Stress oxydant et vieillissement

Abstract

Le vieillissement est un processus qui continue à fasciner les biologistes de tous horizons, qu’ils s’intéressent à l’évolution, à la génétique, à la signalisation ou à la toxicité de l’environnement. De nombreuses théories, parfois contradictoires, sont proposées pour rendre compte des mécanismes du vieillissement, perçus par certains comme le résultat d’un programme inéluctable, par d’autres comme le fruit d’une suite d’agressions qui pourraient être évitées ou réparées. L’hypothèse « radicalaire » du vieillissement met au premier plan l’accumulation d’agressions oxydantes provoquées par les radicaux libres provenant principalement du métabolisme de l’oxygène et de l’azote. Cette hypothèse, proposée il y a une cinquantaine d’années, demeure l’une des plus populaires chez les spécialistes, même si certaines de ses prédictions n’ont pas été vérifiées de manière satisfaisante. Cet article présente les fondements de cette hypothèse, ses relations avec les autres théories, mitochondriales, métaboliques et génétiques, et la confronte à la réalité têtue des observations expérimentales pour proposer une vision plus intégrée des relations entre vieillissement et stress cellulaires.

A number of theories have attempted to account for ageing processes in various species. Following the « rate of living » theory of Pearl, Harman suggested fifty years ago that the accumulation of oxidants could explain the alteration of physical and cognitive functions with ageing. Oxygen metabolism leads to reactive species, including free radicals, which tend to oxydize surrounding molecules such as DNA, proteins and lipids. As a consequence various functions of cells and tissues can be altered, leading to DNA instability, protein denaturation and accumulation of lipid byproducts. Oxidative stress is an adaptive process which is triggered upon oxidant accumulation and which comprises the induction of protective and survival functions. Experimental evidence suggests that the ageing organism is in a state of oxidative stress, which supports the free radical theory. A number of other theories have been proposed ; some of these are actually compatible with the free radical theory. Caloric restriction is among the best models to increase life span in many species. While the relationship between caloric restriction and corrected metabolic rate is controversial, the decrease in ROS production by mitochondria appears to be experimentally supported. The ROS and mitochondrial theories of ageing appear to be compatible. Genetic models of increased life span, particularly those affecting the Foxo pathway, are usually accompanied by an increased resistance to oxidative insult. The free radical theory is not consistent with programmed senescence theories involving the cell division dependent decrease in telomere length ; however, oxidants are known to alter telomere structure. An appealing view of the role of oxidative stress in ageing is the trade-off principle which states that a phenotypic trait can be evolutionarily conserved because of its positive effects on development, growth or fertility, and despite its negative effect on somatic functions and ageing. It is likely that most cellular stresses which comprise adaptive and toxic functions follow such a rule.