT), born as therapeutic revolution to replace pharmacological treatments, remains a hope and not yet an effective solution. Accordingly, stem cells cannot be conceivable as a "canonical" drug, because of their unique biological properties. A new reorientation in this field is emerging, based on a better understanding of stem cell biology and use of cutting-edge technologies and innovative disciplines. This will permit to solve the gaps, failures, and long-term needs, such as the retention, survival and integration of stem cells, by employing pharmacology, genetic manipulation, biological or material incorporation. Consequently, the clinical applicability of SCT for chronic human diseases will be extended, as well as its effectiveness and success, leading to long-awaited medical revolution. Here, some of these aspects are summarized, reviewing and discussing recent advances in this rapidly developing research field.

Nutrition is known to play an important role in the pathogenesis of Alzheimer's disease. Evidence is obtained that the gut microbiota is a key player in these processes. Dietary changes (both adverse and beneficial) may influence the microbiome composition, thereby affecting the gut-brain axis and the subsequent risk for Alzheimer's disease progression. In this review, the research findings that support the role of intestinal microbiota in connection between nutritional factors and the risk for Alzheimer's disease onset and progression are summarized. The mechanisms potentially involved in these processes as well as the potential of probiotics and prebiotics in therapeutic modulation of contributed pathways are discussed.

Type 2 diabetes (T2D) is commonly regarded as a disease originating from lifestyle-related factors and typically occurring after the age of 40. There is, however, consistent experimental and epidemiological data evidencing that the risk for developing T2D may largely depend on conditions early in life. In particular, intrauterine growth restriction (IUGR) induced by poor or unbalanced nutrient intake can impair fetal growth and also cause fetal adipose tissue and pancreatic β-cell dysfunction. On account of these processes, persisting adaptive changes can occur in the glucose-insulin metabolism. These changes can include reduced ability for insulin secretion and insulin resistance, and they may result in an improved capacity to store fat, thereby predisposing to the development of T2D and obesity in adulthood. Accumulating research findings indicate that epigenetic regulation of gene expression plays a critical role in linking prenatal malnutrition to the risk of later-life metabolic disorders including T2D. In animal models of IUGR, changes in both DNA methylation and expression levels of key metabolic genes were repeatedly found which persisted until adulthood. The causal link between epigenetic disturbances during development and the risk for T2D was also confirmed in several human studies. In this review, the conceptual models and empirical data are summarized and discussed regarding the contribution of epigenetic mechanisms in developmental nutritional programming of T2D.

PURPOSE: Intrauterine undernutrition is associated with increased risk of type 2 diabetes. Children born premature or small for gestational age were reported to have abnormal retinal vascularization. However, whether intrauterine famine act as a trigger for diabetes complications, including retinopathy, is unknown. The aim of the current study was to evaluate long-term effects of perinatal famine on the risk of proliferative diabetic retinopathy (PDR).METHODS: We studied the risk for PDR among type 2 diabetes patients exposed to perinatal famine in two independent cohorts: the Ukrainian National Diabetes Registry (UNDR) and the Hong Kong Diabetes Registry (HKDR). We analysed individuals born during the Great Famine (the Holodomor, 1932-1933) and the WWII (1941-1945) famine in 101 095 (3601 had PDR) UNDR participants. Among 3021 (251 had PDR) HKDR participants, we studied type 2 diabetes patients exposed to perinatal famine during the WWII Japanese invasion in 1942-1945.RESULTS: During the Holodomor and WWII, perinatal famine was associated with a 1.76-fold (p = 0.019) and 3.02-fold (p = 0.001) increased risk of severe PDR in the UNDR. The risk for PDR was 1.66-fold elevated among individuals born in 1942 in the HKDR (p < 0.05). The associations between perinatal famine and PDR remained statistically significant after corrections for HbA1c in available 18 507 UNDR (padditive interaction < 0.001) and in 3021 HKDR type 2 diabetes patients (p < 0.05).CONCLUSION: In conclusion, type 2 diabetes patients, exposed to perinatal famine, have increased risk of PDR compared to those without perinatal famine exposure. Further studies are needed to understand the underlying mechanisms and to extend this finding to other diabetes complications. (Less)

Background Evidence was previously provided for sex-related differences in the human gut microbiota composition, and sex-specific discrepancy in hormonal profiles was proposed as a main determinant of these differences. On the basis of these findings, the assumption was made on the role of microbiota in the sexual dimorphism of human diseases. To date, sex differences in fecal microbiota were demonstrated primarily at lower taxonomic levels, whereas phylum-level differences between sexes were reported in few studies only. In the present population-based cross-sectional research, sex differences in the phylum-level human gut microbiota composition were identified in a large (total n = 2301) sample of relatively healthy individuals from Ukraine. Results Relative abundances of Firmicutes and Actinobacteria, as determined by qRT-PCR, were found to be significantly increased, while that of Bacteroidetes was significantly decreased in females compared to males. The Firmicutes to Bacteroidetes (F/B) ratio was significantly increased in females compared to males. Females had 31 % higher odds of having F/B ratio more than 1 than males. This trend was evident in all age groups. The difference between sexes was even more pronounced in the elder individuals (50+): in this age group, female participants had 56 % higher odds of having F/B ratio > 1 than the male ones. Conclusions In conclusion, sex-specific differences in the phylum-level intestinal microbiota composition were observed in the Ukraine population. The F/B ratio was significantly increased in females compared to males. Further investigation is needed to draw strong conclusions regarding the mechanistic basis for sex-specific differences in the gut microbiota composition and regarding the role of these differences in the initiation and progression of human chronic diseases.

Aging is a biological process with effects at the molecular, cellular, tissue, organ, system, and organismal levels and is characterized by decline in physical function and higher risks of age-related diseases. The use of anti-aging drugs for disease prevention has become a high priority for science and is a new biomedicine trend. Geroprotectors are compounds which slow aging and increase lifespan of the organism in question. The common painkiller aspirin, a member of the non-steroidal anti-inflammatory drug (NSAID) family, is one of the potential geroprotective agents. Aspirin is often used in treatment of mild to moderate pain. It has anti-inflammatory and anti-pyretic properties and acts as an inhibitor of cyclooxygenase which results in inhibition of prostaglandin. Acetylsalicylic acid as an active compound of aspirin also inhibits platelet aggregation and is used in the prevention of arterial and venous thrombosis. Aspirin has shown life-extending effects in numerous model organisms. This chapter reviews the evidence for clinical efficacy of aspirin including cardiovascular disease prevention, anti-cancer effects, and improvement of cognitive function. However, there are some limitations of these therapies, including the risk of excessive bleeding. We have also summarized numerous experimental and analytical data that support health and longevity benefits of aspirin treatment by affecting pro-longevity pathways.

Improving healthspan is the main objective of anti-ageing research. Currently, innovative gene therapy-based approaches seem to be among the most promising for preventing and treating chronic polygenic pathologies, including age-related ones. The gene-based therapy allows to modulate the genome architecture using both direct (e.g., by gene editing) and indirect (e.g., by viral or non-viral vectors) approaches. Nevertheless, considering the extraordinary complexity of processes involved in ageing and ageing-related diseases, the effectiveness of these therapeutic options is often unsatisfactory and limited by their side-effects. Thus, clinical implementation of such applications is certainly a long-time process that will require many translation phases for addressing challenges. However, after overcoming these issues, their implementation in clinical practice may obviously provide new possibilities in anti-ageing medicine. Here, we review and discuss recent advances in this rapidly developing research field.

Anise hyssop, Agastache foeniculum, is a widely used medicinal herb with known antioxidant properties. We studied how dietary supplementation with dried A. foeniculum leaf powder affected physiological and metabolic traits as well as activities of antioxidant enzymes and markers of oxidative stress in Drosophila melanogaster. Dietary hyssop extended the lifespan in a sex and genotype independent manner over a broad range of concentrations up to 30 mg/ml. Dietary supplementation with the herb significantly increased fecundity, resistance to oxidative stress and starvation. Higher transcript levels of Drosophila insulin-like peptide (dilp2) and decreased dilp3 and dilp6 transcripts together with increased levels of glycogen and triacylglycerols support an alteration of insulin signaling by the plant extract. Increased enzymatic activities of superoxide dismutase and aconitase as well as elevated protein and low molecular mass thiols also supported an alteration of free radical process in flies treated with dietary A. foeniculum leaf powder. Thus, physiological and metabolic traits as well as free radical processed may be affected by active compounds detected in extracts of anise hyssop leaves and contribute to the increased lifespan and reproductive (egg-laying) activity observed.

Background Gut microbiota plays an important role in physiological and pathological processes of the host organism, including aging. Microbiota composition was shown to vary significantly throughout the life course. Age-related changes in the composition of microbiota were reported in several human studies. In present study, age-related dynamics of phylogenetic profile of gut microbiota was investigated in 1550 healthy participants from Ukrainian population. Results Significant changes in the microbiota composition determined by qRT-PCR at the level of major microbial phyla across age groups have been observed. The relative abundance of Actinobacteria and Firmicutes phyla increased, while that of Bacteroidetes decreased from childhood to elderly age. Accordingly, the Firmicutes/Bacteroidetes (F/B) ratio was shown to significantly increase until elder age. In both sexes, odds to have F/B > 1 tended to increase with age, reaching maximum values in elder age groups [OR = 2.7 (95% CI, 1.2–6.0) and OR = 3.7 (95% CI, 1.4–9.6) for female and male 60–69-year age groups, respectively, compared to same-sex reference (0–9-year) age groups]. Conclusions In conclusion, data from our study indicate that composition of the human intestinal microbiota at the level of major microbial phyla significantly differs across age groups. In both sexes, the F/B ratio tends to increase with age from 0–9-year to 60–69-year age groups. Further studies are needed for a better understanding of mechanisms underlying age-related dynamics of human microbiota composition.

Background Gut microbiota composition is known to depend on environmental (diet, day length, infections, xenobiotic exposure) and lifestyle (alcohol/drug intake, physical activity) factors. All these factors fluctuate seasonally, especially in areas with highly variable climatic conditions between seasons. Seasonal microbiota changes were reported in several previous studies. The purpose of our study was to investigate whether there is a seasonal variability in the gut microbiota composition in Ukrainian population. In contrast to previous studies performed on small-size samples using a longitudinal design, we used cross-sectional design with a large sample size (n = 769). Determination of microbial composition at the level of major microbial phyla was performed by qRT-PCR. Results The relative abundance of major taxonomic groups of gut microbiota was found to be affected by month of sampling. Actinobacteria were more abundant and Bacteroidetes were less abundant in summer-derived samples compared to those obtained during other seasons, whereas Firmicutes content was seasonally independent. The Firmicutes to Bacteroidetes (F/B) ratio was significantly higher in summer-derived samples than in winter-derived ones. Odds to have F/B > 1 were 3.3 times higher in summer samples and 1.9 times higher in autumn samples than in winter ones; neither age, nor sex were significant confounding factors. Conclusions Seasonality of sampling could influence results of human microbiome research, thereby potentially biasing estimates. This factor must be taken into consideration in further microbiome research.

Accumulation of neurotoxic forms of amyloid-β proteins in senile plaques and hyperphosphorylated tau proteins in neurofibrillary tangles is a well-known pathophysiological hallmark of Alzheimer's disease (AD). However, clinical trials with drugs targeting amyloid-β and tau have failed to demonstrate efficacy in treating AD. All currently FDA-approved anti-AD drugs have symptomatic effects only and are not able to cure this disease. This makes necessary to search for alternative therapeutic targets. Accumulating evidence suggests that systemic inflammation and related vascular dysfunction play important etiological roles in AD and precede its clinical manifestation. Therefore, novel therapeutic modalities targeted at these pathophysiological components of AD are intensively developed now. Phytochemicals such as resveratrol, curcumin, quercetin, genistein and catechins are promising anti-AD therapeutics due to their ability to affect major pathogenetic mechanisms of AD, including oxidative stress, neuroinflammation and mitochondrial dysfunction. The implementation of innovative approaches for phytochemical delivery, including the nanotechnology-based ones which enable to significantly enhance their oral bioavailability, would likely provide an opportunity to address many challenges of conventional anti-AD therapies. In this review, roles of inflammation and vascular dysregulation in AD are described and phytobioactive compound-based treatment strategies for AD are discussed.

Metformin is a safe, effective and useful drug for glucose management in patients with diabetes. However in recent years, more attention has been paid to the possibility of using metformin as an anti-aging drug. It was shown to significantly increase the lifespan in some model organisms and delay the onset of age-associated declines. The current review summarizes advances in clinical research on the potential role of metformin in the field of lifespan and healthspan extension. Growing amounts of evidence from clinical trials suggest that metformin can effectively reduce the risk of many age-related diseases and conditions, including cardiometabolic disorders, neurodegeneration, chronic inflammation and frailty. Metformin also holds promise as a drug that could be repurposed for chemoprevention or adjuvant therapy for certain types of cancer. Moreover, metformin induces autophagy by activation of AMPK and can thus be potentially used to promote heathspan by hormesis-like mechanisms. Although long-term intake of metformin is associated with low risk of adverse events, well-designed clinical trials are still required to uncover the potential use of this drug as a geroprotector.

The aging process is known to be associated with heightened oxidative stress and related systemic inflammation. Therefore, antioxidant supplementation is regarded as a promising strategy to combat aging and associated pathological conditions. Food-grade antioxidants from plant-derived extracts are the most common ingredients of these supplements. Phyto-bioactive compounds such as curcumin, resveratrol, catechins, quercetin are among the most commonly applied natural compounds used as potential modulators of the free radical-induced cellular damages. The therapeutic potential of these compounds is, however, restricted by their low bioavailability related to poor solubility, stability, and absorbance in gastrointestinal tract. Recently, novel nanotechnology-based systems were developed for therapeutic delivery of natural antioxidants with improved bioavailability and, consequently, efficacy in clinical practice. Such systems have provided many benefits in preclinical research over the conventional preparations, including superior solubility and stability, extended half-life, improved epithelium permeability and bioavailability, enhanced tissue targeting, and minimized side effects. The present review summarizes recent developments in nanodelivery of natural antioxidants and its application to combat pathological conditions associated with oxidative stress.

Apart from being a safe, effective and globally affordable glucose-lowering agent for the treatment of diabetes, metformin has earned much credit in recent years as a potential anti-aging formula. It has been shown to significantly increase lifespan and delay the onset of age-associated decline in several experimental models. The current review summarizes advances in clinical research on the potential role of metformin in the field of geroprotection, highlighting findings from pre-clinical studies on known and putative mechanisms behind its beneficial properties. A growing body of evidence from clinical trials demonstrates that metformin can effectively reduce the risk of many age-related diseases and conditions, including cardiometabolic disorders, neurodegeneration, cancer, chronic inflammation, and frailty. Metformin also holds promise as a drug that could be repurposed for chemoprevention or adjuvant therapy for certain cancer types. Moreover, due to the ability of metformin to induce autophagy by activation of AMPK, it is regarded as a potential hormesis-inducing agent with healthspan-promoting and pro-longevity properties. Long-term intake of metformin is associated with low risk of adverse events; however, well-designed clinical trials are still warranted to enable potential use of this therapeutic agent as a geroprotector.

Diabetes-related conditions such as chronic hyperglycemia and related oxidative stress and inflammation were repeatedly associated with accelerated telomere shortening in epidemiological studies, although some findings are inconsistent. In present study, we aimed to assess the impact of disturbances in glucose metabolism on association between age and leukocyte telomere length (LTL) in the Ukrainian population. The study was conducted on the 119 adult subjects aged between 43 and 87 years residing in the Kyiv region, Ukraine. LTL was determined by a quantitative PCR-based method. LTL was negatively correlated with the measure of abdominal obesity such as waist-hip ratio, as well as with both fasting plasma glucose (FPG) and two-hour post-load glucose (2hPG) levels. Consistently with previous studies, a significant negative association between LTL and age was observed in individuals with normal (5.6 mmol/L) FPG levels. Unexpectedly, however, no association was found in subjects with impaired glucose metabolism assessed by abnormal FPG or/and 2hPG levels. No association between LTL and age was observed in a logistic regression model; the association between LTL and age became significant after adjusting for FPG level. In the FPG-adjusted model, 1.6-time lower odds to have long telomere length were indicated for each 10 years increase in age. We hypothesize that the attenuation of association between LTL and age in hyperglycemic persons can likely be attributed to the interaction of multidirectional processes determining this relationship.

Fetal stem cell- (FSC-) based therapy is a promising treatment option for many diseases. The differentiation potential of FSCs is greater than that in adult stem cells, and they are more tissue-specific and have lower immunogenicity and better intrinsic homing than embryonic ones. Embryonic stem cells have higher proliferative potential than FSCs but can cause teratomas. Therefore, an evaluation of this potential represents an important biomedical challenge. Since regulation of telomere length (TL) is one mechanism governing cellular proliferation, TL is a useful surrogate marker for cell replicative potential. The prenatal dynamics of TL, however, has never been comprehensively studied. In the present study, dynamics of TL and telomerase activity in the human fetal liver during 5–12 weeks of gestation is examined. Both TL and telomerase activity were positively correlated with week of gestation. For both parameters studied, the trend to increase was evident up to 10th week of gestation. After that, they reached a plateau and remained stable. These findings indicate that telomerase activity remains high during the fetal stage, suggesting high replicative capacity of FSCs and their considerable potential for transplantation therapies. These findings, however, are preliminary only due to small sample size and require further evaluation.

Increasing evidence suggests that risk for age-related disease and longevity can be programmed early in life. In human populations, convincing evidence has been accumulated indicating that intrauterine growth restriction (IUGR) resulting in low birth weight (2.5 kg) followed by postnatal catch-up growth is associated with various aspects of metabolic syndrome, type 2 diabetes and cardiovascular disease in adulthood. Fetal macrosomia (birth weight 4.5 kg), by contrast, is associated with high risk of non-diabetic obesity and cancers in later life. Developmental modification of epigenetic patterns is considered to be a central mechanism in determining such developmentally programmed phenotypes. Growth hormone/insulin-like growth factor (GH/IGF) axis is likely a key driver of these processes. In this review, evidence is discussed that suggests that different aging trajectories can be realized depending on developmentally programmed life-course dynamics of IGF-1. In this hypothetical scenario, IUGR-induced deficit of IGF-1 causes "diabetic" aging trajectory associated with various metabolic disorders in adulthood, while fetal macrosomia-induced excessive levels of IGF-1 lead to "cancerous" aging trajectory. If the above reasoning is correct, then both low and high birth weights are predictors of short life expectancy, while the normal birth weight is a predictor of "normal" aging and maximum longevity.

Insulin-like peptides (ILPs) and components of the insulin signaling pathway are conserved across different animal phyla. Eight ILPs (called DILPs) and two receptors, dInR and Lgr3, have been described in Drosophila. DILPs regulate varied physiological traits including lifespan, reproduction, development, feeding behavior, stress resistance and metabolism. At the same time, different conditions such as nutrition, dietary supplements and environmental factors affect the expression of DILPs. This review focuses primarily on DILP2, DILP3, and DILP5 which are produced by insulin-producing cells in the brain of Drosophila. Although they are produced by the same cells and can potentially compensate for each other, DILP2, DILP3, and DILP5 expression may be differentially regulated at the mRNA level. Thus, we summarized available data on the conditions affecting the expression profiles of these DILPs in adult Drosophila. The accumulated data indicate that transcript levels of DILPs are determined by (a) nutritional conditions such as the protein-to-carbohydrate ratio, (b) carbohydrate type within the diet, (c) malnutrition or complete starvation; (d) environmental factors such as stress or temperature; (e) mutations of single peptides that induce changes in the expression of the other peptides; and (f) dietary supplements of drugs or natural substances. Furthermore, manipulation of specific genes in a cell- and tissue-specific manner affects mRNA levels for DILPs and, thereby, modulates various physiological traits and metabolism in Drosophila.

Diverse physiological pathways have been shown to regulate longevity, stress resistance, fecundity and feeding rates, and metabolism in Drosophila. Here we tesed physiological traits in flies with Rheb and Myc- Rheb overexpressed in gut progenitor cells, known as enteroblasts (EBs). We found that activation of TOR signaling by overexpression of Rheb in EBs decreases survival and stress resistance. Additionall, we showed that Myc co-expression in EBs reduces fly fecundity and feeding rate. Rheb overexpression enhanced the level of whole body glucose. Higher relative expression of the metabolic genes dilps, akh, tobi and pepck was, however, observed. The role of TOR/Myc in the regulation of genes involved in lipid metabolism and protein synthesis was established. We showed a significant role of TOR/Myc in EBs in the regulation of the JAK/STAT, EGFR and insulin signaling pathways in Drosophila gut. These results highlight the importance of the balance between all different types of cells and confirm previous studies demonstrating that promotion of homeostasis in the intestine of Drosophila may function as a mechanism for the extension of organismal lifespan. Overall, the results demonstrate a role of TOR signaling and its downstream target Myc in EB cells in the regulation of Drosophila physiological processes.

Accumulating evidence suggests that adversities at critical periods in early life, both pre- and postnatal, can lead to neuroendocrine perturbations, including hypothalamic-pituitary-adrenal axis dysregulation and inflammation persisting up to adulthood. This process, commonly referred to as biological embedding, may cause abnormal cognitive and behavioral functioning, including impaired learning, memory, and depressive- and anxiety-like behaviors, as well as neuropsychiatric outcomes in later life. Currently, the regulation of gene activity by epigenetic mechanisms is suggested to be a key player in mediating the link between adverse early-life events and adult neurobehavioral outcomes. Role of particular genes, including those encoding glucocorticoid receptor, brain-derived neurotrophic factor, as well as arginine vasopressin and corticotropin-releasing factor, has been demonstrated in triggering early adversity-associated pathological conditions. This review is focused on the results from human studies highlighting the causal role of epigenetic mechanisms in mediating the link between the adversity during early development, from prenatal stages through infancy, and adult neuropsychiatric outcomes. The modulation of epigenetic pathways involved in biological embedding may provide promising direction toward novel therapeutic strategies against neurological and cognitive dysfunctions in adult life.

Aging-associated alterations in composition, diversity and functional features of intestinal microbiota are well-described in the modern literature. They are suggested to be caused by an age-related decline in immune system functioning (immunosenescence) and a low-grade chronic inflammation (inflammaging), which accompany many aging-associated pathologies. The microbiota-targeted dietary and probiotic interventions have been shown to favorably affect the host health and aging by an enhancement of antioxidant activity, improving immune homeostasis, suppression of chronic inflammation, regulation of fat deposition and metabolism and prevention of insulin resistance. Recently, a high effectiveness and safety of novel therapeutic application such as fecal microbiota transplantation in the prevention and treatment of age-related pathological conditions including atherosclerosis, type 2 diabetes and Parkinson's disease has been demonstrated. In this review, recent research findings are summarized on the role of gut micribiota in aging processes with emphasis on therapeutic potential of microbiome-targeted interventions in anti-aging medicine.

There exist numerous experimental and epidemiological data indicating that malnutrition in early development may influence the risk of developing metabolic disorders in adult life, including type 2 diabetes mellitus (T2DM). Epidemiological evidence for such a relationship was mostly obtained in quasi-experimental studies (natural experiments) carried out on the populations of different countries. These studies revealed that exposure to famine in prenatal and/or early postnatal development is associated with increased risk of developing type 2 diabetes in adult life. Epigenetic regulation of gene activity is considered to be the main mechanism linking starvation in early life and increased risk of type 2 diabetes in adulthood. It is believed that exposure to famine during pregnancy may induce persistent epigenetic variations that are thought to have some adaptive value in the early postnatal development but that also lay grounds for metabolic disorders, including type 2 diabetes, in later life. The present review consolidates and discusses the data indicating the possibility of early developmental programming of type 2 diabetes obtained in the course of quasi-experimental studies.

Type 2 diabetes mellitus is characterized by shorter leukocyte telomere length, but the relationship between leukocyte telomere length and type 2 diabetes mellitus development is rather questioned. Fasting and post-load glycaemia associated with different types of insulin resistance and their relation with leukocyte telomere length remains unknown. We compared leukocyte telomere length and fasting or post-load glucose levels in persons who do not receive glucose lowering treatment. For 82 randomly selected rural residents of Ukraine, aged 45+, not previously diagnosed with type 2 diabetes mellitus, the WHO oral glucose tolerance test and anthropometric measurements were performed. Leukocyte telomere length was measured by standardized method of quantitative monochrome multiplex polymerase chain reaction in real time. Spearman’s or Pearson’s rank correlation was used for correlation analysis between fasting plasma glucose or 2-h post-load plasma glucose levels and leukocyte telomere length. Logistical regression models were used to evaluate risks of finding short or long telomeres associated with fasting plasma glucose or 2-h post-load plasma glucose levels. No association of fasting plasma glucose and leukocyte telomere length was revealed, whereas 2-h post-load plasma glucose levels demonstrated a negative correlation ( P Impact statement • Contradictory epidemiologic data have been obtained about the link between the leucocyte telomere length (LTL) and diabetes. Type 2 diabetes (T2D) is likely to be pathophysiologically heterogeneous, but comparison of the association of LTL separately with fasting plasma glucose (FPG) and 2-h post-load plasma glucose (2hPG) levels has not been done before. Thus, the study of LTL changes associated with different types of hyperglycaemia, that largely determine the heterogenity of T2D is important. • In a population-based study of rural Ukrainians, we were the first to demonstrate that the increase of 2hPG (but not FPG) level increases the chances of revealing short telomeres. • The obtained data can help to clarify the relationship between the LTL shortening and different conditions of the insulin resistance (mainly liver resistance in high FPG and mostly muscle and adipose tissue resistance in high 2hPG).

Traditionally, genetics and lifestyle are considered as main determinants of aging-associated pathological conditions. Accumulating evidence, however, suggests that risk of many age-related diseases is not only determined by genetic and adult lifestyle factors but also by factors acting during early development. Type 2 diabetes (T2D), an age-related disease generally manifested after the age of 40, is among such disorders. Since several age-related conditions, such as pro-inflammatory states, are characteristic of both T2D and aging, this disease is conceptualized by many authors as a kind of premature or accelerated aging. There is substantial evidence that intrauterine growth restriction (IUGR), induced by poor or unbalanced nutrient intake, exposure to xenobiotics, maternal substance abuse etc., may impair fetal development, thereby causing the fetal adipose tissue and pancreatic beta cell dysfunction. Consequently, persisting adaptive changes may occur in the glucose-insulin metabolism, including reduced capacity for insulin secretion and insulin resistance. These changes can lead to an improved ability to store fat, thus predisposing to T2D development in later life. The modulation of epigenetic regulation of gene expression likely plays a central role in linking the adverse environmental conditions early in life to the risk of T2D in adulthood. In animal models of IUGR, long-term persistent changes in both DNA methylation and expression of genes implicated in metabolic processes have been repeatedly reported. Findings from human studies confirming the role of epigenetic mechanisms in linking early-life adverse experiences to the risk for T2D in adult life are scarce compared to data from animal studies, mainly because of limited access to suitable biological samples. It is, however, convincing evidence that these mechanisms may also operate in human beings. In this review, theoretical models and research findings evidencing the role of developmental epigenetic variation in the pathogenesis of T2D are summarized and discussed.

Rationale: Association between different components of metabolic syndrome and the rate of age-related telomere shortening was reported repeatedly, although some findings are inconsistent across studies, suggesting the need for further research on the topic. In the present study, we examined relationships between different components of metabolic syndrome (MetS); glucose tolerance reflected in 2-h post-load plasma glucose (2hPG) levels and age on the leukocyte telomere length (LTL) in Ukraine population. Methods: The study was conducted on the 115 adult individuals residing in the Kyiv region (Ukraine). Among them, 79 were diagnosed with MetS according to the International Diabetes Federation definition. LTL were determined by a qPCR-based method. Multivariate logistic regression (MLR) and artificial neural networks (ANN) modeling were used for the analysis of the results. ROC-analysis was also performed to compare the predictively values of this models. Results: MetS was associated with a high (OR = 3.0 CI 1.3–6.7; p = 0.01) risk of having shorter telomeres that remained significant after adjusting for age, gender and 2hPG levels. Fasting plasma glucose (FPG) levels and other MetS components did not affect the magnitude of the relationship and did not reveal the independent influence of these factors. The level of 2hPG in turn, demonstrated a significant relationship (OR = 1.3 CI 1.0–1.6 per 1 mmol/l; p = 0.04) with LTL regardless of the presence of MetS. The non-linearity of the interactions between age, gender and 2hPG level was revealed by neural network modeling (AUC = 0.76 CI 0.68–0.84). Conclusion: Our study found that impaired glucose tolerance, but not FPG levels, affected the association between LTL and MetS, which may be also indicative for pathophysiological differences in these hyperglycemia categories. 2hPG levels can provide an opportunity for a more accurate diagnostics of MetS and for evaluating the rate of aging in patients with MetS. Further research, however, is needed to verify this assumption.

Aging, as a physiological process mediated by numerous regulatory pathways and transcription factors, is manifested by continuous progressive functional decline and increasing risk of chronic diseases. There is an increasing interest to identify pharmacological agents for treatment and prevention of age-related disease in humans. Animal models play an important role in identification and testing of anti-aging compounds; this step is crucial before the drug will enter human clinical trial or will be introduced to human medicine. One of the main goals of animal studies is better understanding of mechanistic targets, therapeutic implications and side-effects of the drug, which may be later translated into humans. In this chapter, we summarized the effects of different drugs reported to extend the lifespan in model organisms from round worms to rodents. Resveratrol, rapamycin, metformin and aspirin, showing effectiveness in model organism life- and healthspan extension mainly target the master regulators of aging such as mTOR, FOXO and PGC1α, affecting autophagy, inflammation and oxidative stress. In humans, these drugs were demonstrated to reduce inflammation, prevent CVD, and slow down the functional decline in certain organs. Additionally, potential anti-aging pharmacologic agents inhibit cancerogenesis, interfering with certain aspects of cell metabolism, proliferation, angioneogenesis and apoptosis.

The development of interventions aimed at improving healthspan is one of the priority tasks for the academic and public health authorities. It is also the main objective of a novel branch in biogerontological research, geroscience. According to the geroscience concept, targeting aging is an effective way to combat age-related disorders. Since aging is an exceptionally complex process, system-oriented integrated approaches seem most appropriate for such an interventional strategy. Given the high plasticity and adaptability of the epigenome, epigenome-targeted interventions appear highly promising in geroscience research. Pharmaceuticals targeted at mechanisms involved in epigenetic control of gene activity are actively developed and implemented to prevent and treat various aging-related conditions such as cardiometabolic, neurodegenerative, inflammatory disorders, and cancer. In this review, we describe the roles of epigenetic mechanisms in aging; characterize enzymes contributing to the regulation of epigenetic processes; particularly focus on epigenetic drugs, such as inhibitors of DNA methyltransferases and histone deacetylases that may potentially affect aging-associated diseases and longevity; and discuss possible caveats associated with the use of epigenetic drugs.

Background Quercetin is regarded as a promising phytochemical in treating metabolic syndrome (MetS). Methods Present study is a randomized, placebo-controlled, double-blind clinical trial aimed at evaluating effects of quercetin on different aspects of MetS in patients aged 60 + . Study participants consumed two quercetin-containing or placebo tablets 3 times per day (daily dose = 240 mg) during 3 months. Results Quercetin administration decreased body weight (−0.32 kg; p = 0.007) and body mass index (−0.12 kg/m2; p = 0.01). The blood pressure was also decreased: systolic blood pressure: −7.7 mm Hg (p Conclusion These findings indicate that quercetin may be effective in treating MetS. This trial was registered by Ukrainian Registry of Clinical Trials on October 30, 2017 (registration №1339).

Life expectancy has grown dramatically in modern times. This increase, however, is not accompanied by the same increase in healthspan. Efforts to extend healthspan through pharmacological agents targeting aging-related pathological changes are now in the spotlight of geroscience, the main idea of which is that delaying of aging is far more effective than preventing the particular chronic disorders. Currently, anti-aging pharmacology is a rapidly developing discipline. It is a preventive field of health care, as opposed to conventional medicine which focuses on treating symptoms rather than root causes of illness. A number of pharmacological agents targeting basic aging pathways (i.e., calorie restriction mimetics, autophagy inducers, senolytics etc.) are now under investigation. This review summarizes the literature related to advances, perspectives and challenges in the field of anti-aging pharmacology.

A number of experimental and epidemiological investigations have provided evidence that the health status and aging rate may largely depend on the conditions of early development. Several recent studies provided data suggesting that effects of stresses in early development can be inherited transgenerationally, causing changes of various characteristics in subsequent generations. It has been shown that epigenetic factors associated with regulation of genetic expression, including DNA methylation and modifications of histones and microRNAs, can play a key role in transgenerational inheritance. Until now, it has been generally accepted that the complete erasure of epigenetic marks takes place during gametogenesis and early embryogenesis. In recent years, however, several papers obtained data demonstrating that, in certain cases, epigenetic modifications induced during early ontogenesis could not be erased completely and be transmitted to descendants, affecting their phenotype over several generations. This review provides data of epidemiological and experimental studies showing the possibility of transgenerational inheritance of life expectancy and longevity-associated traits in several generations.

The Barker hypothesis of ‘foetal origin of adult diseases’ has led to emphasize the concept of ‘developmental programming’, based on the crucial role of epigenetic factors. Accordingly, it has been demonstrated that parental adversity (before conception and during pregnancy) and foetal factors (i.e., hypoxia, malnutrition and placental insufficiency) permanently modify the physiological systems of the progeny, predisposing them to premature ageing and chronic disease during adulthood. Thus, an altered functionality of the endocrine, immune, nervous and cardiovascular systems is observed in the progeny. However, it remains to be understood whether the haematopoietic system itself also represents a portrait of foetal programming. Here, we provide evidence, reporting and discussing related theories, and results of studies described in the literature. In addition, we have outlined our opinions and suggest how it is possible to intervene to correct foetal mal-programming. Some pro-health interventions and recommendations are proposed, with the hope of guarantee the health of future generations and trying to combat the continuous increase in age-related diseases in human populations.

Background Chronic oxidative stress and inflammation are known to be among the leading causes of ageing. Therefore, dietary supplementation with bioactive phytochemicals having antioxidant and anti-inflammatory activities is currently regarded as a promising therapeutic strategy to combat ageing and associated pathological conditions. Methods Curcumin, a lipophilic polyphenol compound derived from the rhizome of the turmeric plant, is recognized as one of the most promising anti-ageing agents now. In this review, the research findings indicative of therapeutic potential of curcumin in combating age-related diseases are summarized and discussed. Results Evidence for antioxidant, immunomodulatory, anti-inflammatory, anti-microbial, cardio-protective, nephro-protective, hepato-protective, anti-neoplastic, anti-rheumatic and hypoglycaemic effects of curcumin has been provided in numerous in vitro and in vivo studies. One important challenge in its clinical application is poor bioavailability related to hydrophobic properties, low solubility and stability, and also quick systemic elimination due to intensive intestine-liver metabolism. Conclusions To overcome current limitations, innovative biotechnological strategies, such as the nanodelivery-based ones, are under active investigation now.

In Drosophila melanogaster, lifespan and fitness traits were investigated as a function of mating status. Four mating protocols were used: virgin males and females, males and females allowed to copulate only once; males and females that had multiple copulations with one partner over the 5-day mating period; and polygamous males and females that had multiple copulations with different partners over the 5-day mating period. Virgin females had the longest lifespan, and polygamous females had the shortest lifespan, potentially due to injuries, infections or exposure to toxic accessory gland products obtained from different males. Reduced lifespan was also observed in males mated to multiple females. Unexpectedly, mating decreased the amount of food eaten by flies. Mating to different partners decreased the amount of fat in both sexes. The number of eggs laid and their quality was increased in females mated to multiple males. Mating status influenced superoxide dismutase (SOD) and peroxidase (PX) activities, as well as the content of advanced glycation end products (AGEs). The mRNA levels of the insulin receptor (InR) gene were significantly increased in the polygamously mated female group compared to the virgin group. Levels of dTOR mRNA were lower in polygamous females. These results indicate that insulin/IGF-1 signaling (IIS) and Drosophila target of rapamycin (dTOR) pathways can mediate the link between mating status and longevity in Drosophila.

Non-genetic inheritance of metabolic state over multiple generations has been widely reported in insects. The present study uses the fruit fly, Drosophila melanogaster, to assess whether lifespan, physiological traits and metabolism are affected by the dietary protein-to-carbohydrate ratio (P:C) of the prior adult generation. Groups of parental flies were fed diets with different P:C ratios. Their progeny groups were raised on the same diet so the only variable in the experiments was the diet fed to the parents. Parental P:C affected the lifespan of female offspring, however had no impact on F1 males survival. Low parental P:C increased feeding rate in progeny. An increase in the P:C ratio from 0.03 to 0.65 decreased the levels of body glucose and trehalose in the offspring and a similar tendency was observed in the levels of circulating hemolymph glucose and trehalose. Offspring also accumulated less triglycerides but more glycogen when parents were fed a low P:C diet. Our study indicates that the parental dietary P:C ration has a strong impact on the lifespan, reproduction, appetite and metabolism in the offspring generation.

Research in the field of gerontology has traditionally focused on later stages of the life cycle. Accumulating evidence, however, suggests that both the rate of age-related functional decline and the later-life health status can be programmed during early development. The central role of epigenetic mechanisms (including DNA methylation, histone modifications and regulation by non-coding RNAs) in mediating these long-term effects has been elucidated. Both rate and direction of age-associated change of epigenetic patterns (“epigenetic drift”) were shown to be largely dependent on early-life environmental conditions. Inter-individual divergences in epigenetic profiles may occur through the stochastic errors in maintaining epigenetic marks, but they can also be adaptively mediated by environmental cues. Recent cohort studies indicate that ticking rate of epigenetic clock, estimated by a DNA methylation-based methods, may be developmentally adjusted, and that individual's discrepancies between epigenetic and chronological age may be programmed early in life. In this Perspective article, recent findings suggesting the importance of early-life determinants for life-course dynamics of epigenetic drift in humans are summarized and discussed.

There is increasing evidence that stress during development can affect adult-life health status and longevity. In the present study, we examined life span (LS), fly weight, fecundity and expression levels of longevity-associated genes (Hsp70, InR, dSir2, dTOR and dFOXO) in adult Drosophila melanogaster flies reared in normal [low density (LD), ~ 300–400 eggs per jar] or crowded [high density (HD), more than 3000 eggs per jar] conditions by using the order (day) of emergence as an index of the developmental duration (HD1-5 groups). Developmental time showed a significant trend to increase while weight showed a significant trend to decrease with increasing the timing of emergence. In both males and females eclosed during first 2 days in HD conditions (HD1 and HD2 groups), both mean and maximum LSs were significantly increased in comparison to LD group. In males, mean LS was increased by 24.0% and 23.5% in HD1 and HD2 groups, respectively. In females, corresponding increments in mean LS were 23.8% (HD1 group) and 29.3% (HD2 group). In HD groups, a strong negative association with developmental time has been found for both male and female mean and male maximum LSs; no association with growth rate was observed for female maximum LS. The female reproductive activity (fecundity) tended to decrease with subsequent days of eclosion. In HD groups, the levels of expression of all studied longevity-associated genes tended to increase with the timing of eclosion in males; no differences were observed in females. On the basis of findings obtained, it can be assumed that the development in conditions of larval overpopulation (if not too extended) could trigger hormetic response thereby extending the longevity. Further studies are, however, needed to confirm this assumption.

Health impacts of low-dose ionizing radiation are significant in important fields such as X-ray imaging, radiation therapy, nuclear power, and others. However, all existing and potential applications are currently challenged by public concerns and regulatory restrictions. We aimed to assess the validity of the linear no-threshold (LNT) model of radiation damage, which is the basis of current regulation, and to assess the justification for this regulation. We have conducted an extensive search in PubMed. Special attention has been given to papers cited in comprehensive reviews of the United States (2006) and French (2005) Academies of Sciences and in the United Nations Scientific Committee on Atomic Radiation 2016 report. Epidemiological data provide essentially no evidence for detrimental health effects below 100 mSv, and several studies suggest beneficial (hormetic) effects. Equally significant, many studies with in vitro and in animal models demonstrate that several mechanisms initiated by low-dose radiation have beneficial effects. Overall, although probably not yet proven to be untrue, LNT has certainly not been proven to be true. At this point, taking into account the high price tag (in both economic and human terms) borne by the LNT-inspired regulation, there is little doubt that the present regulatory burden should be reduced.

SUMMARYFruit flies have eight identified Drosophila insulin-like peptides (DILPs) involved in regulation of carbohydrate concentrations in hemolymph as well as accumulation of storage metabolites. In the present study, we investigated diet-dependent roles of DILPs encoded by genes dilp1–5, and dilp7 in regulation of insect appetite, food choice, accumulation of triglycerides, glycogen, glucose, and trehalose in fruit fly body and carbohydrates in hemolymph. We found that dilp2 gene predominantly influences body glycogen level, dilp3 – trehalose level in hemolymph, while dilp5 and dilp7 affect triglyceride level. Fruit fly appetite was found to be regulated by dilp3 and dilp7 genes. Our data contribute to the understanding of Drosophila as a model for further studies of metabolic diseases and may serve as a guide for uncovering the evolution of metabolic regulatory pathways.HIGHLIGHTSDifferent Drosophila insulin-like peptides play distinctive roles in metabolism, physiology and appetite regulation.Lack of Dilp2 and Dilp5 abrogates glycogen accumulation on high carbohydrate dietsLack of Dilp3 leads to build-up of trehalose in haemolymph on high-carbohydrate-low-protein dietsLack of Dilp3 and Dilp7 leads to increased consumption of protein on low-carbohydrate-high-protein dietsGRAPHICAL ABSTRACT

Every organism must adapt and respond appropriately to the source of nutrients available in its environment. Different mechanisms and pathways are involved in detecting the intracellular and extracellular levels of macronutrients including amino acids. Detection of amino acids in food sources is provided by taste cells expressing T1R1 and T1R3 type receptors. Additionally, cells of the intestine, pancreas or heart sense amino acids extracellularly. Neuronal and hormonal regulation integrates and coordinates the signals at the organismal level. Amino acid-sensitive mechanisms including GCN2 protein, mTOR and LYNUS machinery adjust cellular process according to the availability of specific amino acids. Triggering these mechanisms by genetic manipulations or by external manipulations with diets has a significant impact on lifespan. In model organisms, the restriction of protein or specific amino acids within the diet leads to lifespan-extending effects. However, the translation of results from model organisms to application in humans has to take into account lifestyle, psychology, social aspects and the possibility to choose what to eat and how it is cooked.

There is accumulating evidence that aging phenotype and longevity may be developmentally programmed. Main mechanisms linking developmental conditions to later-life health outcomes include persistent changes in epigenetic regulation, (re)programming of major endocrine axes such as growth hormone/insulin-like growth factor axis and hypothalamic-pituitary-adrenal axis and also early-life immune maturation. Recently, evidence has also been generated on the role of telomere biology in developmental programming of aging trajectory. In addition, persisting changes of intestinal microbiota appears to be crucially involved in these processes. In this review, experimental and epidemiological evidence on the role of early-life conditions in programming of aging phenotypes are presented and mechanisms potentially underlying these associations are discussed.

Hyperglycemia-induced overproduction of reactive oxygen species (ROS) is an important contributor to type 2 diabetes (T2D) pathogenesis. The conventional antioxidant therapy, however, proved to be ineffective for its treatment. This may likely be due to limited absorption profiles and low bioavailability of orally administered antioxidants. Therefore, novel antioxidant agents that may be delivered to specific target organs are actively developed now. Metallic nanoparticles (NPs), nanosized materials with a dimension of 1–100 nm, appear very promising for the treatment of T2D due to their tuned physicochemical properties and ability to modulate the level of oxidative stress. An excessive generation of ROS is considered to be the most common negative outcome related to the application of NPs. Several nanomaterials, however, were shown to exhibit enzyme-like antioxidant properties in animal models. Such NPs are commonly referred to as “nanoantioxidants.” Since NPs can provide specifically targeted or localized therapy, their use is a promising therapeutic option in addition to conventional therapy for T2D. NP-based therapies should certainly be used with caution given their potential toxicity and risk of adverse health outcomes. However, despite these challenges, NP-based therapeutic approaches have a great clinical potential and further translational studies are needed to confirm their safety and efficacy.

Social insects are likely one of the most attractive models for deeper insight into aging research since they have a caste system in which the same genome, due to the differential gene expression, can produce both a short-lived worker and a long-lived queen. In various species of social insects such as ants, wasps, termites, and bees, queens and workers demonstrate up to a 100-fold difference in longevity, with reproductive queens having longer lifespan than nonreproductive workers. The mechanisms mediating this plasticity are more fully characterized in honey bee, Apis mellifera. In this organism, the caste switching was found to be determined by differing larval diets. There is increasing evidence for the central role of epigenetic regulation of gene expression in driving both short-lived worker and long-lived queen phenotypes. The research of various molecular and physiological aspects of the social insect biology is likely a promising approach to identify pathways associated with longevity regulation and to developing treatment strategies to target these pathways.

Social insects are promising model organisms in the study of longevity mechanisms. They have a caste system, in which the same genomes may produce phenotypes significantly distinguished by longevity. The ontogenetic trajectories of bees depend on the duration of supply by a specific nutrient mixture (royal jelly) at the larval stage. Longer feeding by the royal jelly leads to the formation of the queen epigenome, which is different from the epigenome of a working bee. Such epigenetic differences, in turn, induce endocrine changes manifested in increased synthesis of juvenile hormone and activation of TOR (target of rapamycin) signaling pathway, as well as in the modulation of insulin/IGF-1 pathway in queen-destined larvae. In adults, these processes influence the synthesis of vitellogenin (egg yolk precursor determining many aspects of insect ontogenesis). Epigenetic and andocrine mechanisms that underlie differences in longevity among the castes of social insects are discussed.

Recent experimental studies demonstrate that medications targeting aging (antioxidants, calorie restriction mimetics, autophagy inductors, etc.) can substantially promote health and extend lifespan. Pharmacologically targeting aging appears to be more effective in preventing age-related pathology compared with treatments targeted to particular pathologies. The development of new antiaging drugs represents a great opportunity for the pharmaceutical and healthcare industries.