[Polyphenols of natural origin against age-related disorders of tissue homeostasis.]

Aging-related disorders of tissue homeostasis may lead to excessive cell proliferation in the form of cancer and to extracellular matrix expansion in the form of fibroses. Death rates attributed to both of the conditions are decreased, according to epidemiological evidence, upon increased dietary intakes of polyphenols, including flavonoids, stilbenes, lignans, and curcuminoids. That is, polyphenols, although they have very different structures, unidirectionally influence the two opposite sides of balance in tissue homeostasis: the cells, which are able, and the extracellular matrix, which is unable to proliferate. The common features of fibroses and cancer are the transformation of fibroblasts into myofibroblasts (MF) and the epithelial- and endothelial-to-mesenchymal transitions (EMT and EndMT), which shift cell proportions in tissues toward MF. The increased ability of MF to produce collagen promotes fibroses in non-cancerous tissues, and EMT and EndMT enhance cancer progression. These processes are influenced by not polyphenols themselves due to their interactions with different sterically suitable targets, but by polyphenol oxidation products, which are all highly electrophilic. By binding to the SH-groups of the KEAP1 protein complexed with the NRF2 protein, they release NRF2, which is generally known as a transcription factor involved in activating the genes implicated in cell antioxidant defenses. In the present review, attention is drawn to the published data about NRF2 ability to attenuate TGFß1 signaling, which promotes fibroblasts conversion into MF and enhances EMP and EndMP, that is increases the phenotypic instability of cells. Thus, the anticarcinogenic and antifibrotic effects of polyphenols may both involve cell phenotype stabilization, which may contribute to the geroprotector effects of polyphenols.

Effect of Polyphenolic Composition BP-C2 on Lung Carcinogenesis Induced by Urethane in Progeny of Irradiated Male BALB/c Mice.

We studied the effects of polyphenolic composition BP-C2, comprising molybdenum with lignin derivatives, on lung carcinogenesis induced by urethane in the progeny of F0 male BALB/c mice preconceptionally exposed to radiation in a dose of 1 Gy. The multiplicity of lung tumors in the progeny of irradiated mice was higher than in the progeny of non-irradiated male parents by 50% in females and 43% in males (p<0.05). In F1 mice (progeny of irradiated F0 male parents treated with BP-C2), the multiplicity of lung tumors was also higher, but this increase was less pronounced: 35% in females (p=0.3852) and 23% in males (p=0.0766). We have demonstrated that administration of BP-C2 to irradiated parents (F0) efficiently inhibits carcinogenesis in their F1 progeny. The use of BP-C2 in irradiated male parents and their progeny not only reduced the multiplicity of tumors, but also normalized body weights in the F1 progeny. Our study demonstrates potential of the polyphenolic composition BP-C2 for chemoprophylaxis of radiation-induced transgenerational carcinogenesis.

[Innovative concept of aging prevention for modern Russia.]

The article presents an innovative concept for aging prevention of older citizens based on using elements of the International Classification of Functioning, Disability and Health which taking into account the influence of aging processes on changes in health and social adaptation of older citizens. The functional features of the departmental systems of health care and social protection of the population operating in Russia that impede their integration within the framework of providing comprehensive medical and social assistance to citizens of older age groups are analyzed. The biopsychosocial model of functioning and disability has advantages in comparison to another models given possibility of developing a social adaptation and implementation of an integrated systematic approach to the prevention of aging. A set of measures is proposed and justified to improve the efficiency, quality and accessibility of services health care for elderly by restructuring the functional interaction of departmental structures, attraction of resources and potential of non-governmental, public organizations, scientific and educational centers, professional communities and volunteers.

[The lifespans of scholars referred to different disciplines according to data from diverse sources: Inferences and challenges.]

Human lifespan is known to correlate positively with education level. In the present paper, it is explored whether there are significant differences in lifespan among those whose education may be reasonably rated as the highest possible, i.e. among scholars referred to different scientific disciplines. The publications where the lifespans of scholars were estimated against the general population are reviewed, and the estimates are compared with those derived from the Database of Persons Included in Encyclopedias (DBPE), which has been being developed by the authors since 2008 based on Wikipedia records. With all caveats associated with the peculiarities of the procedures of including biographic data in Wikipedia, the estimates derived from the latest version of DBPE correspond to earlier estimates and confirm the conclusions based on other data sources: scholars' mean age at death (MAD) and life expectancy (LE) steadily increased since the Medieval period up to the modern time, were higher than those of the general population, and where the highest among the scientific elite. An unexpected finding was that MAD and LE of economists were usually the highest, whereas those of the mathematicians were lowest compared with specialists in other research fields. The difference between the two extreme cases ranges from ca. 3 to 5 years in different historical periods. Further examination of the difference between the extremes may reveal what factors behind it may be at work generally, even though they manifest themselves less overtly in other cases.

[Structure and main stages of the process of long-term state support by the state of elderly generation.]

The article deals with the problem of modeling the process of providing the state support aimed senior citizens. Its structuring is substantiated with the allocation of individual modules - functional stages and the relevant typed statuses of patients. The influence of the main groups of factors on the formation of personal packages of services, including medical, social, psychological and educational components, is considered. In the article the implementation of the functions of systemic support for the provision of comprehensive medical, social and psychological assistance to citizens of the older generation for the identified functional stages have been analyzed. Technologies are proposed that contribute to the optimization of the system of state support for senior citizens, based on the use of a biopsychosocial approach and distribution of the load between departments and structures while ensuring the systemic unity of the process.

[Integral assessment of the biopsychosocial status of older citizens and implementation of the systemic support components.]

The article discusses the problems of determining the need of citizens of older age groups in complex medical, social and psychological assistance in the framework of the implementation of a personalized approach to the service provision. The concept of an integral assessment of the biopsychosocial status of older citizens has been introduced. Based on the ranking of subjects according to the degree of decrease in body functions due to ageing and the development of age-associated diseases, an algorithm for the implementation of the assessment has been proposed. The possibility of using this algorithm has been substantiated, and its features have been shown on the example of St. Petersburg as a model region, taking into account its technical, personnel and organizational potential. The requirements for the implementation of the systemic support components for the provision of comprehensive medical, social and psychological assistance to senior citizens in the process of organizational and technical support for an integrated assessment of their biopsychosocial status have been defined.

[Menopausal hormonal therapy and breast cancer.]

The most common treatment for menopausal syndrome is menopausal hormone therapy (MHT), however, the safety of MHT, due to the risk of developing and recurrent breast cancer (BC), is still a matter of debate. The review presents the results of randomized cohort studies of this issue. It has been shown that MHT increases the risk of developing of breast cancer and disease recurrence after treatment. Risk of breast cancer developing in women getting MHT, depends on body mass index (BMI), duration of hormone use and dose of drugs, and is greater in thin women comparing with women with increased BMI, and also greater in estrogen-progestin combined MHT users comparing with estrogen-only users. It was found that in women using MHT hormone-dependent forms of cancer developed more often, but by the time of diagnosis, disease was found in more advanced stage and metastases in lymph nodes were found more often comparing with patients who did not use MHT. Risk of breast cancer recurrence is less with the use of low doses of vaginal estrogen. An alternative option for the relief of menopausal disorders in breast cancer patients during and after treatment is using of pineal gland hormone melatonin, since, along with its anti-aging properties, it is able to suppress cancer at the stages of initiation, progression and metastasis and has the ability to reduce the toxic effects of anticancer drugs while increasing their effectiveness.

Evaluation of the genotoxic and antigenotoxic potential of lignin-derivative BP-C2 in the comet assay in vivo.

The genotoxic and antigenotoxic potential of BP-C2, a novel lignin-derived polyphenolic composition with ammonium molybdate, was investigated as a radioprotector/radiomitigator for civil applications and as a medical countermeasure for radiation emergencies. Using the alkaline comet assay and methyl methanesulfonate (MMS, 40 mg/kg) as the DNA-damaging agent, these effects of BP-C2 on liver, bone marrow cells and blood leukocytes in rats were studied. The DNA damage was estimated by the DNA content in the comet tail (TDNA, %) 1, 6 and 18 h post exposure to MMS. BP-C2 at doses of 20, 200 and 2000 mg/kg did not exert genotoxic activity in the tested tissues in rats. BP-C2 administered at doses of 20, 100 and 200 mg/kg 1 h before MMS significantly (p < 0.01) mitigated MMS-induced DNA damage, showing a strong genoprotective effect in the liver. In blood leukocytes and bone marrow samples of animals treated with BP-C2, the TDNA % was slightly higher than in the negative control (vehicle) but significantly lower than in the positive control (MMS). Thus, BP-C2 exerted a genoprotective effect against MMS-induced DNA damage to a greater extent towards liver cells, requiring further evaluation of this substance as a genoprotective agent.

[State support to elderly citizens: which gerontology needs modern Russia? (Part 1).]

The article discusses the causal relationship between the low efficiency of state policy in extending the period of active longevity. It is characterized by the absence of a correlation between basic and applied research in the field of aging and the use of an unsystematic approach to the development, implementation of targeted federal and regional programs aimed improving the quality of life older citizens. It is shown that the current negative situation, characterized by an aggravating decline in the quality and accessibility of state medical, social and psychological assistance to elderly citizens, is largely due to the incompleteness of existing laws and regulations in the field of their social support. The lack of both scientific justification for programs and terminological correctness allows officials to use a formalized, extensive approach when planning the development of the healthcare and social protection sectors, which do not take into account population aging. The problem of positioning gerontology as a scientific discipline that provides a synthesis of natural science, applied and socio-humanitarian knowledge, a complex of four scientific areas: biology, medicine, psychology, sociology is considered. The unity of the components of gerontology provides scientific background for improving public policy aimed on adapting socio-economic development to the demographic processes of population aging.

[State support to elderly citizens: which geriatric needs modern Russia? (Part 2).]

The publication continues to consider the cause-subsequent relationships of low efficiency of the state policy in the field of prolonging the period of active longevity altogether with unsystematic approaches to the formation and implementation of state programs. In the context of the analysis of the reasons for the insufficient effectiveness of existing state programs in the field of improving social support for senior citizens, geriatrics is positioned as an integral part of gerontology - an area of applied research that provides solutions to medical, social, psychological and other problems that arise among citizens of elderly. In particular, these problems are associated with the psychophysiological, socio-economic, educational, cultural and legal status of this category of citizens. Geriatric care and its status as a basic component of comprehensive medical and social assistance to senior citizens are formalized. The influence of gerontology and geriatrics in the process of providing systemic support for improving the quality of life of senior citizens, which is one of the priorities of Russian state policy, is substantiated. The motivation is the need to amend existing laws and regulations governing the provision of state support to senior citizens, systematic processing of existing government programs in this area, based on the use of a scientific approach to solving the problem of adapting the state to the aging processes of society.

Exploring bioactivity potential of polyphenolic water-soluble lignin derivative.

Many natural substances exhibit anti-inflammatory activity and considerable potential in prophylaxis and treatment of allergies. Knowing exact molecular targets, which is required for developing these as medicinal products, is often challenging for multicomponent compositions. In the present study we examined novel polyphenolic substance, a water-soluble fraction of wood lignin (laboratory code BP-Cx-1). In our previous study, a number of polyphenolic components of BP-Cx-1 (flavonoids, sapogenins, phenanthrenes etc.) were identified as the major carriers of biological activity of BP-Cx drug family, and several molecular targets involved in cancer and/or inflammation signaling pathways were proposed based on the results of the in vitro and in silico screening studies. In the present study, half maximal inhibitory concentration (IC50) of BP-Cx-1 was established with a radioligand method and a range of IC50 values between 22.8 and 40.3 µg/ml were obtained for adenosine receptors A1, A2A and prostaglandin receptors EP2, IP (PGI2). IC50 for serotonin 5-HT1 and for glucocorticoid GR receptors were 3.0 µg/ml and 12.6 µg/ml, respectively, both being within the range of BP-Cx-1 concentrations achievable in in vivo models. Further, distribution of [3H] labelled BP-Cx-1 in NIH3T3 murine fibroblasts and MCF7/R carcinoma cells was studied with autoradiography. [3H]-BP-Cx-1 (visualized as silver grains produced by tritium beta particles) was mainly localized along the cell membrane, in the perinuclear region and in the nucleus, suggesting ability of BP-Cx-1 to enter cells and bind to membrane or cytosol receptors. In our experiment, we observed the effect of BP-Cx-1 on maturation of dendritic cells (DCs): downregulation of expression of the lipid-presentation molecule CD1a, co-stimulatory molecules CD80, CD83 and CD 40, decreased production of pro-inflammatory cytokines IL-4 and TNF-α and increased production of anti-inflammatory cytokine IL-10. It is hypothesized that [3H]-BP-Cx-1 detectable in the nucleus is part of the activated GR complex, known to be involved in regulation of transcription of genes responsible for the anti-inflammatory response. Based on IC50, cell distribution data and results of the experiment with DCs it is suggested that the in vivo effects of BP-Cx-1 are mediated via GR and 5-HT1 receptors thus promoting development of tolerogenic effector function in dendritic cells.

[Network analysis of cognitive, oculomotor and speech parameters in schizophrenia]. / Setevoi analiz kognitivnykh, glazodvigatel'nykh i rechevykh pokazatelei pri shizofrenii.

OBJECTIVE: To determine the network connections between clinical, cognitive, speech and oculographic parameters in patients with schizophrenia. MATERIAL AND METHODS: The study included 104 patients with schizophrenia and schizophrenia spectrum disorders and 70 healthy subjects. Clinical assessment of the patients was performed using a number of scales: PANSS, CDSS, YMRS, SAS and BAS. Basic cognitive functions were assessed by BACS. Eye movements were recorded using the SMI RED-500 non-invasive eye tracking system. Several experimental paradigms were used - free viewing of animal images with subsequent description of these images, performing progressive saccades in the experimental Go/NoGo scheme, and performing anti-saccades. RESULTS: The severity of clinical symptoms, cognitive impairments, oculomotor parameters and characteristics of speech structure of written speech are largely independent, although not completely isolated from each other. Cognitive and oculomotor parameters have the largest number of connections. In this case, the results of cognitive tests are the central element of the «network¼ that connects other groups. CONCLUSION: Further development of the approach should be aimed at studying the influence of node changes on the structure of the network that would potentially allows the identification of the most effective points of application of therapeutic and rehabilitation programs.

[Cytoflavin effect on locomotor and psychoemotional status in physiological and pathological aging.]

Currently, the actual problem is the correction of motor, cognitive and psychoemotional disorders in physiological aging, as well as in various pathological processes that accompany aging and accelerate it. In this regard, it became necessary to search for drugs that can restore age-related disorders of the brain. The aim of the study was to evaluate the possibility of Cytoflavin as a pharmacological corrector of age-dependent disorders of the functions of the cerebral cortex during physiological and pathological, accelerated aging. The mouse sensorimotor cortex of the brain was the material for study. The transgenic male mice with HER2/neu overexpression at the age of 2 and 10 months were used as an experimental model, male wild-type FBV/N mice at the age of 2 and 18 months served as a control. We studied locomotor activity, orientational research behavior and the psychoemotional status of animals using the «open field¼ test and the Suok test. It was found that in old FBV/N mice, after the cytoflavin treatment, recovery of locomotor functions and orientational-research behavior is observed. Under conditions of HER2/neu overexpression after the Cytoflavin treatment, an improvement in motor functions occurs. It was also shown that the studied drug has an anxiolytic effect on both wild-type FBV/N mice and transgenic HER2/neu mice during aging. Thus, the positive effect of Cytoflavin on the dynamics of the behavior of experimental mice during physiological and pathological accelerated aging allow to suggest that in the late stages of ontogenesis, Cytoflavin restores the cerebral cortex functions and prevents neurodegeneration.

[FAS- and TNF-dependent ways participation in apoptosis mechanisms in hypotalumus in physiological and pathological aging.]

The cell resistance to apoptosis can be related to the activity of cytokine-dependent signaling. So, the aim of the work is to investigate the mechanisms of cytokine-dependent FAS/TNF-mediated regulation of apoptosis of neurosecretory cells in the physiological and pathological (overexpression of the oncogene HER-2/Neu) aging. HER2/Neu transgenic accelerated aged mice of different ages and wild type FVB/N were examined. The apoptosis level of neurons in hypothalamic sections (supraoptic and paraventricular nuclei) (TUNEL) and expression of caspase-8, CD178 (FASL), FAS, FADD, TRADD (Western blotting) was determined. Participation of the proinflammatory component in the aging process is shown. FAS, adapter proteins associated with the death domain (FADD and TRADD), caspase-8 expression is activated in hypothalamus in FVB/N mice (wild type) during aging, and it correlates with an increase in the apoptosis level. HER-2/Neu expression leads to the extrinsic apoptotic pathway suppression. In this case, the reception of an apoptotic signal (FAS-receptor expression) and its further transmission (expression of FADD and TRADD) is suppressed. However, in young transgenic mice, increased expression of TRADD can activate one of the survival ways - NF-κB, ERK or PI3K-AKT cascade. Thus, the HER-2/Neu tyrosine kinase receptor plays a role in the mechanism of cell resistance to age-dependent apoptosis, and the FAS/TNF-signaling pathway is one of the targets of HER-2/Neu.

[Regional System of Integrated Health and Social Care for Elderly People: Experience and Expertise of Saint-Petersburg.]

The article examines the challenges of creating a system of integrated health and social care for elderly people (the System) in Russia, these challenges being of particular significance in the light of the negative effects of the COVID-19 pandemic on the quality of life and mental and general health of elderly people, which need to be mitigated with due consideration of the dynamics of progression of age-associated chronic diseases of elderly people. The article describes the structure of the System, and the conditions and background of its establishment. It also looks at the components of system-based support of improvement of quality of life of elderly people. The article argues that it is essential to use the positive and negative experiences of different regions, to implement the practical and scientific expertise in the field of gerontology and geriatrics made so far in Russia, and to establish a meaningful and equal partnership among the state, research organizations, communities of professionals and non-public organizations. The authors suggest to look on Saint-Petersburg as a model region when establishing the System. The article contains a list of the major projects and events in the city from 2012 to 2020 aimed to provide system-based support for integrated health and social care for elderly people, not affiliated with any federal programs. Unbiased evaluation of the experience and expertise of Saint-Petersburg and other regions of Russia will allow to use them when establishing similar systems in other Russia's regions that do not possess sufficient resources. The authors suggest to establish the System in a step-wise manner at the federal district level. For example, a pilot project may be launched in the North-Western Federal District using the experience and expertise of Saint-Petersburg.

[System-Based Support of Improvement of Quality of Life for Elderly People in Russia: Outlook and Challenges.]

The article examines the outlook and challenges relating to the provision of system-based support of healthcare providers and social services in the course of delivering their healthcare, mental health and social services to elderly people, in particular amidst a crisis, such as the COVID-19 pandemic. The article gives the definition of integrated health and social care, its structure and the algorithm of delivering integrated health and social care to elderly people. The article argues that a system of integrated health and social care will improve the quality of life of older populations and extend their active longevity through a person-centered social services plan offered according to an older person's needs. The article gives the definition and a detailed description of the goals of system-based support of integrated health and social care for older populations. It describes the conditions for providing such system-based support in one specific region of the country. The article analyses the structure, aims and type of entity of the Geriatric Service which is viewed by the authors as a building block of the system of integrated health and social care for elderly people, and discusses the issues relating to coordination of activities among various divisions of the Geriatric Service and their cooperation with social services and healthcare providers. The article explains why it is important to establish a special research and methodological unit - the Center for System-Based Support - within the Geriatric Service.

[Comparative analysis of experimental data about the effects of various polyphenols on lifespan and aging.]

To analyze experimental data on the effect of various polyphenolic compounds on lifespan of mice, we approximated survival curves with the Gompertz model in its minimal form, which does not account for the heterogeneity of samples and the age-independent mortality. The plots of regressions of log0 (logarithm of the initial mortality) on  (the rate of aging) in series of control samples were used to assess the deviations of vectors directed from control to experimental data from the slopes of the control regressions. The analysis of published data suggests that resveratrol, polyphenol-containing grape skin extract, metformin, tocopherol, and the antioxidant SkQ1 do not produce changes beyond those possible upon comparing of different samples of a control population. The effect of the polyphenolic composition BP-C3 on female SHR mice is unique in being associated with a significant decrease in the rate of aging. The effect may be partly contributed to by the antioxidant properties of BP-C3. Its antioxidant capacity determined in vitro is comparable with that of established antioxidants, such as dihydroquercetin. Its effects in vivo include the ability to ameliorate reduction in the peroxide-decomposing activity of RBC lysates from male BALB/c mice treated with 5-fluorouracil.

[Absence of photoperiodism and digestive enzymes in rats: the role of the age and endogenous melatonin level.]

We studied the effect of prolonged absence of a photoperiodic signal (constant lighting and constant darkness) on the changes of digestive enzymes' activity in late postnatal ontogenesis of rats. Age-related alterations are characterized as a change in activity of enzymes, as well as a redistribution of the functional activity between the amylo- and lipolytic links, the upper and lower divisions of the gastrointestinal tract. It was shown that along with age, the activity of enzymes is affected both by the absence of photoperiodism and by the level of melatonin associated with the light regime. In conditions of light deprivation the age-related changes characterizing the «aging¼ of the digestive system are observed later compared with standard illumination and especially constant illumination.

Analysis of HER-2/neu Receptor Expression and the Level of Neuronal Apoptosis in HER-2/neu Transgenic Mice during Aging.

We studied neuronal death in the sensorimotor cortex, hippocampus, and supraoptic and paraventricular nuclei of the hypothalamus and dynamics of HER-2/neu expression in late ontogenesis in young and old transgenic HER-2/neu mice. Wild-type FVB/N mice served as the control. The intensity of apoptosis (TUNEL) and HER-2/neu expression (Western blotting) in the same brain regions were measured. HER-2/neu was detected in the cortex, hippocampus, and hypothalamus of transgenic and wild-type mice, and its expression increased with age. The effect of HER-2/neu on the intensity of cell death in various brain regions depended on the stage of ontogenesis and animal genotype. Enhanced expression of HER-2/neu determines low rate of cell death in the studied brain regions during pathological ageing.

[Gender-specific effects of neonatal administration of melatonin on lifespan and age-associated patholgy in 129/Sv mice.]

Melatonin was administered at the dose of 1,2 mcg per capita (an equivalent to pediatric dosages) at days 1, 3 and 5 postpartum to 129/Sv mice, which were followed thereafter till their natural deaths. In adult males, findings included a decrease in body weight and an increase in the contribution of pulmonary lesions, which were revealed upon postmortem examinations, to the overall mortality. In adult females, no changes in body weight occurred, the proportion of middle- and late-age mice having irregular estrous cycles increased, and mortality associated with uterine hemangiomas was accelerated. Trends in malignant tumor yields were different: a decrease in males and an increase in females. Tends in survival patterns were expressed as significant increases or decreases in the lifespans of the last 25% and 10% of male or female survivors respectively. An analysis of the complete survivorships curves in terms of the Gompertz model showed that changes in the initial mortality and aging rate were within the limits determined by the artifactual component of the Strehler-Mildvan correlation between these parameters. On a whole, the trends found in the present work were opposite in males and females being mostly favorable for the former and adverse for the latter. Gender specificity should be kept in mind upon considering the use of melatonin by children and their mothers.