[Analysis of the association of polymorphic variants of SYP1A2, GSTT1,GSTM1, GSTP1, XRCC1, XRCC3, AR and VDR genes with predisposition to the development of prostate cancer].

One of the risk factors for the development of malignant tumors, including prostate cancer, is an individual genetic predisposition due to the various unfavorable polymorphic variants of normal genes. The aim of the study was to com- pare the frequency of different genotypes of polymorphic vari- ants of genes CYPJA2, GSTT, GSTM, GSTP1 (xenobiotics detoxification), XRCC1, XRCC3,(DNA repair) and VDR, AR (transcription factors) in patients with prostate cancer and in control group to determine their association with genetic pre- disposition to this disease. According to the results obtained the rs1544410 AA genotype (VDR gene) and the presence of less than 20 CAG repeats in the 1st exon (AR gene) are the risk factors for the development of prostate cancer. The het- erozygous genotype 722 CT (XRCC3 gene) demonstrated the protective effect.

[Telomere length, telomerase activity, stress and aging].

The review is dedicated to analysis of data available at present time concerning possible influence of stress upon telomere lengths and telomerase activity, as well as various ways of counteracting it. Present-day telomerase theory of aging gains a new impetus, shedding light upon the influence of psychological state of humans and their ability to counteract stress, upon the process of aging. It also tends to regard telomere shortening and the decrease in the activity of telomerase as a marker of level of the ability to adapt to both inner and outer influences. Both aging and age-dependent diseases are proved to be substantially retarded not only by the administration of drugs, but also by psychological means, which forms a good way towards healthy longevity. With complete understanding of the impossibility to prevent or even to slow down natural senescence itself, these methods allow to remove causes, which accelerate senescence, and to increase the average human longevity.

[Mosaic forms of ataxia-telangiectasia].

Ataxia-telangiectasia (AT) is a severe hereditary autosomal recessive neurodegenerative disease associated with accelerated aging and caused by mutation in both alleles of atm gene. This gene encodes a key protein of cell response to DNA damage--an ATM protein kinase. Normally, upon formation of DNA double strand breaks ATM is autophosphorylated and its active form phospho-ATM (P-ATM) appears. Here we describe a mosaic form of AT in which cells of the same patient with normal atm gene demonstrated the accumulation of P-ATM in response to DNA double-strand breaks-inducing factors whereas in cells bearing a mutant form of atm P-ATM was not detected. The epigenetic markers such as histone deacetylases SIRT1 and SIRT6, and trimethylated forms of histone H3 - H3K9me3 and H3K27me3--were studied in the nuclei of primary fibroblasts derived from patients with different forms of AT and the increase of SIRT6 level was revealed.

[Diagnostics of ataxia-telangiectasia by the express-test found on the method of indirect immunofluorescence].

Ataxia-telangiectasia (AT) is a hereditary severe neurodegenerative disease developing, when mutations take place in both alleles of the atm gene, which encodes the key protein of the cellular response to DNA damage (DDR)--ATM proteinkinase. In response to the occurrence of double-strand DNA breaks, the ATM proteinkinase pass the autophosphorylation, and its active form--the phospho-ATM (P-ATM) appears in cells. In the nuclei of cells having the atm gene, P-ATM is revealed, being absent in cells with mutated forms of this gene, by means of the application of the modified method of indirect immunofluorescence. This peculiarity may be applied in the clinic, in order to confirm the diagnosis of AT.

[Violation of the homologous chromosomes approchement as the answer to the small doses of roentgen irradiation].

Any violation of the homologous chromosome DNA repair leads to the genome instability, characteristic for hereditary syndromes and for aging cells. Using low doses of ionizing radiation (3-10 cGy) we have found any transference of the homologous centromere loci of the chromosome 1 (1q12) from the periphery to the cen- tre of the nucleus in the lymphocytes of young healthy donors. The same effect was found after any influence of RNA-polymerase inhibitor a-amanitine. Some changes in the chromatin structure during aging (70-80 years old patients) result in the difficulties in chromosome displacement, accompanied with any trouble in the appro- achement of the homologous chromosome loci as an answer to low doses of radiation.

[The factor analysis results of the relationship of socio-demographic, clinical and functional indicators with the likelihood of identifying age-related disorders in the population in North-Western Russia].

By using the method of factor analysis (principal component method) the determinants of disease in elderly and senile patients were searched with an estimate of their influence degree in the population of the North-West Russia. The data from medical records of 712 patients of both sexes aged 59 to 98 years were analyzed. The factor 1 proved to be associated with: marital status, living conditions, family relationships, bad habits, appearance, cough, diet, hearing and vision, laxatives, joint health, ability to move and sleep disturbances. Factor 2 combined diseases of older: cerebral stroke, myocardial infarction, cardiac arrhythmia, diabetes, kidney disease, obesity, thyroid disease, Parkinson's disease, lung disease, anemia, arthritis, osteoporosis, the number of surgeries and joint diseases. The factor 3 was found to self-association ability before and after admission to the assessment of the patients' mental state for MMSE test after admission. It is concluded that the development of age-related (especially the musculoskeletal system pathology) is associated with social characteristics and living conditions of patients, and treatment of the most age-related diseases requires consideration of comorbidity.

[The influence of age of donors on the ability of cells to homologous recombination DNA repair].

Old and young donors cells show different ability to homologous recombination (shown on the first stage--the chromosome transference) in vitro, that we suppose could be the reasons of the genome instability in aging. Homologous recombination, induced by X-radiation, is limited in cells taken from donors older than 70 years. Alpha-amanitin, the RNA-polymerize II repressor, in toxic doze, could induce the chromosome transference in the cells from all studied groups: from old and young donors and donors with repair process defect (with BRCA 1, 2 mutations). Summarized effect of X-radiation and alpha-amanitin does not increase the induction of the chromosome transference.

[Telomere length in the population of long-lived persons of North-West region of Russia].

Interdisciplinary study of telomere length, polymorphism of genes of renin-angiotensin (ACE) and serotonin (5HTR2A and 5HTTPR) systems in population of aged and old inhabitants of the North-West of Russia was conducted, in their relations to data from clinical and geriatric anamnesis, and psychological functioning. Regular link between telomere length and respondent's age was demonstrated in subgroups of old respondents and long-livers, by method of factor analysis.

[Distribution of serotonin transporter 5-HTTLPR gene polymorphism in population of the North-West of Russia].

Genetic polymorphism of the promotor zone of the gene of serotonin transporter (5HTT) is related to adaptive ability of humans, along with ability of conducting emotional control. Consequently, 5HTT polymorhisms form a constructive model of enhanced resistance to psychoemotional strain in aged humans. The paper is dedicated to tracing back relations between 5HTT polymorphic variants, and psychological characteristics of the long-livers of the North-Western Russia, as well as the geriatric ones.

[Metformin slows down ageing processes at the cellular level in SHR mice].

It has been shown recently that metformin, the indirect mTOR-kinase inhibitor, significantly increases medium (by 37.8%) and maximum (by 10.3%) life span of SHR mice (Anisimov et al., 2008). We obtained fibroblasts from skin of 11-, 16-, 19- and 23-months-old SHR mice treated with metformin since the third and ninth day of life. We studied markers of cellular senescence in these fibroblasts. Significant differences were observed between the average number of senescence-associated heterochromatic foci (SAHF), the average of area nuclei and fluorescence intensity of nucleus after staining for gamma-H2AX in control and experimental animals. Also, we showed that metformin prevented the accumulation of fibroblasts with large area of nuclei; high activity of senescence-associated beta-galactosidase (SA-beta-gal), and high fluorescence intensity after staining for gamma-H2AX. It appears that accumulation of large quantity of senescence markers within a cell triggers it to enter the aging process. It appears that the increase of "old" cell population above the threshold disrupts the normal function of certain tissues, organs, and finally, the whole organism. It appears that metformin delays the "old" cells accumulation and prolongs the organism youth.

[Distribution of structural polymorphisms of angiotensin-converting enzyme and serotonin receptor 5-HT2A genes among long-livers of North-Western Russia].

In the group of long-livers of the North-West of Russia, I/D polymorphism of angiotensin-converting enzyme (ACE) gene and C102T polymorphism of serotonin receptor (5-HT2A) gene were studied. No reliable differences in allele frequency of these genes between long-livers and young people were detected. Nevertheless, highly pronounced difference in the A1/A2 allele frequency of 5-HT2A gene between populations of the North-West of Russia, on the one hand, and of the USA, on the other hand, was discovered (i.e. 0.397(A1), 0.603(A2), and 0.615(A1), 0.385(A2), respectively). Differences of this kind between the two populations deserve special consideration, conditioning the necessity of further detailed analysis of other genes of the serotonin system in the populations of other regions of Russia.

[Syndrome of premature ageing in ataxia-telangiectasia patients].

Ataxia-telangiectasia (AT), a genetic disorder due to mutation of gene atm characterized by progressive neurological abnormalities in combination with oculocutaneous telangiectasias, immunodeficiency, and increased frequency of malignant formations, is inherited according to autosome recessive mechanism. Cells of the patients with AT show increased radio sensitivity and some markers of premature ageing. The telomere lengths are sharply shortened in these cells already from the birth. We studied radio sensitivity (at the dose 2 Gy) and manifestations of premature ageing markers in cultured skin fibroblasts obtained from two unrelated AT patients and their heterozygous parents. We have shown that all the markers studied, that is HP1-gamma, phosphorylation of the histone variant H2AX (gamma-H2AX), and focuses 53BP1, indicate premature ageing of both the patients' and their blood relatives' cells. However, cells of the heterozygous carriers express premature ageing to a less extent. Investigation of the repair process characteristics (the amount of gamma-H2AX and the deal of cells with focuses 53BP1 in their nuclei) after X-ray irradiation has given following results: the patients' cells complete repair only half even in 24 after irradiation, while the healthy donor's cells complete repair in 24 h. Heterozygous cells also reliably differ from healthy donor's cells. Only in the case of apoptosis marker, p21, heterozygous cells do not differ from normal cells, whereas the patients' cells differ significantly. It has been noted that the mutation of gene atm is related to suppression of DNA double-strand breaks (DSBs) repair systems, which, in its turn, is in accordance with the increased radio sensitivity and premature ageing at the cell level in the AT families.

[Cellular repair potential in families of ataxia-telangiectasia patients].

The key protein of the global cellular response to DNA damage is proteinkinase ATM. Ataxia-telangiectasia (AT), a genetic disorder due to mutations in both alleles of ATM gene, is characterized by numerous neurological abnormalities, increased frequency of malignant tumors, premature ageing and increased radio sensitivity. AT is the most frequently found disease displaying inherited radio sensitivity. The data accumulated by this time on the role of the protein ATM in regulation of cellular response to DNA damage and detailed description of its proteins-targets allows to analyze repair potential and manifestation of premature ageing markers both in the cells obtained from AT patients and in the cells of their heterozygous parents. Primary skin fibroblasts obtained from AT patients and their heterozygous parents were analyzed by the flow cytometry and comet assay. It has been shown that cells of the patient AT8SP do not initiate cell cycle blockade after ionizing irradiation during all the experiment, unlike the healthy donor cells where cell cycle blockade is observed. Irradiated cells of the heterozygous parents demonstrated less brightly expressed changes in cell cycle parameters than healthy donor's cells did. The ability to repair DNA double-strand breaks (DSBs) after irradiation is reduced in the cells of AT patients and their heterozygous parents in comparison with the healthy donor's cells. Cells of the healthy donor were capable to repair not less than 90 % of DNA damage for 2.5 h. The repair efficiency in the cells of AT patients came only to about 30 % of DNA damage and in the cells of heterozygous carries of the disease was approximately 50 %. The difference in the dynamics of DNA damage repair process in different proband's families is in accordance with the reports about great phenotypic variety of the given disease.

[Polymorphisms of genes of rennin-angiotensine system and their correlation with psychological manifestations of birth stress].

Study of correlation of polymorphisms of genes of the rennin-angiotensine system--insertion-deletion (I/D) polymorphism of the angiotensine-converting enzime (ACE), and the polymorphism of angiotensinogen (AGT), consisting in submission of T into C in the 704 position (M235T)--with various characteristics of psychological functioning and clinical characteristics in women giving birth, was conducted. The group consisted of 56 young female Ss, without chronic diseases in the anamnesis, no complication in the course of pregnancy, birth normal and timely, state of the child normal in all cases. Basing on factor analysis of 7 psychological induces, providing integral assessment of state of the Ss in the course la late pregnancy, giving birth, and the immediately following post partum period, statistically reliable correlation between such first-rate psychological process as creativity, and polymorphism of the gene of angiotensinogene, was demonstrated, as well as difference in distribution of genotypes between the group of women giving birth, and general population. Statistically relevant correlation between presence of the deletion (D) allele of the ACE gene, and heightened level of neuroticization, reported by us earlier, was observed in this case, as well. No significant links between religiosity/spirituality, and genetic data was found. These results are in concordance with present-day views concerning the role of the rennin-angiotensine system in the providing of active adaptation to stressful conditions; they tend to provide fresh outlook upon the comparative study of input of heredity, and education, into the ontogenesis of higher psychological functions in normal humans.

[The atypical of Werner syndrome: effect of laminopathy].

A case of adult progeria has been described. During detailed studies of the cells from this patient the nuclear lamina and cytoskeleton aberrations were detected. It has been suggested that this case is an atypical form of Werner syndrome with laminopathy--not the WRN helicase-nuclease defect.

Mitochondria-targeted plastoquinone derivatives as tools to interrupt execution of the aging program. 5. SkQ1 prolongs lifespan and prevents development of traits of senescence.

Very low (nano- and subnanomolar) concentrations of 10-(6'-plastoquinonyl) decyltriphenylphosphonium (SkQ1) were found to prolong lifespan of a fungus (Podospora anserina), a crustacean (Ceriodaphnia affinis), an insect (Drosophila melanogaster), and a mammal (mouse). In the latter case, median lifespan is doubled if animals live in a non-sterile vivarium. The lifespan increase is accompanied by rectangularization of the survival curves (an increase in survival is much larger at early than at late ages) and disappearance of typical traits of senescence or retardation of their development. Data summarized here and in the preceding papers of this series suggest that mitochondria-targeted antioxidant SkQ1 is competent in slowing down execution of an aging program responsible for development of age-related senescence.

[Discrimination of heterozygote currency of ataxia-telangiectasia by indirect immunofluorescent analysis].

The qualitative differences in P53 protein stabilization after ionizing irradiation in different doses were found in cells of members of ataxia-telangiectasia (AT) family--proband AT6SP, her sister AT(S)6SP and father AT(F)6SP. The method of indirect immunofluorescence with confocal microscopy was used.

[Possible correlation of polymorphism of angiotensin-converting enzyme gene with psychological aspects of birth stress].

The paper presents results of a pilot study of genetic correlates of adaptive strategies characteristic for religious and (or) spiritual people in stress, induced by unusual and (or) extreme conditions. Birth stress, experienced by 79 young normal female urban dwellers Ss in the course of late pregnancy, giving birth, and the immediately following period post partum, was chosen as model of stress in general. Their state, as well as the state of the child, was monitored in each case by professional physicians, and assessed according to standard obstetric procedures. 3 kinds of standard psychological tests, providing assessment of neurotization, creativity, and the scope of religious/spiritual sensations, were conducted. The latter formed focal point of our research. As in has recently been supposed, religious/spiritual people tend to be more adaptive in illness and stress, which is quite important for clinical practice. The first aim of our study was to test whether religious/spiritual sensations in stress tend to occur as part of general neurotization; or, as part of creative response in the service of the ego; or, finally, they form a specific dimension of adaptive strategies. In home to simultaneously assess possible genetic determination of each of these options, we have introduced intro our study a module of assessment of genetic I/D polymorphisms of ACE gene, primarily linked to the status of the renin-angiotensin system. As a result of factor analysis, existence of 3 strong trends was demonstrated. 1. Neurotization, creativity, religious/spiritual processes tend to form 3 independent aspects of response of normal humans to birth stress. 2. Frequency of occurrence of D-allele tends to reveal strong correlation with only one of these 3 options, which is the generall level of neurotization. The latter conclusion corresponds well to what is currently known about the role of renin-angiotensin system primarily in regulation of cardiovascular system, and probably adaptation to stress. 3. Frequency of occurrence of D-allele in the mother tends to reveal inverse correlation with the Apgar index of the child (assessment of its physiological state in the course of the first several minutes after birth, based upon such characteristics as heart beat rate, ability to independent breathing, state of the skin, etc.), and is not linked to usual standard biometric parameters of newborn children. Continuing to work on this model, we intend to formally assess possible impact of heredity via other genes upon psychological, especially religious and spiritual aspects of adaptation to stress of women in birth; and also approach to possible genetic correlates of the state of newborn children.