[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.

Seasonality of birth in children and young adults (0-29 years) with type 1 diabetes in Ukraine.

AIMS/HYPOTHESIS: Numerous epidemiological studies have shown differences in seasonality of birth patterns between the general population and the group who develop type 1 diabetes mellitus. This finding indicates that environmental factors operating during pre- and/or postnatal development could be aetiologically important. We examined whether the pattern of month of birth for type 1 diabetes patients in Ukraine differs from that for total live births. METHODS: Data consist of prevalent cases of type 1 diabetes in Ukraine by the end of 2003. Cases are restricted to persons born after 1 January 1960, diagnosed with type 1 diabetes before the age of 30 years (n = 20,117). People born during the same time in the general population (n = 29,105,560) were the reference standard. Seasonal patterns were estimated using logistic regression with harmonic terms. RESULTS: We found a strongly significant seasonal pattern of type 1 diabetes incidence rates (p < 0.001), with the lowest rates in December and the highest in April. The rate ratio between the extremes was 1.32 (95% CI 1.27-1.39). Tests for seasonal patterns in subgroups defined by sex and age or by sex and date of birth were all significant with p values less than 0.02. We found no interactions with sex (p = 0.142) or age at diagnosis (p = 0.207), but found a strong interaction with period of birth (p < 0.0001). CONCLUSIONS/INTERPRETATION: The results obtained indicate that early-life factors linked to seasons may influence type 1 diabetes risk later in life.

[Role of seasonal factors in pre- and postnatal ontogenesis for etiology of type 1 diabetes mellitus].

Type 1 diabetes mellitus is a chronic disease characterized by autoimmune degradation of insulin-producing beta-cells. It was shown in a number of epidemiological studies of seasonality of birth in children with type 1 diabetes that the autoimmune process began during fetal and postnatal development. No such studies were carried out in the former Soviet Union countries. The aim of the present study is to compare the seasonal birth month pattern in patients with type 1 diabetes (10780 men and 9337 women) born in 1960-2002 to that in the total population of Ukraine (14 785601 men and 13 911370 women) born during the same period. Significant differences were found between these two populations: chi-squared = 103.97, p < 0.0001 and 135.17, p < 0.0001 in men and women, respectively. The results of cosinor analysis showed similar sinusoidal birth patterns of patients with type 1 diabetes in all sub-groups, irrespective of the age of clinical disease expression: 0-9, 10-19, or 20-29 years. In all cases, the highest and lowest predispositions to type 1 diabetes were inherent in the people born in spring and autumn, respectively. We propose that seasonal differences in the birth pattern in the two above populations could be due to long-term programming of glucose-insulin metabolism determined by the effect of certain seasonal factors during early ontogenesis.

[Molecular and cellular aspects of radiation hormesis in Drosophila melanogaster]. / Molekuliarnye i kletochnye aspekty radiatsionnogo gormezisa u Drosophila melanogaster.

The long-term effects of the R-irradiation of D. melanogaster at the 1-hour egg stage with the dosages of 0.25, 0.50, 0.75, 1.0, 2.0 and 4.0 Gy were investigated. DNA samples were isolated from whole 5-6-days adult males. The aliquots of DNA were digested by S1-nuclease. Preimaginal stage lethality increased with irradiation dose increasing. At the same time, decrease in imaginal LS (life span) was observed after irradiation with the greatest dose (4 Gy) only. Moreover, hormesis by LS has revealed: in males irradiation with 0.25, 0.75 and 1 Gy increased the mean LS, and with 0.25 and 0.5 Gy caused the maximum LS; in females exposures with 0.25, 0.75 and 2 Gy increased the maximum LS. The densitometric assay of DNA electrophoregrams showed decrease by 39.2% of the part of high-molecular-weight DNA in control as a result of S1-nuclease action. Samples of DNA from the irradiated flies were more stable to enzyme action. The higher stability of DNA originated from the irradiated flies could be the result of reparation system activation. Ultrastructural changes induced at the egg stage by irradiation at the dose of 0.75 Gy testify the increased transcriptional activity of the brain cells.

Seasonal programming of adult longevity in Ukraine.

Longevity was significantly associated with season of birth in 101,634 individuals who died in Kiev during the period 1990-2000. The relationship between age at death and month of birth showed a very similar pattern for both men and women. Mean values for the age at death were lowest for subjects born in April-July, and highest for individuals born at the beginning and end of the year. Minimum and maximum ages at death, analysed according to month of birth, differed by 2.6 years in men and 2.3 years in women. For all major causes of death causes, the mean age at death for persons born in the fourth quarter was the highest. These results suggest that, in this population, longevity is affected by prenatal or early postnatal seasonal factors. This is consistent with the hypothesis that the rate of ageing may be programmed in response to environmental influences at critical periods of early development.

The accelerated occurrence of age-related changes of organism in Chernobyl workers: a radiation-induced progeroid syndrome?

The rate of aging was studied in 306 persons working at Chernobyl Atomic Power Station after the accident by means of integral and partial biological age assessment. An accelerated rate of aging was found in 81% of men and in 77% of women in comparison with a control random population sample of Kiev. Persons younger than 45 years appeared to be more vulnerable to radiation. The biological age of persons who worked in the contaminated zone immediately after the disaster exceeded the biological age in those who arrived in Chernobyl 4 months later. The biological age in the investigated persons exceeded its average populational value for 5 years (the integral biological and partial cardiopulmonary age) and for 11 years for the partial psychological age. These data may underlie the concept of radiation progeroid syndrome as the form of accelerated aging.

[Hereditary effects on the rate of aging in humans]. / Nasledstvennye vliianiia na temp stareniia organizma cheloveka.

Twin samples of various ages (154 pairs) were studied in transverse section and under longitudinal observation to assess the quantitative correlation of genetic and environmental influences on the age changes of 320 characters specifying different functional systems of the human organism: nervous, cardiovascular, respiratory, immune, endocrine, locomotor, metabolic, somatic, and mental. An evidence was obtained for a decrease in relative role of inheritance and increase in environmental (both systemic and scholastic) influences on the age-related changes in various organs and body systems of humans in aging. Therefore, the rates of aging and health status in humans may be controlled to some extent by exerting selective influences on the corresponding environmental factors.

Heredity, age and cancer.

A factor analysis of mortality from gastric cancer in the populations of 41 countries has been made. It is concluded that the interrelation between age and cancer has both a biological and a chronological component. On the one hand, tumour development is linked to the molecular-genetic and systemic-physiological mechanisms of ageing. On the other, increasing mortality from cancer with age reflects the number of years for which the organism was exposed to the carcinogenic action. Each of these mechanisms is illustrated by the factor model of mortality from gastric cancer. Hereditary effects on both mechanisms that relate age and cancer are discussed.

Age, sex, and mortality from cardiovascular disease (factor model).

The factor analysis of mortality from cardiovascular diseases in the populations of 17 European countries is presented. The results obtained can be summed up as follows: (1) in different age groups mortality from heart and vessel diseases is determined by various factors which are independent in the statistical sense; (2) the factor structures of mortality from ischemic heart disease, brain vessel damage, and hypertension are only partially coincident; each of these diseases seems to have its own specific pathophysiological mechanisms; and (3) the factor structure of male and female mortality has considerable differences in the young and few differences in the older age group. Some problems of the pathogenesis and prophylactics of cardiovascular diseases are discussed.

[The erythrocyte: aging of the cell and aging of the body]. / Eritrotsit: starenie kletki i starenie organizma.

The factor analysis of the osmotic erythrocyte resistance involved 380 human subjects of both sexes aged from 20 to 106 years. It has been found that body aging is accompanied by a more marked aging of the blood cells during their circulation in the blood.

[Age, sex and ischemic heart disease mortality (factor model)]. / Vozrast, pol i smertnost' ot ishemicheskoi bolezni serdtsa (faktornaia model').

A mathematical model of age mortality due to coronary heart disease among populations of the 24 European countries was made on the basis of the principal components method. It was shown that age and sex differences of mortality can be described by means of three different factors which are statistically independent on each other. Possible pathogenetic mechanisms underlying the formation of the three factors are discussed.

[Balanced hereditary polymorphism and the mortality from cardiovascular diseases in the populations of 17 countries of Europe. I. A correlation analysis]. / Balansirovannyi nasledstvennyi polimorfizm i smertnost' ot serdechno-sosudistykh zabolevanii v populiatsiiakh semnadtsati stran Evropy. Soobshchenie I. Korreliatsionnyi analiz.

The correlation analysis of ratios between six polymorphic genetic systems (ABO, MNSs, Rh, Hp, Gm, HLA) and mortality from ishemic heart disease, brain vascular lesions, and hypertensive disease in 17 European populations has been made. A statistically significant correlation has been established between the populational frequency of most of the 50 phenotypes and genes under study, and mortality. The qualitative structure of correlations and their quantitative expression depend on the cause of death, age and sex. The possible mechanisms of relationship between the genetic populational differences and mortality from cardiovascular diseases are discussed.

[Balanced hereditary polymorphism and the mortality from cardiovascular diseases in the populations of 17 countries of Europe. II. A component analysis]. / Balansirovannyi nasledstvennyi polimorfizm i smertnost' ot serdechno-sosudistykh zabolevanii v populiatsiiakh semnadtsati stran Evropy. Soobshchenie II. Komponentnyi analiz.

Based on the factor analysis (the method of principal components with a varimax rotation of axes), a study was performed on the component structure of interpopulational variations in frequencies of the 50 phenotypes and genes of six polymorphic human systems (ABO, MNSs, Rh, Hp, Gm, HLA). The genetic differences of populations have been found to be related to a small number of independent factors; 7 principal components have extracted 79% of dispersion from the primary data. Five of these components are coupled with mortality from the cardiovascular diseases. The component structure of mortality has specificity in relation to localization of pathological process, age and sex.

[Phenogenetics of human dermatoglyphics (a factorial model)]. / Fenogenetika pal'tsevykh dermatoglifov cheloveka (faktornaia model').

The factor analysis was made of the intrapair differences of the quantitative characteristics of the finger dermatoglyphics in mono- and dizygotic twins. The mechanisms determining "laterality" and "locality" of separate factors are discussed. The developmental model is proposed that suggests existence of several embryonic fields and subsequent incorporation of the genes to control the formation of finger prints.

[Component model of human lymphocyte blast transformation stimulated by phytohemagglutinin]. / Komponentnaia model' blasttransformatsii limfotsitov cheloveka, stimulirovannykh fitogemaggliutininom.

A method of major components was used to develop a mathematical model which permits representing a set of parameters characterizing the process of human peripheral blood lymphocyte PhGA-blasttransformation as nine mutually independent units (components). A quantitative estimation is made for the dependence of blasttransformation parameters on the contribution of separate components which was shown to vary from 5.6 to 24.0%.