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Function of Heat Shock genes in Human Ageing

#3303


The Role of Molecular-Genetic Mechanisms of Resistance to the Stress Impact in Human Senility and Active Longevity

Tech Area / Field

  • BIO-CHM/Biochemistry/Biotechnology
  • BIO-CGM/Cytology, Genetics and Molecular Biology/Biotechnology
  • MED-OTH/Other/Medicine

Status
8 Project completed

Registration date
22.06.2005

Completion date
23.11.2011

Senior Project Manager
Genisaretskaya S V

Leading Institute
Institute of Gerontology, Russia, Moscow

Supporting institutes

  • Institute of Bioorganic Chemistry, Russia, Moscow\nInstitute of Immunological Engineering, Russia, Moscow reg., Lyubuchany

Collaborators

  • University of Turku / Finnish-Russian Joint Biotechnology Laboratory, Finland, Turku

Project summary

The aim of this Project is to study the role of functional activity of heat shock genes and the expression of heat shock proteins of р70 (HSP70) family in phagocytic and lymphoid cells in human resistance to stress for various age groups including long-livers.

Nowadays, the pace of population ageing is greatly accelerated. Topicality of the given project is connected with the increased number in contemporary life of technogenic catastrophes, unfavourable ecological and biogeochemical factors of environment, social problems, terroristic acts as the stress factors with negative influence on human health inducing premature ageing, development of pathologies of elderly and senile ages.

Resistance of the organism cells to various stresses is directly correlated with the life span of the inpidual. Cell resistance to the stress impacts is mostly dependent on the heat shock gene functions controlling the synthesis of anti-stress heat shock proteins (HSPs) various families: р25, р40, р60, р70, р90, etc. Various stress factors induce up-regulation of reactive oxygen species (ROS) production, especially by phagocytic cells. Excess production of oxygen radicals has damaging effect on membranes, DNAs, intensifies lipid oxidation leading to a development of a number of pathologies of elderly and senile ages: atherosclerosis, essential arterial hypertension, senile dementia of Alzheimer’s type, Parkinson's disease, cancer, etc. For the prophylaxis of pathologies resulting from the stress impacts on the organism, it is important to take into account basic mechanisms of regulation of ROS production by the cells. HSP70 were demonstrated to participate directly in ROS synthesis restriction affecting the main enzyme of their production – NADPH-oxidase. On the other hand, it is known that exogenous HSP70 interact with Toll-like receptors on the surface of phagocytic cells – the main producers of ROS, and activate synthesis of pro-inflammatory cytokines by these cells that induces ROS generation. Complex involvement of HSP70 into the regulation of stress-induced processes in the organism is also supported by HSP70 capability to prevent apoptosis induced by a pro-inflammatory cytokine – tumor necrosis factor-α (TNF-α). Thus, one of the possible mechanisms of HSP anti-stress effect could be the regulation by these proteins of the process of programmed death of lymphocytes needed for normal immune system functioning. The study of the role of HSP70 in regulation of ROS production by immunocompetent cells and in the process of their apoptosis is a main part of the project.

In order to develop new approaches to the formation of elevated protection against health disturbances and maintaining of an active life mode in elderly and senile age, hormesis phenomenon consisting in the induction of the resistance to strong and even lethal stresses through preliminary exposure of the organism to moderate or weak stresses is undoubtedly of interest. The reaction to moderate stress results in growth of protective potential of the organism and enables its optimal adaptation to the environmental changes and survival even in conditions of strong stress impacts. Thus, planed in the framework of the project the study of the role of HSP70 in the phenomenon of hormesis is a topical research, since the protective potential of all organs and tissues depends on the level of HSP70 expressions by the cells.

A wide spectrum of techniques for the isolation of enriched populations of mononuclear cells and neutrophils from peripheral blood of patients of various ages, multiparameter flow cytofluorimetry, confocal and electron microscopy, induced cell chemiluminescence, hybridoma technology, analytical and preparative biochemistry, functional activity evaluation of heat shock genes in various age groups, modifications of heat shock gene functions of human mononuclear cells and neutrophils by different pharmaceutical preparations, etc., will be used in the research.


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