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BACKGROUNDThe current linear-no-threshold paradigm assumes that any exposure to ionizing radiation carries some risk, thus every effort should be made to maintain the exposures as low as possible. Here, we examined whether background... more
BACKGROUNDThe current linear-no-threshold paradigm assumes that any exposure to ionizing radiation carries some risk, thus every effort should be made to maintain the exposures as low as possible. Here, we examined whether background radiation impacts human longevity and cancer mortality.METHODSOur data covered the entire US population of the 3139 US counties, encompassing over 320 million people. The data on background radiation levels, the average of 5-year age-adjusted cancer mortality rates, and life expectancy for both males and females in each county, was extracted using publicly available tools from official sources, and analyzed with JMP®™ software.RESULTSWe found for the first time that life expectancy, the most integrative index of population health, was approximately 2.5 years longer in people living in areas with a relatively high vs. low background radiation (≥ 180 mrem/year and ≤ 100 mrem/year, respectively; p < 0.005; 95% confidence interval [CI]). This radiation-i...
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The complete resulting annotation of the gray whale transcriptome assembly. (XLSX 13480Â kb)
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Research Interests: Aging, Stem Cell, Budding Yeast, Saccharomyces cerevisiae, Humans, and 14 moreAge, Biogerontology, Animals, Cell Polarity, Aging and Longevity, Clinical Sciences, Model System, Rejuvenation, Polarity, Mrna Translation, Age Related Diseases, Gene expression and regulation, mRNA regulation, and Protein Transport
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Although different aspects of cancer immunity are a subject of intensive investigation, an integrative view on the possible molecular links between immunoregulators and cancer-associated genes has not yet been fully considered. In an... more
Although different aspects of cancer immunity are a subject of intensive investigation, an integrative view on the possible molecular links between immunoregulators and cancer-associated genes has not yet been fully considered. In an attempt to get more insights on the problem, we analyzed these links from a network perspective. We showed that the immunoregulators could be organized into a miRNA-regulated PPI network―the immunoregulatory network. This network has numerous links with cancer, including (i) cancerassociated immunoregulators, (ii) direct and indirect protein-protein interactions (through the common protein partners), and (iii) common miRNAs. These links may largely determine the interactions between the host’s immunity and cancer, supporting the possibility for co-expression and post-transcriptional co-regulation of immunoregulatory and cancer genes. In addition, the connection between immunoregulation and cancer may lie within the realm of cancer-predisposing condition...
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Tissue fibrosis is a major driver of pathology in aging and is involved in numerous age-related diseases. The lungs are particularly susceptible to fibrotic pathology which is currently difficult to treat. The mouse bleomycin-induced... more
Tissue fibrosis is a major driver of pathology in aging and is involved in numerous age-related diseases. The lungs are particularly susceptible to fibrotic pathology which is currently difficult to treat. The mouse bleomycin-induced fibrosis model was developed to investigate lung fibrosis and widely used over the years. However, a systematic analysis of the accumulated results has not been performed. We undertook a comprehensive data mining and subsequent manual curation, resulting in a collection of 213 genes (available at the TiRe database, www.tiredb.org), which when manipulated had a clear impact on bleomycin-induced lung fibrosis. Our meta-analysis highlights the age component in pulmonary fibrosis and strong links of related genes with longevity. The results support the validity of the bleomycin model to human pathology and suggest the importance of a multi-target therapeutic strategy for pulmonary fibrosis treatment.
One of the important questions in aging research is how differences in transcriptomics are associated with the longevity of various species. Unfortunately, at the level of individual genes, the links between expression in different organs... more
One of the important questions in aging research is how differences in transcriptomics are associated with the longevity of various species. Unfortunately, at the level of individual genes, the links between expression in different organs and maximum lifespan (MLS) are yet to be fully understood. Analyses are complicated further by the fact that MLS is highly associated with other confounding factors (metabolic rate, gestation period, body mass, etc.) and that linear models may be limiting. Using gene expression from 41 mammalian species, across five organs, we constructed gene-centric regression models associating gene expression with MLS and other species traits. Additionally, we used SHapley Additive exPlanations and Bayesian networks to investigate the non-linear nature of the interrelations between the genes predicted to be determinants of species MLS. Our results revealed that expression patterns correlate with MLS, some across organs, and others in an organ-specific manner. T...
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Interventional studies on genetic modulators of longevity have significantly changed gerontology. While available lifespan data is continually accumulating, further understanding of the aging process is still limited by the poor... more
Interventional studies on genetic modulators of longevity have significantly changed gerontology. While available lifespan data is continually accumulating, further understanding of the aging process is still limited by the poor understanding of epistasis and of the non-linear interactions between multiple longevity-associated genes. Unfortunately, based on observations so far, there is no simple method to predict the cumulative impact of genes on lifespan. As a step towards applying predictive methods, but also to provide information for a guided design of epistasis lifespan experiments, we developed SynergyAge - a database containing genetic and lifespan data for animal models obtained through multiple longevity-modulating interventions. The studies included in SynergyAge focus on the lifespan of animal strains which are modified by at least two genetic interventions, with single gene mutants included as reference. SynergyAge, which is publicly available at www.synergyage.info, pr...
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One important question in aging research is how differences in genomics and transcriptomics determine maximum lifespan in various species. Despite recent progress, much is still unclear on the topic, partly due to the lack of samples in... more
One important question in aging research is how differences in genomics and transcriptomics determine maximum lifespan in various species. Despite recent progress, much is still unclear on the topic, partly due to the lack of samples in non-model organisms and due to challenges in direct comparisons of transcriptomes from different species. The novel ranking-based method that we employ here is used to analyze gene expression in the gray whale and compare its de novo assembled transcriptome with that of other long- and short-lived mammals. Gray whales are among the top 1% longest-lived mammals. Despite the extreme environment, or maybe due to a remarkable adaptation to its habitat (intermittent hypoxia, Arctic water and high pressure), gray whales reach at least the age of 77 years. In this work, we show that long-lived mammals share common gene expression patterns between themselves, including high expression of DNA maintenance and repair, autophagy, ubiquitination, apoptosis, and i...
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Gray whale, Eschrichtius robustus (E. robustus), is a single member of the family Eschrichtiidae, which is considered to be the most primitive in the class Cetacea. Gray whale is often described as a "living fossil". It is... more
Gray whale, Eschrichtius robustus (E. robustus), is a single member of the family Eschrichtiidae, which is considered to be the most primitive in the class Cetacea. Gray whale is often described as a "living fossil". It is adapted to extreme marine conditions and has a high life expectancy (77 years). The assembly of a gray whale genome and transcriptome will allow to carry out further studies of whale evolution, longevity, and resistance to extreme environment. In this work, we report the first de novo assembly and primary analysis of the E. robustus genome and transcriptome based on kidney and liver samples. The presented draft genome assembly is complete by 55% in terms of a total genome length, but only by 24% in terms of the BUSCO complete gene groups, although 10,895 genes were identified. Transcriptome annotation and comparison with other whale species revealed robust expression of DNA repair and hypoxia-response genes, which is expected for whales. This preliminary...
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In spite of a growing body of research and data, human ageing remains a poorly understood process. Over 10 years ago we developed the Human Ageing Genomic Resources (HAGR), a collection of databases and tools for studying the biology and... more
In spite of a growing body of research and data, human ageing remains a poorly understood process. Over 10 years ago we developed the Human Ageing Genomic Resources (HAGR), a collection of databases and tools for studying the biology and genetics of ageing. Here, we present HAGR's main functionalities, highlighting new additions and improvements. HAGR consists of six core databases: (i) the GenAge database of ageing-related genes, in turn composed of a dataset of >300 human ageing-related genes and a dataset with >2000 genes associated with ageing or longevity in model organisms; (ii) the AnAge database of animal ageing and longevity, featuring >4000 species; (iii) the GenDR database with >200 genes associated with the life-extending effects of dietary restriction; (iv) the LongevityMap database of human genetic association studies of longevity with >500 entries; (v) the DrugAge database with >400 ageing or longevity-associated drugs or compounds; (vi) the Cell...
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In spite of a growing body of research and data, human ageing remains a poorly understood process. To facilitate studies of ageing, over 10 years ago we developed the Human Ageing Genomic Resources (HAGR), which are now the leading online... more
In spite of a growing body of research and data, human ageing remains a poorly understood process. To facilitate studies of ageing, over 10 years ago we developed the Human Ageing Genomic Resources (HAGR), which are now the leading online resource for biogerontologists. In this update, we present HAGR's main functionalities, including new additions and improvements to HAGR. HAGR consists of five databases: 1) the GenAge database of ageing-related genes, in turn composed of a dataset of >300 human ageing-related genes and a dataset with >2000 genes associated with ageing or longevity in model organisms; 2) the AnAge database of animal ageing and longevity, featuring >4000 species; 3) the GenDR database with >200 genes associated with the life-extending effects of dietary restriction; 4) the LongevityMap database of human genetic association studies of longevity with >500 entries; 5) the DrugAge database with >400 ageing or longevity-associated drugs or compounds...
The lungs are highly sensitive to tissue fibrosis, with a clear age-related component. Among the possible triggers of pulmonary fibrosis are repeated inhalations of fine organic particles. How age affects this response, is still far from... more
The lungs are highly sensitive to tissue fibrosis, with a clear age-related component. Among the possible triggers of pulmonary fibrosis are repeated inhalations of fine organic particles. How age affects this response, is still far from being fully understood. We examined the impact of middle-age on gene expression in pulmonary fibrosis, using the novel "inhalation challenge set" mouse model. Our results demonstrate that the response of female mice to exposure of Pantoea agglomerans extract primarily involves various immune-related pathways and cell-cell/cell-extracellular matrix interactions. We found that middle-age had a strong effect on the response to the P. agglomerans-induced lung fibrosis, featured by a more rapid response and increased magnitude of expression changes. Genes belonging to innate immunity pathways (such as the TLR signaling and the NK-cell mediated cytotoxicity) were particularly up-regulated in middle-aged animals, suggesting that they may be poten...
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Hundreds of genes have been identified as being involved in the control of lifespan in the four common model organisms (yeast, worm, fruit fly and mouse). A major challenge is to determine if longevity-associated genes (LAGs) are... more
Hundreds of genes have been identified as being involved in the control of lifespan in the four common model organisms (yeast, worm, fruit fly and mouse). A major challenge is to determine if longevity-associated genes (LAGs) are model-specific or may play a universal role as longevity regulators across diverse taxa. A wide-scale comparative analysis of the 1,805 known LAGs across 205 species revealed that (i) LAG orthologs are substantially over-represented, from bacteria to mammals, especially noted for essential LAGs; (ii) the effects on lifespan, when manipulating orthologous LAGs in different model organisms, were mostly concordant, despite of a high evolutionary distance between them; (iii) the most conserved LAGs were enriched in translational processes, energy metabolism, development, and DNA repair. The least conserved LAGs were enriched in autophagy (Fungi), G-proteins (Nematodes), and neuroactive ligand-receptor interactions (Chordata). The results also suggest that antag...
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Aging is a major worldwide medical challenge. Not surprisingly, identifying drugs and compounds that extend lifespan in model organisms is a growing research area. Here, we present DrugAge (http://genomics.senescence.info/drugs/), a... more
Aging is a major worldwide medical challenge. Not surprisingly, identifying drugs and compounds that extend lifespan in model organisms is a growing research area. Here, we present DrugAge (http://genomics.senescence.info/drugs/), a curated database of lifespan-extending drugs and compounds. At the time of writing, DrugAge contains 1316 entries featuring 418 different compounds from studies across 27 model organisms, including worms, flies, yeast and mice. Data were manually curated from 324 publications. Using drug-gene interaction data, we also performed a functional enrichment analysis of targets of lifespan-extending drugs. Enriched terms include various functional categories related to glutathione and antioxidant activity, ion transport and metabolic processes. In addition, we found a modest but significant overlap between targets of lifespan-extending drugs and known aging-related genes, suggesting that some but not most aging-related pathways have been targeted pharmacologica...
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The vast majority of research on the impact of age on skin wound healing (WH) compares old animals to young ones. The middle age is often ignored in biogerontological research despite the fact that many functions that decline in an... more
The vast majority of research on the impact of age on skin wound healing (WH) compares old animals to young ones. The middle age is often ignored in biogerontological research despite the fact that many functions that decline in an age-dependent manner have starting points in mid-life. With this in mind, we examined gene expression patterns during skin WH in late middle-aged versus young adult male mice, using the head and back punch models. The rationale behind this study was that the impact of age would first be detectable at the transcriptional level. We pinpointed several pathways which were over-activated in the middle-aged mice, both in the intact skin and during WH. Among them were various metabolic, immune-inflammatory and growth-promoting pathways. These transcriptional changes were much more pronounced in the head than in the back. In summary, the middle age has a significant impact on gene expression in intact and healing skin. It seems that the head punch model is more sensitive to the effect of age than the back model, and we suggest that it should be more widely applied in aging research on wound healing.
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Idiopathic pulmonary fibrosis (IPF) is an age-related fatal disease with unknown etiology and no effective treatment. In this study, we show that primary cultures of fibroblasts derived from lung biopsies of IPF patients exhibited (i)... more
Idiopathic pulmonary fibrosis (IPF) is an age-related fatal disease with unknown etiology and no effective treatment. In this study, we show that primary cultures of fibroblasts derived from lung biopsies of IPF patients exhibited (i) accelerated replicative cellular senescence (CS); (ii) high resistance to oxidative-stress-induced cytotoxicity or CS; (iii) a CS-like morphology (even at the proliferative phase); and (iv) rapid accumulation of senescent cells expressing the myofibroblast marker α-SMA. Our findings suggest that CS could serve as a bridge connecting lung aging and its quite frequent outcome -- pulmonary fibrosis, and be an important player in the disease progression. Consequently, targeting senescent cells offers the potential of being a promising therapeutic approach.
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As the level of interest in aging research increases, there is a growing number of geroprotectors, or therapeutic interventions that aim to extend the healthy lifespan and repair or reduce aging-related damage in model organisms and,... more
As the level of interest in aging research increases, there is a growing number of geroprotectors, or therapeutic interventions that aim to extend the healthy lifespan and repair or reduce aging-related damage in model organisms and, eventually, in humans. There is a clear need for a manually-curated database of geroprotectors to compile and index their effects on aging and age-related diseases and link these effects to relevant studies and multiple biochemical and drug databases. Here, we introduce the first such resource, Geroprotectors (http://geroprotectors.org). Geroprotectors is a public, rapidly explorable database that catalogs over 250 experiments involving over 200 known or candidate geroprotectors that extend lifespan in model organisms. Each compound has a comprehensive profile complete with biochemistry, mechanisms, and lifespan effects in various model organisms, along with information ranging from chemical structure, side effects, and toxicity to FDA drug status. Thes...
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ABSTRACT
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The role of cellular senescence (CS) in age-related diseases (ARDs) is a quickly emerging topic in aging research. Our comprehensive data mining revealed over 250 genes tightly associated with CS. Using systems biology tools, we found... more
The role of cellular senescence (CS) in age-related diseases (ARDs) is a quickly emerging topic in aging research. Our comprehensive data mining revealed over 250 genes tightly associated with CS. Using systems biology tools, we found that CS is closely interconnected with aging, longevity and ARDs, either by sharing common genes and regulators or by protein-protein interactions and eventually by common signaling pathways. The most enriched pathways across CS, ARDs and aging-associated conditions (oxidative stress and chronic inflammation) are growth-promoting pathways and the pathways responsible for cell-extracellular matrix interactions and stress response. Of note, the patterns of evolutionary conservation of CS and cancer genes showed a high degree of similarity, suggesting the co-evolution of these two phenomena. Moreover, cancer genes and microRNAs seem to stand at the crossroad between CS and ARDs. Our analysis also provides the basis for new predictions: the genes common to...
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Qualitative and quantitative differences in correlative and regressive links between superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase were assessed in the mice liver by two- and three-dimensional statistical methods.... more
Qualitative and quantitative differences in correlative and regressive links between superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase were assessed in the mice liver by two- and three-dimensional statistical methods. Paired linear correlation analysis indicated SOD-CAT tandem as the correlatively acting enzymatic pair. Three-dimensional analysis revealed uniform response surfaces which exhibited higher activities at disproportional values of the other two and lower activities at proportional activities of the other two enzymes. The direct effect of the enzymes on each other was positive [table: see text] while the effect of their product was always negative.
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Correlative and regressive relations between the gaseous exchange, thermoregulation and mitochondrial protein content were analyzed by two- and three-dimensional statistics in mice. It has been shown that the pair wise linear methods of... more
Correlative and regressive relations between the gaseous exchange, thermoregulation and mitochondrial protein content were analyzed by two- and three-dimensional statistics in mice. It has been shown that the pair wise linear methods of analysis did not reveal any significant correlation between the parameters under exploration. However, it became evident at three-dimensional and non-linear plotting for which the coefficients of multivariable correlation reached and even exceeded 0.7-0.8. The calculations based on partial differentiation of the multivariable regression equations allow to conclude that at certain values of VO2, VCO2 and body temperature negative relations between the systems of gaseous exchange and thermoregulation become dominating.
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To date, most studies of Shc family of signaling adaptor proteins have been focused on the near-ubiquitously expressed ShcA, indicating its relevance to age-related diseases and longevity. Although the role of the neuronal ShcC protein is... more
To date, most studies of Shc family of signaling adaptor proteins have been focused on the near-ubiquitously expressed ShcA, indicating its relevance to age-related diseases and longevity. Although the role of the neuronal ShcC protein is much less investigated, accumulated evidence suggests its importance for neuroprotection against such aging-associated conditions as brain ischemia and oxidative stress. Here, we summarize more than decade of studies on the ShcC expression and function in normal brain, age-related brain pathologies and immune disorders with a focus on the interactions of ShcC with signaling proteins/pathways, and the possible implications of these interactions for changes associated with aging.
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The aim of the present study was to examine a possible involvement of leukotrienes (LTs) in lipopolysaccharide (LPS)-induced body temperature (Tb) response. We examined the effect of MK-886, an inhibitor of LT synthesis, on changes in Tb,... more
The aim of the present study was to examine a possible involvement of leukotrienes (LTs) in lipopolysaccharide (LPS)-induced body temperature (Tb) response. We examined the effect of MK-886, an inhibitor of LT synthesis, on changes in Tb, plasma tumor necrosis factor-alpha (TNF-alpha), hypothalamic LT, and PGE2 production. Intraperitoneal injection of LPS (50 microgramg/mouse) led to a decrease in Tb starting 1 h after the injection. The hypothermic effect of LPS was accompanied by a significant elevation in TNF-alpha level in plasma and in LT and PGE2 production by ex vivo-incubated hypothalamus. MK-886 (1 mg/kg ip) administered 4 h before LPS efficaciously prevented LPS-induced hypothermia in mice. Pretreatment of mice with MK-886 did not alter the LPS-stimulated increase in plasma TNF-alpha. MK-886 significantly inhibited LT and enhanced PGE2 production in hypothalamus compared with LPS alone. These results suggest that 1) LPS-induced hypothermia may be mediated by LTs and 2) the...
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Research Interests: Genetics, Geriatrics, Aging, Longevity, Humans, and 3 moreAnimals, Life Expectancy, and Internationality
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Understanding the genetic basis of human longevity remains a challenge but could lead to life-extending interventions and better treatments for age-related diseases. Toward this end we developed the LongevityMap... more
Understanding the genetic basis of human longevity remains a challenge but could lead to life-extending interventions and better treatments for age-related diseases. Toward this end we developed the LongevityMap (http://genomics.senescence.info/longevity/), the first database of genes, loci, and variants studied in the context of human longevity and healthy ageing. We describe here its content and interface, and discuss how it can help to unravel the genetics of human longevity.
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The vast majority of studies on longevity have focused on individual genes/proteins, without adequately addressing the possible role of interactions between them. This study is the first attempt towards constructing a... more
The vast majority of studies on longevity have focused on individual genes/proteins, without adequately addressing the possible role of interactions between them. This study is the first attempt towards constructing a &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;longevity network&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; via analysis of human protein-protein interactions (PPIs). For this purpose, we (i) compiled a complete list of established longevity genes from different species, including those that most probably affect the longevity in humans, (ii) defined the human orthologs of the longevity genes, and (iii) determined whether the encoded proteins could be organized as a network. The longevity gene-encoded proteins together with their interacting proteins form a continuous network, which fits the criteria for a scale-free network with an extremely high contribution of hubs to the network connectivity. Most of them have never been annotated before in connection with longevity. Remarkably, almost all of the hubs of the &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;longevity network&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; were reported to be involved in at least one age-related disease (ARD), with many being involved in several ARDs. This may be one of the ways by which the proteins with multiple interactions affect the longevity. The hubs offer the potential of being primary targets for longevity-promoting interventions.
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ABSTRACT Using one-, two-, and three-dimensional statistical methods, there were analyzed peculiarities of distribution and the degree of the correlative-regressional dependence between the parameters characterizing the oxygen consumption... more
ABSTRACT Using one-, two-, and three-dimensional statistical methods, there were analyzed peculiarities of distribution and the degree of the correlative-regressional dependence between the parameters characterizing the oxygen consumption rate (V O2), body temperature (BT), activities of three key enzymes of the antioxidant system - superoxide dismutase (SOD), catalase (CL), and glutathion peroxidase (GP) in 15 females of the laboratory population of Mus musculus. The performed studies have shown that the three-dimensional non-linear models better correspond to the actual data and clearly demonstrate specificity of the antioxidant enzymes, as regulatory targets. Changes of the SOD and CL activities depend mainly on V O2, whereas GP can be the target equally accessible for the regulatory factors of oxidative processes and thermoregulation.