Stress, aging, and neurodegenerative disorders. Molecular mechanisms.
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Aging↗
Biomedical subjects
O Toussaint
Publications and source records attributed to O Toussaint.
Reciprocal relationships between the resistance to stresses and cellular aging.
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Calcium↗
The thermodynamics and evolution of complexity in biological systems.
Recent advances in nonequilibrium thermodynamics leads to the conclusion that similar processes, constrained by the second law of thermodynamics, give rise to the emergence of structure and process in a broad class of dissipative systems. The second law suggests that, in systems moved away from equilibrium, processes can emerge so that the system organizes in a way that reduces the effect of the applied gradient. If dynamic and or kinetic conditions permit, self organization processes can be expected. As biosystems grow and develop, they should increase their total dissipation, and develop more complex structures with more energy flow, increase their cycling activity, develop greater diversity and generate more hierarchical levels. As a corollary to this general statement, biosystems which do not increase their total dissipation, are organisms dedicated to death, like observed during the aging of any biosystem. Species which survive in ecosystems are those that funnel energy into their own production and reproduction and contribute to autocatalytic processes which increase the total dissipation of the ecosystem while at same time surviving within the constraints of their changing environment. In a broad class of biosystems, stress and aging have similar thermodynamic properties and suggests common underlying principles.
Aging↗
Low levels of reactive oxygen species as modulators of cell function.
In this paper, we present various arguments supporting the hypothesis that reactive oxygen species (ROS) could be responsible for the modulation of various cellular functions, besides their well known toxic effects. We first review the recent evidence indicating that ROS are able to modulate genome expression through specific and precise mechanisms during cell activation. The role of the nitrogen reactive radicals such as nitric oxide is separately analyzed because of its specific role in the nervous and vascular systems. The action of the other ROS on gene activation will then be reviewed by first looking at their possible involvement in the activation of transcription factors like NF-kappa B. Arguments will then be developed in favor of the implication of the ROS in the cellular effects of PMA, TNF-alpha and other cytokines on the modulation of the genetic expression. Possible mechanisms will be presented for linking the production of the ROS with cell activation. In a general way we postulate that ROS can play a role of secondary messengers in several cell responses to external stimuli. In the second part of the paper, we will examine the long term influence of ROS and their possible roles in cellular aging. Different links exist between ROS and aging and the relationship between them is probably indirect. We propose to consider the effect of ROS as one of the multiple challenges that cells have to face, the cell being considered as a global system which must optimize its energy expenditure for carrying out its basic functions such as turnover, differentiated phenotype functions, multiplication, defense and repair processes. This thermodynamic point of view will help to understand the effect of low ROS stresses, among others, on accelerated aging.
Animals↗
Effects of modulations of the energetic metabolism on the mortality of cultured cells.
Since cells are open systems which exchange material with their surroundings, they can be considered as open systems far from equilibrium and in this way, they follow the principles of thermodynamics of open systems. This approach stresses the fact that cells optimize their use of energy according to their functions. However, with time and/or under environmental challenges, cells can reorganize themselves at other lower levels of energy production and utilization (Toussaint et al. (1991) Mech. Ageing Dev. 61, 45-64). Considered as optimized systems, cells can adapt their behaviours according to the balance between, on one side, their energetic potential and the level of their defence systems, and on the other side, the intensity of the stress. Mainly three types of behaviour can be theoretically predicted. If the stresses are very low, the damages generated are instantaneously repaired and the cellular system remains at its steady state of energy production and utilization. If the stresses are of an intermediary intensity, it is predicted that the cell can leave its steady state of energy production and utilization and find a new one characterized by a lower level of entropy production and a higher level of errors. Third, if the stresses are of a very high intensity which can be cytotoxic, the level of the energetic potential of the cell is directly related to cell survival. We tested the latter prediction in the present work in two ways. First, the level of energy production was lowered by partially uncoupling the mitochondria. Then the effect of stresses under tert-butylhydroperoxide or ethanol was investigated in order to look for a synergistic effect on cell death with the mitochondria uncoupling. Secondly, the effect of a modification of the energetic sources during the stress was tested. Besides a protective effect found with specific defence systems, the presence of energetic metabolites such as D-glucose, pyruvate/malate, glutamate/malate, was tested and found to be protective. The effect of a stimulator of the energetic metabolism, naftidrofuryl oxalate, was also investigated and found protective. The experimental data provide good evidence that energetic factors can modulate the resistance of cells to various stresses.
Adenosine Triphosphate↗
Importance of Se-glutathione peroxidase, catalase, and Cu/Zn-SOD for cell survival against oxidative stress.
Eukaryotic cells have to constantly cope with highly reactive oxygen-derived free radicals. Their defense against these free radicals is achieved by natural antioxidant molecules but also by antioxidant enzymes. In this paper, we review some of the data comparing the efficiency of three different antioxidant enzymes: Cu/Zn-superoxide dismutase (Cu/Zn-SOD), catalase, and selenium-glutathione peroxidase. We perform our comparison on one experimental model (human fibroblasts) where the activities of these three antioxidant enzymes have been modulated inside the cells, and the repercussion of these changes was investigated in different conditions. We also focus our attention on the protecting role of selenium-glutathione peroxidase, because this enzyme is very rarely studied due to the difficulties linked to its biochemical properties. These studies evidenced that all three antioxidant enzymes give protection for the cells. They show a high efficiency for selenium-glutathione peroxidase and emphasize the fact that each enzyme has a specific as well as an irreplaceable function. They are all necessary for the survival of the cell even in normal conditions. In addition, these three enzymes act in a cooperative or synergistic way to ensure a global cell protection. However, optimal protection is achieved only when an appropriate balance between the activities of these enzymes is maintained. Interpretation of the deleterious effects of free radicals has to be analyzed not only as a function of the amount of free radicals produced but also relative to the efficiency and to the activities of these enzymatic and chemical antioxidant systems. The threshold of protection can indeed vary dramatically as a function of the level of activity of these enzymes.
Animals↗
[Arguments in favour of the concept of critical threshold of accumulation of errors in cell death. Qualities and limits of this concept in cell aging].
The concept of critical threshold of error accumulation explains how a cell dies when it it confronted, abruptly or after a certain accumulation time, to a level of errors which is not sustainable anymore for the cell. Arguments in favour of this concept will be developed, which have mostly arose from the study of the cellular system of free radical production and elimination but also from the system of free energy production and utilisation. On one hand, this concept cannot explain how the level of errors can increase during normal ageing, in which cell death is not necessary involved. On the other hand, this concept can be a basis to explain the occurrence of some age-related pathologies where the relative resistance of the various cell types constituting an organ to intense stresses can be responsible for the occurrence of dysfunctions in this organ. The main point is that this concept takes into consideration the relative level of the defence systems confronted to the stress. Such a consideration of the cellular defence systems constitutes the basis for a global theory of cellular aging explaining how the level of errors can progressively increase with time, spontaneously of after intense non lethal stresses.
Cell Death↗
[Critical review of theories on cell aging. From Hayflick's basis concept to the concept of critical threshold of accumulation of errors].
The goal of this review of the theories of cellular ageing is first to distinguish the theories on the basis of logical criteria following the dichotomies genetic/environmental and deterministic/stochastic. The second purpose is to show, from such criteria, that these theories can be integrated in a more general concept, which is the concept of critical threshold of error accumulation, taking into account the protective role of defenses systems avoiding a quick increase in the level of intracellular errors.
Cellular Senescence↗
Relationship between the critical level of oxidative stresses and the glutathione peroxidase activity.
The production and removal of the various oxygen-derived free radicals is a dynamic and complex process which normally results in a steady state of very low concentrations of these reactive molecules in the cell. The mathematical modelling of this process showed that any lowering of the glutathione peroxidase activity will increase the steady state level of the hydroperoxides and will decrease the level of organic peroxides necessary to destabilize the system. In this paper, we experimentally tested this relationship by the estimation of the level of peroxidative stresses which lead to cell degeneration in the presence of more or less active selenium-dependent glutathione peroxidase (GPX). The enzyme was inhibited by mercaptosuccinate (MS) and the cells were submitted to various extents of oxidative stress using tert-butylhydroperoxide (TBHP). Critical levels of this peroxidative molecule could be determined by the determination of the concentration leading to 50% cell death. A relationship between this critical level of TBHP and the GPX activity was established. The critical level strongly decreased with the inhibition of GPX and was found to be zero when 44% of the GPX activity is inhibited. Presented in this way, the results clearly show the pattern of the inverse relationship between the susceptibility of the cell to oxidative stress and the GPX activity.
Cell Survival↗
Importance of various antioxidant enzymes for cell stability. Confrontation between theoretical and experimental data.
A theoretical model was developed taking into account the production and destruction of oxygen-derived free radicals. The steady state of the system was derived by using the rate equations of these reactions, and the stability of the system was tested. In the simplified model, only one stable steady state was found. However, we know that glutathione peroxidase can be inhibited by hydroperoxides, and, when incorporated into the model, this effect led to a complex situation with the presence of some stable and some unstable domains according to the concentration of either the enzyme or the hydroperoxide. This qualitative description of the system was compared with experimental data on the protection given by three antioxidant enzymes, and concordance of data was found which allows some quantification of the system. A general view of the efficiency of the three antioxidant enzymes and of the stability of the system according to their concentrations could be produced.
Animals↗
Aging as a multi-step process characterized by a lowering of entropy production leading the cell to a sequence of defined stages. II. Testing some predictions on aging human fibroblasts in culture.
The concepts of irreversible thermodynamics have been used in order to develop a theory of aging considered as a multi-step process leading the cell through a sequence of defined stages characterized by a lower level of entropy production and finally to a critical level of errors involving cell death (Toussaint et al., 1991). One of the predictions of this model is that external stresses which can be considered as fluctuations would accelerate the evolution of the cell from one state to the other according to the intensity of the stress. Seven morphotypes have been observed in the serially cultivated human fibroblasts, cells passing progressively from one morphotype to the other. In this paper, we experimentally tested the effect of two different molecules, tert-butylhydroperoxide and ethanol, in order to determine their influence on the shift from one morphotype to the other. When applied for a single period of time on cultivated cells, both molecules effectively showed a modification in the pattern of the different morphotypes which was dependent on the stress intensity: a decreased proportion of the early morphotypes and an increased proportion of the late and post-mitotic morphotypes were observed within three days after the stresses. Similar results were obtained when successive stresses were performed at every subculture. The results also indicated that all stages are not equally stable with morphotypes III and IV being the most stable. The positive effect on the increased shift of these cells from one morphotype to the other by two different stresses firms one of the prediction of the thermodynamic model which states that cellular aging can be considered as a multi-step process which can be speeded up by various external modifications.
Cell Division↗
Aging as a multi-step process characterized by a lowering of entropy production leading the cell to a sequence of defined stages.
The principles of the thermodynamics of irreversible processes which occur in biological cells considered as open systems, have been reviewed and applied in order to describe a possible evolution of cells during aging. The main feature of such an approach is that cells operating in a steady state, optimize their free energy production by lowering their entropy production which is kept to a minimum. Instabilities can however occur which can lead the cell from one steady state to another characterized by a lower production of entropy. Concomitantly, the level of errors or entropy of the system will increase. The process will continue and the cell will go from one state to another until a critical level is attained where the cell can not cope any more with keeping its organization and will die. The effect of stresses and mitosis have been also considered in this model. Such an approach stresses that cells can only subsist as a whole in certain states which are the result of the genetic constitution but also of the optimalization of cellular functions given their requirement in energy and the fluctuations from the environmental changes. In this respect, it reconciles both programmed and stochastic theories of aging.
Aging↗
Comparative study of oxygen toxicity in human fibroblasts and endothelial cells.
The resistance of human pulmonary fibroblasts (WI-38) and human umbilical vein endothelial cells to oxygen toxicity (1 atm O2) was compared. Endothelial cells were more sensitive than fibroblasts. They contained also less antioxidant enzymes except for SOD: respectively 132%, 96%, 70%, 59%, and 21% of the SOD, GSH peroxidase, GSH reductase, catalase, and G6PD content of fibroblasts. However, they contained 1.81-fold more GSH than fibroblasts. Their lower content of antioxidant enzymes can explain their higher sensitivity to oxygen. The efficiency of natural antioxidant molecules and enzymes in the protection of cells incubated 3 days under 1 atm O2 was studied. alpha-tocopherol added in the culture medium led to a significant protection, contrary to the result for ascorbic acid. Microinjection of catalase, SOD, and GSH peroxidase directly into the cells was also tested: the protection was concentration dependent for both types of cells but SOD did not protect the endothelial cells. Lower activities of the other enzymes were needed to achieve protection of the endothelial cells, compared to fibroblasts. Since endothelial cells were also shown to display lower antioxidant enzyme activities, it can be hypothesized that their content is optimized for survival in physiological conditions.
Ascorbic Acid↗
Catalytic oxidation of 2-aminophenols and ortho hydroxylation of aromatic amines by tyrosinase.
The usual substrates of tyrosinase, a copper-containing monooxygenase (EC 1.14.18.1), are monophenols and o-diphenols which are both converted to o-quinones. In this paper, we studied the reaction of this enzyme with two new classes of substrates: aromatic amines and o-aminophenols, structural analogues of monophenols and o-diphenols, respectively. They undergo the same catalytic reactions (ortho hydroxylation and oxidation), as documented by product analysis and kinetic studies. In the presence of tyrosinase, arylamines and o-aminophenols are converted to o-quinone imines, which are isolated as quinone anils or phenoxazones. As an example, in the presence of tyrosinase, 2-amino-3-hydroxybenzoic acid (an o-aminophenol) is converted to cinnabarinic acid, a well-known phenoxazone, while p-aminotoluene (an aromatic amine) gives rise to the formation of 5-amino-2-methyl-1,4-benzoquinone 1-(4-methylanil). Kinetic studies using an oxygen electrode show that arylamines and the corresponding monophenols exhibit similar Michaelis constants (Km = 0.11-0.49 mM). In contrast, the reaction rates observed for aromatic amines are relatively slow (Kcat = 1-3 min-1) as compared to monophenols (1320-6960 min-1). The enzymatic conversion of arylamines by tyrosinase is different from the typical ones: N-oxidation and ring hydroxylation without further oxidation. This difference originates from the regiospecific hydroxylation (ortho position) and subsequent oxidation of the intermediate o-aminophenol to the corresponding o-quinone imine. Finally, the well-known monooxygenase activity of tyrosinase was also confirmed for the aromatic amine p-aminotoluene, with 18O2.(ABSTRACT TRUNCATED AT 250 WORDS)
Amines↗
[Preliminary study of the use of thermography].
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Adolescent↗
Cellular aging and the importance of energetic factors.
The in vitro aging of human fibroblasts has become a classical model for studying cellular aging. This model was lately redefined by showing that these cells represent a stem cell system in which they progressively pass through seven morphotypes. Experimental data showed that external conditions that can be considered as stresses for the cells, can modulate the genome expression by speeding up the passage of the cells from one morphotype to the other. In this article, we will interpret these observations from the point of view of the thermodynamics of far from equilibrium open systems, which shows the importance of the production and the use of energy, both responsible for the generation of a given amount of entropy production. In stable systems like these cell morphotypes, such a production is constant but external stresses can prematurely destabilize the steady state of entropy production and, in doing so, accelerate the process of aging. It is also predicted that cells submitted to a stress will use part of their energy in response to the stress. Some experimental data in favor of such an interpretation have been obtained and more will be presented here that show that both cell death and accelerated cell aging under stress are modulated by the level of energy metabolism. All theoretical and experimental arguments presented in this article will show that cellular aging is related to stress and also to energy production through a very elaborate system of regulatory processes necessary for the cell to survive and to perform specific functions according to its differentiated state. This regulatory system also permits the cell to adapt its response according to the intensity of external as well as internal challenges and one of these responses will influence the cellular aging rate.
Cell Death↗