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Coronavirus disease 2019 (COVID-19), caused by the novel coronavirus severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), is an ongoing global public health challenge. Current clinical data suggest that, in COVID-19 patients, arterial hypertension (AH) is one of the most common cardiovascular comorbidities; it can worsen outcomes and increase the risk of admission to intensive care unit (ICU). The exact mechanisms through which AH contributes to the poor prognosis in COVID-19 are not yet clear. The putative relationship between AH and COVID-19 may be linked to the role of angiotensin-converting enzyme 2 (ACE2), a key element of the AH pathophysiology. Another mechanism connecting AH and COVID-19 is the dysregulation of the immune system resulting in a cytokine storm, mediated by an imbalanced response of T helper cells subtypes. Therefore, it is essential to optimize blood pressure control in hypertensive patients and monitor them carefully for cardiovascular and other complications for the duration of COVID-19 infection. The question whether AH-linked ACE2 gene polymorphisms increase the risk and/or worsen the course of SARS-CoV-2 infection should also receive further consideration.

Mortality in insects consuming high-protein-and-low-carbohydrate diets resembles a type III lifespan curve with increased mortality at an early age and few survivors that live a relatively long lifespan. We selected for a Drosophila line able to live for a long time on an imbalanced high-protein-low-carbohydrate diet by carrying out five rounds of breeding to select for the most long-lived survivors. Adaptation to this diet in the selected line was studied at the biochemical, physiological and transcriptomic levels. The selected line of flies consumed less of the imbalanced food but also accumulated more storage metabolites: glycogen, triacylglycerides, and trehalose. Selected flies also had a higher activity of alanine transaminase and a higher urea content. Adaptation of the selected line on the transcriptomic level was characterized by down-regulation of genes encoding serine endopeptidases (Jon25i, Jon25ii, betaTry, and others) but up-regulation of genes encoding proteins related to the immune system, such as antimicrobial peptides, Turandot-family humoral factors, hexamerin isoforms, and vitellogenin. These sets of down- and up-regulated genes were similar to those observed in fruit flies with suppressed juvenile hormone signaling. Our data show that the physiological adaptation of fruit flies to a high-protein-low-carbohydrate diet occurs via intuitive pathways, namely a decrease in food consumption, conversion of amino acids into ketoacids to compensate for the lack of carbohydrate, and accumulation of storage metabolites to eliminate the negative effects of excess amino acids. Nevertheless, transcriptomic adaptation occurs in a counter-intuitive way likely via an influence of gut microbiota on food digestion.

The COVID-19 pandemic caused by the coronavirus SARS-CoV-2 has become a serious challenge for medicine and science. Analysis of the molecular mechanisms associated with the clinical manifestations and severity of COVID-19 has identified several key points of immune dysregulation observed in SARS-CoV-2 infection. For diabetic patients, factors including higher binding affinity and virus penetration, decreased virus clearance and decreased T cell function, increased susceptibility to hyperinflammation, and cytokine storm may make these patients susceptible to a more severe course of COVID-19 disease. Metabolic changes induced by diabetes, especially hyperglycemia, can directly affect the immunometabolism of lymphocytes in part by affecting the activity of the mTOR protein kinase signaling pathway. High mTOR activity can enhance the progression of diabetes due to the activation of effector proinflammatory subpopulations of lymphocytes and, conversely, low activity promotes the differentiation of T-regulatory cells. Interestingly, metformin, an extensively used antidiabetic drug, inhibits mTOR by affecting the activity of AMPK. Therefore, activation of AMPK and/or inhibition of the mTOR-mediated signaling pathway may be an important new target for drug therapy in COVID-19 cases mostly by reducing the level of pro-inflammatory signaling and cytokine storm. These suggestions have been partially confirmed by several retrospective analyzes of patients with diabetes mellitus hospitalized for severe COVID-19.

An increasing body of evidence indicates that initiation and progression of many human diseases depend on epigenetic modifications induced by environmental triggers throughout early-life sensitive stages and, to a lesser extent, during adulthood. These environmental triggers include, among others, exposures to infections, environmental pollutants, substances of abuse, and adverse nutritional conditions. These factors can result in chronic pathological conditions in adult life. Evidence is obtained from epigenome-wide association studies (EWAS) that initiation and progression of these pathologies are largely dependent on long-lasting widespread epigenetic dysregulation caused by environmental insults early in life. For certain diseases, candidate genes have been identified which underlie these associations. In this context, DNA methylation is currently the most intensively studied epigenetic phenomenon. In this chapter, recent epidemiological and observational studies are reviewed indicative of a role of epigenetic factors in mediating the association between life-course adverse environmental exposures and long-term health outcomes.

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.

The insulin&ndash, IGF-1 signaling (IIS) pathway is conserved throughout multicellular organisms and regulates many traits, including aging, reproduction, feeding, metabolism, stress resistance, and growth. Here, we present evidence of a survival-sustaining role for IIS in a subset of gut cells in Drosophila melanogaster, namely the intestinal stem cells (ISCs) and progenitor cells. Using RNAi to knockdown the insulin receptor, we found that inhibition of IIS in ISCs statistically shortened the lifespan of experimental flies compared with non-knockdown controls, and also shortened their survival under starvation or malnutrition conditions. These flies also showed decreased reproduction and feeding, and had lower amounts of glycogen and glucose in the body. In addition, increased expression was observed for the Drosophila transcripts for the insulin-like peptides dilp2, dilp5, and dilp6. This may reflect increased insulin signaling in peripheral tissues supported by up-regulation of the target of the brain insulin gene (tobi). In contrast, activation of IIS (via knockdown of the insulin pathway inhibitor PTEN) in intestinal stem and progenitor cells decreased fly resistance to malnutrition, potentially by affecting adipokinetic hormone signaling. Finally, Pten knockdown to enhance IIS also activated JAK&ndash, STAT signaling in gut tissue by up-regulation of upd2, upd3, and soc36 genes, as well as genes encoding the EGF receptor ligands spitz and vein. These results clearly demonstrate that manipulating insulin levels may be used to modulate various fly traits, which are important determinants of organismal survival.

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.

A century-long rise in life expectancy in all developed countries across the globe is, unfortunately, not accompanied by the same extension of human healthspan. This is because the aging process per se is the main risk factor for most chronic diseases affecting the elderly. Therefore, slowing down the aging rate is believed to be more effective in delaying aging-associated chronic disorders than combating them one by one, which is the conventional approach in a current disease-based paradigm. Now, different drugs designed to treat specific pathological conditions and shown to have pro-longevity properties in experimental models are being increasingly developed and investigated in pre-clinical and clinical trials to determine whether they have potential for human healthspan extension as well. The aim of this chapter is to discuss whether the conventionally used drugs can be repurposed to target the aging process per se. The advances and challenges in this emerging research field are summarized and future research directions are discussed.

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.

Aging population presents a major public health challenge across developed societies. Since phytobioactive compounds (PBCs) including resveratrol, quercetin, curcumin, catechin, and epigallocatechin-3-gallate have been repeatedly reported to demonstrate anti-aging properties, they are increasingly investigated for their anti-aging potential now. The therapeutic efficiency of orally administered PBCs is, however, largely limited by their poor stability, solubility in the gastrointestinal tract, and, subsequently, bioavailability. Apart from the use of polymeric nanoparticles in therapeutics delivery as depicted in Section II, biomaterials have been widely used as drug carriers. One of these biomaterials is lipids, which are a large and diverse group of naturally occurring organic compounds important to cell physiology. It has been reported that PBC-loaded lipid nanocomposites provide many benefits over their conventional formulations, including improved solubility and stability, prolonged half-life, enhanced epithelium permeability and bioavailability, and also improved tissue targeting and minimized side effects. This chapter will summarize recent advances in this research area.

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.

Aging is a multifactorial process which affects all animals. Aging as a result of damage accumulation is the most accepted explanation but the proximal causes remain to be elucidated. There is also evidence indicating that aging has an important genetic component. Animal species age at different rates and specific signaling pathways, such as insulin/insulin-like growth factor, can regulate life span of individuals within a species by reprogramming cells in response to environmental changes. Here, we use an unbiased approach to identify novel factors that regulate life span in Drosophila melanogaster. We compare the transcriptome and metabolome of two wild-type strains used widely in aging research: short-lived Dahomey and long-lived Oregon R flies. We found that Dahomey flies carry several traits associated with short-lived individuals and species such as increased lipoxidative stress, decreased mitochondrial gene expression, and increased Target of Rapamycin signaling. Dahomey flies also have upregulated octopamine signaling known to stimulate foraging behavior. Accordingly, we present evidence that increased foraging behavior, under laboratory conditions where nutrients are in excess increases damage generation and accelerates aging. In summary, we have identified several new pathways, which influence longevity highlighting the contribution and importance of the genetic component of aging., This work was supported by the European Research Council (260632 - ComplexI&Aging to A.S.); the Academy of Finland (252048 to A.S); the Biotechnology and Biological Sciences Research Council (BB/M023311/1 to A.S.); the Centre for International Mobility (CIMO) (TM-12–8391 and TM-13–8919 to N.G.); the Spanish Ministry of Economy and Competitiveness, Institute of Health Carlos III (PI14/00328 to R.P. and PI17/01286 to P.N.); the Autonomous Government of Catalonia (2017SGR696 and SLT002/16/00250 to R.P.); the Ministry of Education and Science of Ukraine (grant number 0117U006426 to O.L.); FEDER funds from the European Union (“A way to build Europe” to R.P.); and the Doctoral Programme in Medicine and Life Sciences of University of Tampere (to T.R). R.S is a Sir Henry Wellcome Postdoctoral Fellow funded by Wellcome (204715/Z/16/Z).

In order to escape extreme environmental conditions plants have developed different survival strategies. The study of plant response to high temperatures is especially interesting in representatives of varied cacti families that have to resist big temperature oscillations. In the present study plants of Aylostera, Echinocactus and Mammillaria genera were exposed to temperatures of 40 or 50 °C for 3 h and peroxidase and superoxide dismutase activity, photosynthetic pigments and flavonoids concentration, and lipid peroxide oxidation level in the stem were determined. Plants with different anatomical structure showed distinct patterns of response to high temperature. Plants of Echinocactus grusonii proved the highest drought and heat resistant with strong antioxidant response and the most expressed xerophytic features of anatomical structures (epidermis and cuticle thickening, calcium oxalate accumulation, water-storage tissue development). Heat stress induced a quick increase of peroxidase activity and flavonoid concentration in this species. Relative heat resistance (40 °C) in Mammillaria bocasana is also facilitated by increased flavonoid concentration, chlorophyll a and carotenoid concentration and also high superoxide dismutase activity under normal conditions. We conclude that the development of antioxidant reactions depends on anatomical protection of plants. More effective anatomical conformation to the stress conditions may be accompanied by rapid response to stress at the antioxidant biochemical level. Less effective protection at the anatomical level to hyperthermia is accompanied by the presence of a larger activity of antioxidant enzymes in conditions without short-term high-temperature stress. Plants which do not possess these qualities, Aylostera flavistyla in particular, suffer more from short-term high-temperature stress.

Interventions such as caloric or dietary restriction extend lifespan in organisms spanning from yeast to primates. Despite its positive influence on longevity, dietary restriction has been found to negatively affect reproduction. Many studies have reported negative correlations between lifespan and reproductive characteristics (such as mating rate, fecundity, reproductive period, and others). Such correlation gives the appearance of a resource‐based trade‐off between these two life‐history traits. Here, we have used nutritional geometry to confirm previous findings in flies that dietary macronutrient balance (protein‐to‐carbohydrate ratio, P:C) impacts both lifespan and reproduction, such that across a series of diets differing in P:C, maximum lifespan was observed at a lower P:C (1:8) than that which supported highest fecundity (1:1.5). We have then addressed the question whether variation among Drosophila melanogasterMeigen (Diptera: Drosophilidae) fruit flies in food intake and egg production within a single dietary treatment is negatively associated with within‐diet variation in lifespan, as might be expected under a resource‐based trade‐off. There was no such association between intake rate, egg production, and longevity. We noted that the smaller sample sizes and smaller inter‐individual variance apparent within — as compared to across — diet treatments may have weakened any signature of a trade‐off between lifespan and reproduction. Thus, we conclude that, whereas dietary macronutrient ratio is a primary determinant of both reproduction and longevity, neither eating less nor laying fewer eggs per se predicted lifespan. This supports the view that there is not a simple quantitative resource‐based trade‐off between lifespan and reproduction, but rather these represent life‐history traits with qualitatively different nutritional optima.

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.

In living organisms most oxygen consumed is reduced to water via four-electron reduction. However, few percentages of oxygen are reduced by consecutive one electron mechanisms giving rise to superoxide anion radical, (O2•-), hydrogen peroxide (H2O2) and hydroxyl radical (HO•) and their derivatives collectively called reactive oxygen species (ROS). Nitric oxide (•NO) is produced at oxidation of arginine by nitric oxide synthase (NOS) or at reduction of nitrites by diverse reductases. Interaction of •NO with O2•- results in formation of peroxinitrite (ONOO-), a powerful oxidant. Additionally, H2O2 can interact with •NO resulting in HO• production. Nitric oxide and its derivatives are collectively called reactive nitrogen species (RNS) and together with ROS they form a group of so-called reactive oxygen/nitrogen species (RONS). Nonspecific effects of RONS are related to their interaction with various components of living organisms, whereas specific effects are based mainly on interaction with specific proteins containing [Fe-S]-clusters and thiol groups of cysteine residues. Most early ROS studies were mainly focused on their deleterious effects, whereas now more delicate mechanisms of their involvement in signaling and toxic processes are under inspection. Studies of RNS activities in biological systems started from their vasodilating effects which lead to discovery of activation of soluble guanylate cyclase. Interestingly, at low ROS and RNS concentrations signaling effects prevail, whereas at their high concentrations they affect biological systems inhibiting due to massive oxidation of cellular components.

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.

The article Alternative NADH dehydrogenase extends lifespan and increases resistance to xenobiotics in Drosophila, written by Dmytro V. Gospodaryov. Olha M. Strilbytska. Uliana V. Semaniuk. Natalia V. Perkhulyn. Bohdana M. Rovenko. Ihor S. Yurkevych. Ana G. Barata. Tobias P. Dick. Oleh V. Lushchak and Howard T. Jacobs, was originally published electronically on the publisher’s internet portal on 20 November 2019 without open access. With the author(s)’ decision to opt for Open Choice the copyright of the article changed on 27 January 2020 to © The Author(s) 2020 and the article is forthwith distributed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The original article has been corrected.

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.

There is accumulating evidence that adult-life health status and rate of age-associated functional decline may be programmed early in life. The key role of epigenetic mechanisms in mediating these life-long effects, including DNA methylation histone modification and regulation by non-coding RNAs, has been demonstrated. Early-life environmental conditions were repeatedly shown to significantly affect life-course change of epigenetic patterns known as “epigenetic drift”. Epigenetic drift may arise following both stochastic errors in maintaining epigenetic marks and adaptive changes directly mediated by specific environmental cues. Recently, DNA methylation-based methods for determining rate of epigenetic aging were developed. Recent cohort studies using these methods have shown that ticking rate of epigenetic aging clock can be adjusted in early life, and that life-course dynamics of individual discrepancies between chronological and epigenetic age might be developmentally programmed. In this chapter, recent evidence suggestive of developmental programming of life-course dynamics of epigenetic drift is reviewed and discussed.

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.

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.

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.

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.

In all eukaryotic organisms, the control of growth, metabolism, reproduction, and lifespan is realized by interactions of genetic and environmental signals. An important player in the regulatory network is the target of rapamycin (TOR) signaling pathway, which is triggered by nutritional cues. Given the pivotal role of TOR in regulating multiple processes in organisms, we inhibited TOR by inducible expression of specific RNAi in Drosophila intestinal stem and progenitor cells or progenitor cells alone. We found that TOR inhibition in stem and progenitor cells shortened the lifespan on both regular diet and under malnutrition. Moreover, flies became more short-lived under starvation or oxidative stress conditions if TOR was inhibited. TOR-RNAi expression resulted in a decrease in body glycogen and TAG levels. All these physiological and metabolic changes might be partially explained by significant changes in mRNA levels for genes encoding the Drosophila insulin-like peptides (dilp2, dilp3 and dilp5) with subsequent effects on insulin signaling to modulate gene expression in peripheral tissues (e.g. tobi and pepck transcripts). In the gut, a strong increase in transcript levels of cytokines upd2, upd3 and downstream target socs36e of the JAK/STAT signaling pathway in the gut indicate an important role for this signaling pathway when TOR is inhibited.

The Pantoea agglomerans 8488 lipopolysaccharide (LPS) was isolated, purified and characterized by monosaccharide and fatty acid analysis. The O-polysaccharide and lipid A components of the LPS were separated by mild acid degradation. Lipid A was studied by electrospray ionization mass spectrometry (ESI-MS) and found to consist of hexa-, penta-, tetra- and tri-acylated species. Two-dimensional nuclear magnetic resonance (NMR) spectroscopy revealed the following structure of the O-polysaccharide repeating unit &rarr, 3)-&alpha, L-Rhap-(1&rarr, 6)-&alpha, D-Manp-(1&rarr, L-Fucp-(1&rarr, 3)-&beta, D-GlcNAcp-(1&rarr, The LPS showed a low level of toxicity, was not pyrogenic, and reduced the adhesiveness index of microorganisms to 2.12, which was twofold less than the control. LPS modified by complex compounds of germanium (IV) and tin (IV) were obtained. It was found that six LPS samples modified by Sn compounds and two LPS samples modified by Ge compounds lost their toxic activity when administered to mice in a dose of LD50 (105 &micro, g/mice or 5 mg/kg). However, none of the modified LPS samples changed their serological activity in an Ouchterlony double immunodiffusion test in agar.

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.

Inspired from plant medicine, a drug that partially compensates for memory decline in aged flies and mice is identified., Cognitive impairments can be devastating for quality of life, and thus, preventing or counteracting them is of great value. To this end, the present study exploits the potential of the plant Rhodiola rosea and identifies the constituent ferulic acid eicosyl ester [icosyl-(2E)-3-(4-hydroxy-3-methoxyphenyl)-prop-2-enoate (FAE-20)] as a memory enhancer. We show that food supplementation with dried root material from R. rosea dose-dependently improves odor-taste reward associative memory scores in larval Drosophila and prevents the age-related decline of this appetitive memory in adult flies. Task-relevant sensorimotor faculties remain unaltered. From a parallel approach, a list of candidate compounds has been derived, including R. rosea–derived FAE-20. Here, we show that both R. rosea–derived FAE-20 and synthetic FAE-20 are effective as memory enhancers in larval Drosophila. Synthetic FAE-20 also partially compensates for age-related memory decline in adult flies, as well as genetically induced early-onset loss of memory function in young flies. Furthermore, it increases excitability in mouse hippocampal CA1 neurons, leads to more stable context-shock aversive associative memory in young adult (3-month-old) mice, and increases memory scores in old (>2-year-old) mice. Given these effects, and given the utility of R. rosea—the plant from which we discovered FAE-20—as a memory enhancer, these results may hold potential for clinical applications.

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.

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.

A growing body of evidence demonstrates that adverse events in early developmental stages may increase the risks for unfavorable health outcomes in adult life, including cancer, neurodegenerative diseases, and type 2 diabetes. This assumption underlies the developmental origins of adult health and disease concept. Accumulated data indicate that epigenetic regulation of gene expression plays an important role in developmental programming of age-associated disorders. Deregulation of the epigenetic pathways has also been shown to contribute to the aging process per se. The role of early life epigenetic events in developmental programming of aging and age-related disorders has been highlighted in many animal studies. Human findings, however, are rather scarce to date. The aim of present chapter is to provide a summary of conceptual frameworks and empirical findings indicating that conditions in early life may program adult health status and risk for aging-associated chronic pathological conditions via epigenetic mechanisms.

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.

Aging is often associated with accumulation of oxidative damage in proteins and lipids. However, some studies do not support this view, raising the question of whether high levels of oxidative damage are associated with lifespan. In the current investigation, Drosophila melanogaster flies were kept on diets with 2 or 10% of either glucose or fructose. The lifespan, fecundity, and feeding as well as amounts of protein carbonyls (PC) and lipid peroxides (LOOH), activities of superoxide dismutase (SOD), catalase, glutathione-S-transferase (GST), and glutathione reductase activity of thioredoxin reductase (TrxR) were measured in "young" (10-day old) and "aged" (50-day old) flies. Flies maintained on diets with 10% carbohydrate lived longer than those on the 2% diets. However, neither lifespan nor fecundity was affected by the type of carbohydrate. The amount of PC was unaffected by diet and age, whereas flies fed on diets with 10% carbohydrate had about fivefold higher amounts of LOOH compared to flies maintained on the 2% carbohydrate diets. Catalase activity was significantly lower in flies fed on diets with 10% carbohydrates compared to flies on 2% carbohydrate diets. The activities of SOD, GST, and TrxR were not affected by the diet or age of the flies. The higher levels of LOOH in flies maintained on 10% carbohydrate did not reduce their lifespan, from which we infer that oxidative damage to only one class of biomolecules, particularly lipids, is not sufficient to influence lifespan.

Background Metagenomic studies confirm that obesity is associated with a composition of gut microbiota. There are some controversies, however, about the composition of gut microbial communities in obese individuals in different populations. To examine the association between body mass index and microbiota composition in Ukrainian population, fecal concentrations of Bacteroidetes, Firmicutes, Actinobacteria and Firmicutes/Bacteroidetes (F/B) ratio were analyzed in 61 adult individuals. Results The relative abundance of Actinobacteria was small (5–7%) and comparable in different BMI categories. The content of Firmicutes was gradually increased while the content of Bacteroidetes was decreased with increasing body mass index (BMI). The F/B ratio also raised with increasing BMI. In an unadjusted logistic regression model, F/B ratio was significantly associated with BMI (OR = 1.23, 95% CI 1,09–1,38). This association continued to be significant after adjusting for confounders such as age, sex, tobacco smoking and physical activity (OR = 1.33, 95% CI 1,11–1,60). Conclusions The obtained data indicate that obese persons in Ukraine adult population have a significantly higher level of Firmicutes and lower level of Bacteroidetes compared to normal-weight and lean adults. Electronic supplementary material The online version of this article (doi:10.1186/s12866-017-1027-1) contains supplementary material, which is available to authorized users.