[Basic principles of creation of multilevel multistage mathematical model of aging].

Current knowledge on the aging allows to elaborate approaches to the creation of multilevel model of multistage of human aging taking into consideration events during the aging at various levels of integration: molecular, cellular, tissue, organ, systemic, organism. The present paper have deals with main states of the mathematical model of multistage aging, principles of its construction, applicability and evaluation of its prognostic power. There are 3 levels of integrative systems: homeostatic (organismal), systemic and cellular-molecular. The definitions of normal and pathological aging are given. The samples of various patterns of aging under the influence of factors accelerating aging (constant illumination or alimentary obesity) or under the factors slowing down aging (treatment with metformin or melatonin) are discussed.

[Investigation of disability prevalence in men and women of advanced age].

Disability prevalence among men and women are investigated using NLTCS surveys conducted in 1982, 1984, 1989, 1994 and 1999 in the US population, on persons older than 65 years, and data from LSADT surveys conducted in 1995, 1997, 1999 and 2001 in the population of the Danish Twins Registry, on persons older than 75 years. In both surveys women are more disabled than men. The probability of becoming disabled and surviving is higher for women than men. The probability of recovering from a disability differs between the sexes statistically insignificant. No time trends are observed in the probabilities of becoming disabled, reversing disability or dying disabled. Calculations show that a decrease in disability prevalence observed in the USA resulted from a decrease in disability prevalence in ages younger than 65 years. Using LSADT data heritability of disability in women older than 75 years is estimated to be 36% (14%; 54%). In men of the same ages the estimate is 11% (0%; 40%) and for both sexes heritability is estimated at 28% (10%; 45%).

[Signal (nondestructive) role of environment in aging].

Adequate pattern of gene activity due to positive environmental influences of natural niches can enhance the resistance of organisms and reduce their aging. But the life expectancy in nature is much below (due to high external mortality) than in laboratory conditions. Some mutated genes, modified products of which are involved in regulatory control circuits, can (in some cases) mistakenly transform inadequate external cues of artificial experimental conditions to the regular reaction of an organism on the quite natural environment. This will lead to significant life span extension of laboratory animals. On the other hand, several lines of evidence suggest that the suitable signal simulating natural one, sent in appropriate time to the proper place, can also increase life span, but without change of a genetic design.

[Gerontology in silico: the emergence of a new discipline].

In this paper the modern views concerning the place of mathematical and computer modeling of aging and aging related pathologies in the current state and in future developments of gerontology are discussed. The review of most perspective directions of research including analyses of demographic, molecular, cellular, and physiological mechanisms of aging, the roles of damage and reparation of DNA, cell proliferation and apoptosis, where application of mathematical modeling is promising is given. Special attention is paid to the results and perspectives of mathematical modeling in experimental gerontology including modeling of aging and longevity in laboratory animals (nematode worms, fruit flies, mice, rats) and humans.

[Effect of epitalon and melatonin on life span and spontaneous carcinogenesis in senescence accelerated mice (SAM)].

Female senescence accelerated mice SAMP-1. (prone) and SAMR-1 (resistant) were exposed 5 times a week monthly to melatonin (with drinking water 20mg/ml during the night hours) or to s.c. injections of epitalon (Ala-Glu-Asp-Gly) at a single dose 1mkg/mouse. Control mice were intact or exposed to injection of 0.1 ml normal saline. The body weight and temperature, food consumption, estrous function were monitored regularly. The life span and tumor incidence were evaluated as well. As age advanced, the weight increased whereas food consumption and body temperature did not change. There was no significant substrain difference in these parameters. Exposure to melatonin or epitalon also failed to influence those indices. As age advanced, the incidence of irregular estrous cycles increased both in SAMP-1 and SAMR-1, whereas the treatment with both melatonin and epitalon prevented such disturbances. SAMP-1 revealed some features of accelerated aging as compared to SAMR-1. The mean life span of the 10% of the last survivors among treated SAMP-1 was shorter than that of SAMR-1, aging rate increased and mortality doubling time decreased. There was a direct correlation between body mass of the two substrains at the age of 3 and 12 months matched by body mass increase and longer life span. Melatonin or epitalon treatment was followed by longer mean and maximum survival in the 10% of the last survivors among SAMP-1. Melatonin involved decreased aging rate and increased mortality doubling time. Malignant lymphomas predominated in SAM without any significant difference in frequency between the substrains. While melatonin failed to influence tumor incidence or term of detection in SAMP-1, neither did epitalon affect frequency. However, it was followed by longer survival in tumor-free animals. No link between melatonin or epitalon treatment, on the one hand, and carcinogenesis, on the other, was reported in SAMR-1.

[Effect of light deprivation on homeostasis, life span and development of spontaneous tumors in HER-2/neu transgenic mice]. / Vliianie svetovoi deprivatsii n pokazateli gomeostaza, prodolzhitel'nost' zhizni i razvitei spontannykh opukholei u transgennykh myshei HER-2/neu.

Twenty five female HER-2/neu transgenic mice (FVB/N), aged 2 months, were surgically deprived of lighting; 30 intact transgenic mice, kept under standard conditions, were in control. Light deprivation was followed by inhibited intake of feed, decreased body mass and delayed age-associated estral disorders, as compared with control. Mean survival rate among experimental mice was higher by 13.5% than in control (p 0.001). Mean life span among the last surviving 10% of the experimental mice was longer than in control by 21.5% while maximum life span--by 21%. Although the number of tumor bearers under 7 months in the study group was twice that in control (p<0.05), they had almost equalized by the end of the experiment. The number of multiple malignancies and the size of tumor and metastases to the lung increased too.

[Serotonin transporter gene polymorphism and factors influencing mental and physical health in aging]. / Sviaz' polimorfnykh variantov gena perenoschika serotonina s faktorami, vliiaiushchimi na fizicheskoe i psikhicheskoe zdorov'e v protsesse stareniia.

Genetic predisposition is thought to exert a certain influence on the indices related to longevity and quality of life. Many of the indices, namely cognitive functioning, stress resistance, metabolism control, may be related to serotonin activity. To study polymorphic serotonin transporter gene variants and their association with features relevant for survival and longevity prognosis, a sample of elderly Russians from Moscow community recruited in the project "Stress-related mechanisms in Russia", comprising 196 subjects, mean age 76.2+/-5.3 years, 155 men, 41 women, has been genotyped. Allele and genotype frequencies have been estimated in 3 groups, aged 60-69, 70-79 and 80-87 years, respectively. A trend (chi2=4.1; p=0.12) to the prevalence of individuals with SS genotype (21.8%), as compared to expected level (14.6%), was found in the group of octogenarians (n=55, mean age 82.8+/-1.9 years). An association analysis between genotype and physiological traits revealed a genotype contribution to past smoking on tendency level (p=0.069), waist to hip ratio (WHR) (p=0.012) and plasma insulin concentration (p=0.02), with a higher frequency of SS genotype among non-smokers and subjects with lower WHR and insulin concentration. Genotype effect on the traits was stronger, being considered in interaction with the age above 80 years. Genotype was not associated with cognitive functioning (MMSE), but proved to be a significant predictor of MMSE performance (p=0.03) in octogenarians. The results obtained are in line with current concepts of serotonin role in smoking, obesity and cognitive functioning.

[Problems in using methods of analyzing gene expression in studying the aging process]. / Voprosy primeneniia metodov analiza ékspressii genov pri izuchenii protsessov stareniia.

Aging processes are now actively investigated on the base of analysis of changes in gene expression. Many of the standard methods (such as hierarchic clustering, method of K-means, SOM (Self-organizing maps), Gene Shaving, etc.) do not take into account the specifics of time sets. In the article the new approach of the analysis and clustering of genes based on the processing of time increments in their expressions is presented. Genes in the resulting groups behave concertedly with any chosen "pilot" gene or simply together. The methods of clustering were tested on the data of gene expressions of C. elegans in aging. In the article the specific claims of believability of the experiments are discussed.

[Immune system senescence and mortality dynamics. Role of antigenic load]. / Starenie sistemy immuniteta i dinamika smertnosti. Analiz roli antigennoi nagruzki.

This paper is dedicated to investigation of the impact of total antigenic load on immunosenescence. Data on pneumonia mortality have been simulated. The results of modelling revealed that antigenic load as well as probability of infecting could account for the shifting in mortality that takes place for different countries. Dynamics of immunosenescence is described by mathematical model for age related changes in T-cell populations. Numerical simulation of the model yields estimates for pneumonia severity at different ages. Probability function is used to describe relationship between pneumonia mortality and age related changes in disease severity.

[Mathematical modeling in gerontology--strategic perspectives]. / Matematicheskoe modelirovanie v gerontologii--strategicheskie perspektivy.

Mathematical description of aging and mortality is presented. A review of tendencies in modeling is discussed and some difficulties related to adequacy and the ways of information presentation in the models are talked about. A short view is given at the two main modeling techniques in biology, namely the models of data and models of a system. Strategic perspectives of modeling in biogerontology are presented in terms of modeling paradigms. One can speak about a general paradigm consisting of postulates, principles and techniques related to a model, which allows a solving different problems with the same model, if the model can be modified to treat the variety of problems. Modification is to be done in the framework of concepts of the model by using a sum of the methods related to it. It is shown how the homeostatic paradigm can be used to predict a specific human longevity.

[Problems of the existence of "optimal" function survival functions in experiments of varying protein supplies to Mediterranean fruit flies]. / Problema sushchestovaniia "optimal'nykh" funktsii dozhitiia na primere éksperimentov variatsii rezhimov proteinovogo pitaniia Mediterranean fruit flies.

The paper is devoted to the discussion of the possibility of analyzing the changes in survival curves of Mediterranean Fruit Flies under different levels of reproduction by means of solving the optimization problem with some objective function. The investigation is carried out on the base of mathematical model with approximations resulting in the analysis of joint changes in survival functions and reproduction in flies subjected to different conditions of protein availability in food. The model describes possible mechanisms of evolutionary selection from the point of view of trade-off in average life span and reproduction.

[Mathematical model of the age-related changes in peripheral T cells population]. / Matematicheskaia model' vozrastnykh izmenenii v populiatsii perifericheskikh T-limfotsitov.

UNLABELLED: An analysis is presented of the data concerning to the decline with the age the human immune system function. The most prominent changes links with T-cellular immunity. The embrace the naive T cells generation rate diminishing, peripheral lymphoid tissue volume shrinkage, absolute and relative concentration of naive T cells in blood decreasing, average length of T cell telomers reducing. The alterations in immune system led to sharp growth of morbidity and mortality caused by infectious agents. Analysis of the data reveal that key variables of this process are memory and naive T cell concentrations in peripheral lymphoid tissue. The proposed long-time mechanism which hold concentration of T cells in physiological limits are based on assumptions that naive and memory T cells disposed in common niche. The average life-time of memory T cells are varied so that general concentration of T cells holds in normal limits. Numerical experiments demonstrate that average life-time of memory T cells grows with aging, limitation of antigenic load led to considerable grow of resistance in middle age but to little grow in older age. Restriction of thymus involution led to grow of resistance in older age but compensate by diminishing of memory power and longevity. CONCLUSION: The proposal model describe the trade-off between naive and memory T cell subpopulations concentrations and proliferative potentials.

[Mathematical modeling and simulation of life history and tradeoffs]. / Matematicheskie modeli istorii zhizni i balansa resursov.

General trends in mathematical life history modeling are reviewed. In modern experimental biogerontology life history consists of all traits that affect fecundity and survival. Tradeoffs are of special importance in the theory of life history, studied either as an evolutionary phenomenon or as a feature of individual life history. Tradeoffs between cost of reproduction and survival are mostly studied and modeled. Special attention is given in the review to statistical modeling of life history (Monte-Carlo techniques). A number of modeling paradigms is presented and their perspectives are discussed.