Radicals r'aging

DC Wallace, S Melov - Nature genetics, 1998 - nature.com
DC Wallace, S Melov
Nature genetics, 1998nature.com
A central hope for those of us who are ageing, whether gracefully or reluctantly, is that the
application of the principles and tools of modern molecular biology and genetics will shed
light on the causes of senescence and suggest new approaches to defer its devastating
effects. There are many ways to die. Hence genetic defects which shorten life may not
provide fundamental insights into senescence. Experimental manipulations which extend
life, however, must address a life-limiting process, and may therefore tell a different story …
A central hope for those of us who are ageing, whether gracefully or reluctantly, is that the application of the principles and tools of modern molecular biology and genetics will shed light on the causes of senescence and suggest new approaches to defer its devastating effects. There are many ways to die. Hence genetic defects which shorten life may not provide fundamental insights into senescence. Experimental manipulations which extend life, however, must address a life-limiting process, and may therefore tell a different story. Increasingly, the toxic effects of reactive oxygen species (ROS) have been implicated as an important factor in senescence and degenerative disease1–3. ROS arise chiefly from normal metabolism, primarily from the mitochondrial respiratory chain wherein excess electrons are donated to molecular oxygen (O2) to generate superoxide anion (O2–•; Fig. 1). Superoxide anion is reduced by the superoxide dismutases (SOD) to hydrogen peroxide (H2O2) and hydrogen peroxide is reduced to water (H2O) by catalase, located primarily in perioxisomes, and by glutathione peroxidase (GPx), located in the mitochondria and cytosol. SOD has three isoforms: SOD1 in the cytosol, SOD2 in the mitochondria, and SOD3 in the extracellular space. Hydrogen peroxide, in the presence of transition metals, can be converted to the highly toxic hydroxyl radical (OH•), and all three of the ROS (O2–•, H2O2, and OH•) can damage macromolecules directly or indirectly. The involvement of ROS in limiting life span has been suggested by analyses of transgenic Drosophila which systemically overexpress both Sod1 and catalase. Particular strains expressing both transgenes have been reported to live up to 30% longer than naturally occurring flies1, whereas flies carrying only one of these constitutively expressed transgenes have not been observed to live longer10–12. ROS toxicity therefore appears to be important for longevity and detoxification of ROS must be balanced to avoid the build-up of any of the three primary ROS. ROS have also been directly implicated in some neurodegenerative diseases, including some cases of familial amyotrophic lateral sclerosis (FALS), a disease associated with the loss of motor function in midlife due to the death of motor neurons13, 14. About
1–2% of FALS patients have been found to harbour mutations in SOD1, which may be either gain-of-function or loss-of-function mutations resulting in an imbalance in ROS detoxification13–15. These apparently disparate observations have now been brought together in an article by Tony Parkes and colleagues on pages 171–174 of this issue8. These investigators created two transgenic lines of flies
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