A midlife crisis for the mitochondrial free radical theory of aging

Abstract

Since its inception more than four decades ago, the Mitochondrial Free Radical Theory of Aging (MFRTA) has served as a touchstone for research into the biology of aging. The MFRTA suggests that oxidative damage to cellular macromolecules caused by reactive oxygen species (ROS) originating from mitochondria accumulates in cells over an animal’s lifespan and eventually leads to the dysfunction and failure that characterizes aging. A central prediction of the theory is that the ability to ameliorate or slow this process should be associated with a slowed rate of aging and thus increased lifespan. A vast pool of data bearing on this idea has now been published. ROS production, ROS neutralization and macromolecule repair have all been extensively studied in the context of longevity. We review experimental evidence from comparisons between naturally long- or short-lived animal species, from calorie restricted animals, and from genetically modified animals and weigh the strength of results supporting the MFRTA. Viewed as a whole, the data accumulated from these studies have too often failed to support the theory. Excellent, well controlled studies from the past decade in particular have isolated ROS as an experimental variable and have shown no relationship between its production or neutralization and aging or longevity. Instead, a role for mitochondrial ROS as intracellular messengers involved in the regulation of some basic cellular processes, such as proliferation, differentiation and death, has emerged. If mitochondrial ROS are involved in the aging process, it seems very likely it will be via highly specific and regulated cellular processes and not through indiscriminate oxidative damage to macromolecules.

Understanding the physiology of the ageing individual: computational modelling of changes in metabolism and endurance

“…However, not all measurements support extensive and increasing oxidative damage with age: only modest increases in carbonyl content, indicating oxidation of proteins, were found in the brain and liver from old rats, but no difference was observed in lipid peroxidation rsfs.royalsocietypublishing.org Interface Focus 6: 20150079 products in the brain beyond six months of age and in the liver beyond one month [20], which is short relative to the 2-3.5 year lifespan of a rat. Many studies have been inspired by the free radical theory of ageing, but a recent review reports results that have often failed to support this theory [21]. However, if oxygen radicals reach their targets via short pathways that are not accessible to antioxidants, contradictions between the theory and the experiments may be resolved [9].…”

“…In 20 000 Australian men and women, 1 h d -1 increase in viewing time was associated with an 18% increase in cardiovascular disease mortality, and an 80% increase for viewing time more than 4 h d rsfs.royalsocietypublishing.org Interface Focus 6: 20150079 endothelial cells and decreasing endothelial nitric oxide synthase (NOS) expression. They also noted that the lowgrade inflammatory marker, C-reactive protein, was twice as high in those with more than 4 h d 21 viewing compared with those less than 2 h d…”

“…Damage and repair are important for ageing. Metabolism is in turn important for damage and repair [6,9,[16][17][18][19][20][21][22].…”

Control of Trx1 redox state modulates protection against methyl methanesulfonate-induced DNA damage via stabilization of p21

“…It will be interesting to investigate other regions of Trx1 in regulating apoptosis by using Trx1 reducing activity dead mutant in the future. In addition, H 2 O 2 can also be neutralized to H 2 O through other antioxidants such as the action of the glutathione peroxidase/glutathione reductase cycle at the expense of reducing equivalents (NADPH) (23). It will be interesting to examine whether glutathione system is as well involved in the protection against MMS-induced DNA damage.…”

Vieillissement

“…Elle a constitué la base de très nombreuses études visant à approfondir la relation entre mitochondries, stress oxydatif et sénescence cellulaire [20]. Bien que cette hypothèse ait été récemment critiquée, au moins pour ce qui concerne les phénomènes de sénescence physiologique et l'impact sur la longévité [20], les mitochondries ont été placées au coeur du vieillissement et leur importance dans les mécanismes de sénescence cellulaire, de même que la complexité de ces mécanismes, n'ont cessé de croître [21]. Les mitochondries sont à la fois source et cible des espèces réactives de l'oxygène (en anglais, reactive oxygen species [ROS]).…”