Mitochondria play a key role in aging and, therefore, are promising targets for developing interventions to increase longevity and slow aging. This chapter describes the role of mitochondria in prolongevity interventions such as dietary restriction and physical exercise. Also discussed is the potential for pharmacological substances, including resveratrol, rapamycin, metformin, urolithins, spermidine, nicotinamide adenine dinucleotide, carnitine, Skulachev quinone, and mitoquinone, to modulate mitochondrial dynamics, function, and biogenesis.

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.

Numerous human chronic pathological conditions depend on epigenetic modifications induced by environmental triggers throughout sensitive stages early in development. Developmental malnutrition is regarded as one of the most important risk factors in these processes. We present an overview of studies that the initiation and progression of many diseases are largely dependent on persisting epigenetic dysregulation caused by environmental insults early in life. For particular disorders, candidate genes were identified that underlie these associations. The current study assessed the most convincing evidence for the epigenetic link between developmental malnutrition and adult-life disease in the human population. These findings were obtained from quasi-experimental studies (so-called 'natural experiments'), i.e. naturally occurring environmental conditions in which certain subsets of the population have differing levels of exposure to a supposed causal factor. Most of this evidence was derived on the DNA methylation level. We discussed DNA methylation as a key player in epigenetic modifications that can be inherited through multiple cell divisions. In this Perspective article, an overview of the quasi-experimental epidemiological evidence for the role of epigenetic mechanisms in the developmental programming by early-life undernutrition is provided.

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 quercetincontaining 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/ m(2); p = 0.01). The blood pressure was also decreased: systolic blood pressure: -7.7 mm Hg (p < 0.001), diastolic blood pressure: -4.1 mm Hg (p = 0.001) relative to baseline values; these effects remained statistically significant after controlling for age, sex and body mass index. Quercetin intervention also improved cholesterol metabolism (serum total cholesterol: -0.44 mmol/L; p = 0.003; low-density lipoprotein cholesterol: -0.41 mmol/L; p = 0.007) and decreased fasting plasma insulin (-2.01 mu U/mL; p = 0.02) and glucose level at 2-hour oral glucose tolerance test (-0.78 mmol/L; p = 0.004). Telomere length and markers of oxidative stress were mostly unchanged except for glutathione level which was significantly decreased (-0.24 mu M/L; p = 0.005) in the quercetin-treated group. 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 No1339).

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.

AbstractIn 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.

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.

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.

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.

Telomere shortening is a well-known hallmark of both cellular senescence and organismal aging. An accelerated rate of telomere attrition is also a common feature of age-related diseases. Therefore, telomere length (TL) has been recognized for a long time as one of the best biomarkers of aging. Recent research findings, however, indicate that TL per se can only allow a rough estimate of aging rate and can hardly be regarded as a clinically important risk marker for age-related pathologies and mortality. Evidence is obtained that other indicators such as certain immune parameters, indices of epigenetic age, etc., could be stronger predictors of the health status and the risk of chronic disease. However, despite these issues and limitations, TL remains to be very informative marker in accessing the biological age when used along with other markers such as indices of homeostatic dysregulation, frailty index, epigenetic clock, etc. This review article is aimed at describing the current state of the art in the field and at discussing recent research findings and divergent viewpoints regarding the usefulness of leukocyte TL for estimating the human biological age.

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.

Wolbachia is an intracellular symbiont that infects a large number of arthropod species, ensuring its success in populations by influencing host reproduction. The wMel strain in Drosophila melanogaster does not cause any strong modifications of sexual reproduction. Consequently, it is not clear how the high infection rates of the bacterium in populations of this species are maintained. The wMel strain is classified into two groups of genotypes - wMel and wMelCS. The wMel genotype is ubiquitous in populations, while wMelCS is rare. In this study, we analyzed fitness-related traits in isofemale lines from the unique natural population from Uman (Central Ukraine), in which we observed preservation of the rare wMelCS genotype despite the fluctuations of infection rates between years. We analyzed these effects of Wolbachia genotype and host genetic background on important fitness parameters such as sensitivity to cold and oxidative stress, female fecundity and lifespan. We found that, in the studied population, Wolbachia had an impact on fitness traits only in certain Drosophila genotypes. Positive effects were manifested in the alterations of fecundity, but at the cost of reduced lifespan and resistance to stress. Based on these findings, we conclude that the effect of bacteria on fitness and stress related traits is context-dependent and is modified by the host genotype, at least in the lines established from the Uman population.

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.

An express method for the diagnosis of the rate of human aging has been developed based on a questionnaire that includes 15 indices of aging. The panel of biomarkers developed for the determination of biological age was validated with the Bayesian method and neural network analysis. The average error in the determination of the biological age estimated with the Bayesian method was 14.5 years. Training of the neural network on a data array of 412 people provided significantly better results: the error was 7.5 years. The proposed method is simple, easy, rapid, and can readily be applied in outpatient and inpatient conditions. It does not require instrumental or laboratory examinations. This technique can be used to prescreen patients at risk of accelerated aging for further in-depth research.

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.

Accumulating evidence suggests that exposure to unfavorable conditions early in life can substantially contribute to the risk of chronic disorders later in life ('developmental programming' phenomenon). The mechanistic basis for this phenomenon remains poorly understood so far, although epigenetic mechanisms such as DNA methylation, histone modifications and microRNA-mediated gene regulation apparently play a crucial role. The key role of epigenetic modifications triggered by unfavorable environmental cues during sensitive developmental periods in linking adverse early-life events to later-life health outcomes is evident from a large body of studies, including methylome-wide association studies and research of candidate genes. Toxic metals (TMs), such as heavy metals, including lead, chromium, cadmium, arsenic, mercury, etc., are among environmental contaminants currently most significantly impacting human health status. Since TMs can cross the placental barrier and accumulate in fetal tissues, exposure to high doses of these xenobiotics early in development is considered to be among important factors contributing to the developmental programming of adult-life diseases in modern societies. In this mini-review, we summarize epidemiological findings indicating that prenatal TM exposure can induce epigenetic dysregulation, thereby potentially affecting adult health outcomes.

Insulin-like peptides (ILPs) belong to the insulin superfamily and act as hormones, neuromediators, and growth factors during the post-embryonic life-cycle stages of insects. These peptides are encoded by different genes in various species. In the genus Drosophila, eight peptides are known, seven of which are likely to bind the Drosophila insulin receptor, whereas DILP8 is a known ligand of the Lgr3 receptor. Binding of DILPs 1-7 to receptors leads to activation of intracellular proteins related to the conserved insulin/IGF (insulin-like growth factors) signaling pathway. The insulin pathway acts within a complex physiological regulatory network involved in the coordination of development, growth, behavior, metabolism, lifespan, and cognitive functions in insects. The current review summarizes recent data about the structure and function of ILPs in fruit flies. The role of environmental factors and genetic manipulations in modulating the functions of DILPs and their association with lifespan and metabolism of Drosophila are assessed. Further investigation and identification of pharmacological or biotechnological interventions that may decrease insulin/IGF signaling could be a highly promising approach for extension of human health span and longevity.

Phytochemicals offer great hope for the development of new drug classes for treating aging-cciated conditions. These compounds may activate pathways involved in aging, such as autophagy, DNA repair, and counteract aging-related systemic oxidative stress and inflammation [1]. Anti-aging potential was reported for several phytobioactive compounds including curcumin, resveratrol, quercetin, epigallocatechin gallate, berberine and several others [2]. The therapeutic potential of orally administered phytochemicals is, however, significantly limited because of their low gastrointestinal absorption, chemical instability, low hydrophilicity, scarce biodistribution and poor penetration/accumulation in the body [3]. These features certainly lead to decreasing the rate and extent of the absorption of oral drugs from solid dosage forms and reducing their bioavailability in the body.

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.