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Stress, a source of longevity?

Hormetic effect: the protective effects of peroxyredoxin (in green) do not increase linearly. After the oxidative stress threshold of 50 μM, the deleterious effects of this oxidative stress become superior to the protective effects.

Nonlinear feedback drives homeostatic plasticity in H2O2 stress response.

Goulev Y(1)(2)(3)(4), Morlot S(1)(2)(3)(4), Matifas A(1)(2)(3)(4), Huang B(5), Molin M(6), Toledano MB(5), Charvin G(1)(2)(3)(4).

Elife April 18, 2017


April 18, 2017

The researchers of Gilles Charvin’s team were interested in the phenomenon of acquisition of tolerance to oxidative stress in yeast. After studying the mechanism of this process, which is linked to a particular enzymatic operating mode, the study published on April 18th in the eLife magazine surprisingly reveals an increased longevity in yeasts exposed to a low dose of stress.

The physiological adaptation of organisms to changes in the environment is a central component of the Living. So-called "homeostatic" systems make it possible to maintain the internal physiological variables at a constant level despite the fluctuations of the external environment. Although they are well described at the molecular level, most of these systems show amazing but still poorly understood properties, such as the acquisition of stress tolerance for example: an organism can acquire resistance to very severe stress if it has been previously pre-exposed to a low stress dose. To better understand this phenomenon of "memory", the team of Gilles Charvin has developed a quantitative methodology to characterize with great precision the response to oxidative stress in baker's yeast.

 

The oxidative stress in question
The presence of oxygenated reactive compounds such as hydrogen peroxide (H2O2) is normal in the body. Harmful but naturally degraded by cellular enzymes such as peroxidases and catalases which are in charge of their regulation, these compounds can lead to a pathological situation when they exceed a certain threshold and cause an oxidative stress state. Factor of inflammation and mutagenesis, this oxidative stress is indeed considered as one of the causes of cancer.

 

Better tolerate oxidative stress
The study carried out by the team of Gilles Charvin first highlighted the mechanisms responsible for the phenomenon of tolerance. For this, the researchers developed a "microfluidic" system that allows to follow the successive divisions of yeast cells while exerting an absolute control of the level of oxidative stress. While "naïve" yeasts support only a relatively small dose of oxidative stress, researchers have found that yeasts, exposed to gradually increasing stress doses, can withstand stress levels up to 10 times the maximum tolerable dose in naïve condition. This resistance capacity largely depends on the time profile used to stress the cells.
After finding that a single enzyme, peroxiredoxin, was necessary and sufficient for this phenomenon, the researchers showed that this process is explained by a non-linear activation of this enzyme in response to increasing external stresses: Concentration of internal stress at equilibrium, as well as enzyme concentration, do not increase proportionally to the level of external stress. This suggests that the stress response system becomes more and more effective as the stress level increases. It is thanks to this non-linear mechanism that pre-treated cells acquire a tolerance to a subsequent severe stress.
At the molecular level, this unusual mechanism is explained by a rare configuration in the organism: peroxiredoxin is indeed an enzyme more abundant than its substrate (H2O2) and is therefore never saturated. As a result, as shown by a mathematical model proposed by researchers, the degradation rate of hydrogen peroxide varies quadratically with the level of external stress, and not linearly as expected for a classical enzymatic mechanism.

 

Hormetic effect
Beyond the phenomenon of tolerance, these experiments reveal a striking increase in longevity in cells exposed to a small dose of oxidative stress. The peroxiredoxin produced in the case of stress thus has the effect of increasing the lifetime of the cells, compared to untreated cells. However, from a certain threshold, this effect would be overcome by the negative effects of oxidative stress. Understanding these mechanisms and their mathematical modeling would help to better understand this so-called "hormetic" effect also observed in other physiological phenomena such as caloric restriction, and for which low-dose stress can be beneficial.

 

This study therefore provides a completely new point de view on the effects of oxidative stress on cell physiology and above all provides a formal framework to better understand the emergence of non-intuitive phenomena influencing stress resistance and aging.

 

This study was funded by the Association for Cancer Research (ARC) and the Foundation for Medical Research (FRM).

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