Larval crowding results in hormesis-like effects on longevity in Drosophila: timing of eclosion as a model.

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.

Early-life exposure to substance abuse and risk of type 2 diabetes in adulthood.

Type 2 diabetes (T2D) is a chronic non-communicable disease that is driven by insulin resistance as a result of increasing obesity and decreasing activity levels that occur with increasing age. This disease generally develops after the age of 40, but it is now increasingly diagnosed in children and young adults. Increasing evidence, however, suggests that T2D can originate during early development. It has been repeatedly found that malnutrition during the gestational period can result in intrauterine growth restriction and low birth weight, which in combination with postnatal catch-up growth may subsequently lead to the development of T2D. There is ample evidence that T2D may also be programmed by maternal substance abuse (the harmful use of psychoactive substances such as illicit drugs or alcohol) during pregnancy and/or lactation. The research activity in this field is currently mainly focused on the childhood health problems following prenatal exposures to substance abuse. The delayed programming effects on adult-onset disorders, including metabolic syndrome and T2D, however, have been reported only rarely. This review provides animal and human evidence that early-life exposure to substance abuse, including alcohol, nicotine, and cocaine, may program not only childhood health outcomes but also life-long metabolic health status, including risk of T2D and related conditions.

[THE EFFECT OF DIETARY RESTRICTION DURING DEVELOPMENT OF DROSOPHILA MELANOGASTER ON THE ACTIVITY OF ANTIOXIDANT SYSTEM ENZYMES].

In the previous study we demonstrated that dietary restriction only at the development stage of Drosophila melanogaster may impact the life span of adult flies. It was important that we didn't use qualitative (restriction of proteins or other macro- or microelements) and not a calorie restriction as well, but quantitative dietary restriction that was the proportional reduction of all food components in the larval medium. In the situations when the larvae were reared in the medium types, that contained protein and carbohydrate components in concentrations of 90-10% of food components compared to the standard one (100%), the males were characterised with the significant increase in the maximum life span. The average life span was also increased, but only in those male individuals that developed in the medium types, that contained 50% and 60% of food components compared to controls. Such an effect we haven't detected in the female flies. To study the biochemical changes associated with the physiological effects we have determined the activity of the antioxidant enzymes--superoxide dismutase (SOD) and catalase. In the male flies the 50% dietary restriction implemented during the development has led to the significant increase in a SOD and catalase activity. Also the flies of both sexes reared in the medium with the 50% of food components have been characterised with the reduction in the accumulation of glycation end products. According to these results, we suggest that the changes in the activity of antioxidant enzymes may play a role in the increase of the flies life span caused by the dietary restriction during the development.

Epigenetic programming by early-life stress: Evidence from human populations.

BACKGROUND: A substantial body of experimental and epidemiological evidence has been accumulated suggesting that stressful events in early life including acute perinatal stress, maternal deprivation or separation, and variation in maternal care may lead to neuroendocrine perturbations thereby affecting reproductive performance, cognitive functions, and stress responses as well as the risk for infectious, cardio-metabolic and psychiatric diseases in later life. RESULTS: Findings from recent studies based on both genome-wide and candidate gene approaches highlighted the importance of mechanisms that are involved in epigenetic regulation of gene expression, such as DNA methylation, histone modifications, and non-coding RNAs, in the long-term effects of exposure to stress in early life. CONCLUSIONS: This review is focused on the findings from human studies indicating the role of epigenetic mechanisms in the causal link between early-life stress and later-life health outcomes.

[GENETIC AND EPIGENETIC DETERMINANTS OF ALZHEIMER'S DISEASE].

Alzheimer's disease (AD) is one of the most important economic, medical and social problems in modern society. Numerous studies have highlighted the role of genetic and epigenetic factors in this disease. Increased risk of AD is associated with certain polymorphic variants of the APOE gene, as well as some other, less affecting genes. In the review, recent studies demonstrating the role of genetic and epigenetic factors in the etiology and pathogenesis of AD are discussed.

[The study of telomere length in patients with Parkinson's disease].

OBJECTIVE: Telomeres which are formed by double-strand breaks and DNA under replication, cause cell cycle arrest resulting in cellular senescence and apoptosis. The erosion of telomeres is an important mechanism for regulating the aging process by limiting cell proliferation. Over the last decade, many investigations in the field of telomeric biology showed that telomeric DNA and telomeric proteins are involved in the pathogenesis of some human diseases. The aim of the study was to compare telomere length in patients with Parkinson's disease (PD). MATERIAL AND METHODS: Telomere length was measured in buccal epithelial cells and leukocytes in PD patients and controls. RESULTS AND CONCLUSION: The length of telomeres in cells of buccal epithelium was shorter in patients with PD than in the control group. In blood cells, telomere length did not differ. It is suggested that shortening of telomeres in buccal epithelial cells may be due to oxidative stress and, hence, it can be used as a marker for the early stages of disease.

Early-life nutritional programming of longevity.

Available data from both experimental and epidemiological studies suggest that inadequate diet in early life can permanently change the structure and function of specific organs or homoeostatic pathways, thereby 'programming' the individual's health status and longevity. Sufficient evidence has accumulated showing significant impact of epigenetic regulation mechanisms in nutritional programming phenomenon. The essential role of early-life diet in the development of aging-related chronic diseases is well established and described in many scientific publications. However, the programming effects on lifespan have not been extensively reviewed systematically. The aim of the review is to provide a summary of research findings and theoretical explanations that indicate that longevity can be influenced by early nutrition.

Reciprocal cross differences in Drosophila melanogaster longevity: an evidence for non-genomic effects in heterosis phenomenon?

Reciprocal cross effects (i.e., differences between reciprocal hybrids that are developed by reversing the strains from which the dam and the sire are taken) are commonly used as a measure of sex-linkage or maternal effects. However, the papers reporting parental effects on life span of experimental animals are scarce. In order to investigate the potential of parent-of-origin effects for the longevity of hybrids, we determined the life spans of the inbred lines of Drosophila melanogaster [Oregon-R (OR), Canton-S (CS) and Uman (Um)] that differ significantly in longevity, as well as the life span of the progeny from the reciprocal crosses among them. The hybridization caused the increase in both flies' mean and maximum life span mainly shifting the survival curves upward proportionally at all ages. This resulted in the reduction in the Gompertz intercept (frailty) whereas the Gompertz slope (the rate of aging) was predominantly unchanged. Better-parent heterosis was observed in hybrids between OR and Um inbred lines and the extent of heterosis was more pronounced in hybrids between CS and Um inbred lines if long-lived parent was used as the female parent, and short-lived parent was used as the male parent in the crossing scheme. Such discrepancy in life span between reciprocal crosses may indicate that non-chromosomal factors are significantly contributing to a heterotic response. Our data are in line with the previous reports suggesting the involvement of non-genomic factors, particularly epigenetic events attributed to hybridization, in the manifestation of heterosis.

[Metabolic programming: theoretical concepts and experimental evidence].

It is known that the poor nutrition during a fetal development may contribute to an increased risk of chronic diseases in adulthood. In a modern literature, this phenomenon is called «the nutritional programming of age-related pathologies¼. It is assumed that the qualitative or quantitative deficiency of certain nutritional components during an early development may lead to the adaptations that contribute to improved survival during the prenatal and early postnatal periods of an ontogenesis. However, the consequence of such adaptive changes may also be the development of various pathological processes at the later stages of life. Recent studies have shown that one of the major mechanisms involved in these adaptations is the epigenetic regulation of a gene activity. In this review, the experimental evidence is provided that processes arising from a quantitatively or qualitatively restricted diet during the early stages of development play an important role in the further life and can greatly influence risk of various age-related diseases and life span.

Long-term health consequences of early-life exposure to substance abuse: an epigenetic perspective.

A growing body of evidence highlights the importance of the nutritional or other environmental stimuli during critical periods of development in the long-term programming of organ systems and homeostatic pathways of the organism. The adverse influences early in development and particularly during intrauterine life have been shown to programme the risks for adverse health outcomes in adult life. The mechanisms underlying developmental programming remain still unclear. However, increasing evidence has been accumulated indicating the important role of epigenetic regulation including DNA methylation, histone modifications and non-coding RNAs in the developmental programming of late-onset pathologies, including cancer, neurodegenerative diseases, and type 2 diabetes. The maternal substance abuse during pregnancy, including smoking, drinking and psychoactive drug intake, is one of the important factors determining the process of developmental programming in modern human beings. The impact of prenatal drug/substance exposure on infant and early childhood development is currently in the main focus. The long-term programming effects of such exposures on aging and associated pathologies, however, have been reported only rarely. The purpose of this review is to provide a summary of recent research findings which indicate that maternal substance abuse during pregnancy and/or neonatal period can programme not only a child's health status, but also can cause long-term or even life-long health outcomes via mechanisms of epigenetic memory.

[Effect of dietary restriction during development on the level of expression of longevity-associated genes in Drosophila melanogaster].

It is well known that dietary restriction (DR) may substantially affect the life span (LS) of various model organisms including Drosophila melanogaster. In our recent studies, it has been revealed that the reduction of the content of main nutrients in larval medium may lead to an increase of flies' LS. Analysis of these data suggested that the most likely candidate for such long-term adaptive changes is insects' epigenome (i.e., persistent changes in the activity of genes that are not related to changes in the DNA structure). To examine whether the observed effects may be associated with long-term changes in the epigenetic regulation of genes associated with aging and longevity, in the present study we determined the level of expression of InR and Sir2 genes that are related to the effects of DR. In the larvae developed in DR conditions, the significant increase in the level of transcription of both these genes compared to the controls has been detected. The adult males have shown a significant increase in the level of expression of InR gene while no such changes were observed in females. The Sir2 gene expression level was not different from the control level in adults of both sexes. It has been suggested that larval nutritional stress may lead to the induction of adaptive epigenetic rearrangements and, therefore, it can extend the flies' longevity.

[Effect of the histone deacetylase inhibitor sodium butyrate on the viability and life span in Drosophila melanogaster].

Histone acetylation (one of the most important epigenetic mechanisms controlling gene expression) has been recently shown to be involved in life span (LS) determination. There are some data indicating the geroprotective potential of histone deacetylase (HDAC) inhibitors. In the present study, the effects of HDAC inhibitor, sodium butyrate (SB), on the parameters of viability and LS of Drosophila melanogaster were studied. Since SB is an efficient inducer of epigenetic changes, it can be assumed that its use as a life-extending agent (geroprotector) can be quite promising.

[Epigenetic epidemiology of age-related diseases].

Many studies have shown that our organism is mostly sensitive to different influences in pre- and postnatal periods of ontogenesis. During the critical periods of maturation, these influences induce changes in the organism that relate to ontogenetic plasticity and lead to permanent changes in structure and function of different organ systems of the organism. It is suggested that the main molecular mechanisms of so-called "ontogenetic programming" are based on changes that occur on the epigenetic level, including changes in the genetic expression not connected with modifications of DNA structure. The present review deals with experimental and epidemiologic evidences of the role of epigenetic processes in aging and determination of susceptibility to some age-related diseases, such as cancer, cardiovascular and neurodegenerative diseases, and insulin-independent diabetes.

[Cancer incidence and mortality after low-dose radiation exposure: epidemiological aspects].

Current recommendations for limiting exposure to ionizing radiation are based on the linear-no-threshold (LNT) model for radiation carcinogenesis under which every dose, no matter how low, carries with it some cancer risk. In this review, epidemiological evidences are discussed that the LNT hypothesis is incorrect at low doses. A large set of data was accumulated that showed that cancer risk after ordinarily encountered radiation exposure (natural background radiation, medical X-rays, etc.) is much lower than projections based on the LNT model. The discovery of the low-level radiation hormesis (stimulating effect) implies a non-linear dose-response curve in the low-dose region. The further studies in this field will provide new insights about the mechanisms of radiation carcinogenesis.

[Predisposition to type II diabetes in Ukraine residents exposed to famine 1932-1933 during prenatal development].

It has been shown in a number of studies that the early-life exposition to famine can have long-term consequences for human health. In the present study, the analysis of type 2 diabetes (T2D) prevalence in Ukraine residents born before, during, and after the famine 1932-1933 was performed. It has been found that T2D prevalence is increased in the people exposed to the peak of the famine during prenatal development compared with those not exposed to famine. Such differences are predominantly expressed in those persons born during the first half-year, and they are absent in those born during the second half-year thus pointing to the role of seasonal factors in driving famine-induced disease pathogenesis. We hypothesized that prenatal exposure to famine can result in induction of the long-term metabolic changes that have adaptive significance during early postnatal development but predispose to metabolic disorders at the late stages of life.

[Dependence of acoustic-motor reaction of healthy individuals from geomagnetic activity].

During February-April, 2008 using special computer test, a daily monitoring of simple acoustic-motor reaction was carried out in 18 healthy tested individuals. We found a significant decrease in the speed of acoustic-motor reaction the day before and the same day geomagnetic disturbance occurred, as well as the same and 2-3 days after a geomagnetic calm occurred. Presumably, either an essential increase or a decreases of geomagnetic activity are adverse factors for the functional state of a central nervous system.

[Reproductive overload in D. melanogaster females--its connection with longevity].

The conception of individual reproduction is that fruit flies are genetically designed to oviposit at the highest possible rate. This rate is maintained right up to the moment when the organism begins to age, and the senescence is characterized by the reproduction rate falling exponentially. The population can be divided into z, s, m, and l-phenotypes depending on their resource allocation. The main part of the population consists of m-phenotype flies with a balanced resource allocation. The flies with z-phenotype are infecund; s flies do not reach senility; and l flies, in which the allocation is biased toward somatic organism maintenance, outlast the period of oviposition and die only after they have completely used up their reproductive potential. Individual reproductive patterns and reproductive phenotypes are analyzed for two D. melanogaster populations consisting of 493 and 474 flies. It is shown that there is a mortality curve for each phenotype, and that a part of the population dies out "prematurely" due to reproductive overload.

[Epigenetic etiology of age-related diseases].

In mini-review, the possible role of the epigenetic factors in adaptive potential capacity and etiology of age-related diseases is discussed. The assumption is made that the opportunity of purposeful influence on epigenetic processes can be used in future for development of interventions to delay aging and extend human life span.