Free radicals in aging: causal complexity and its biomedical implications

Superoxide generated adventitiously by the mitochondrial respiratory chain can give rise to much more reactive radicals, resulting in random oxidation of all classes of macromolecules. Harman's 1956 suggestion that this process might drive aging has been a leading strand of biogerontological thinking since the discovery of superoxide dismutase. However, it has become apparent that the many downstream consequences of free radical damage can also be caused by processes not involving oxidation. Moreover, free radicals have been put to use by evolution to such an extent that their wholesale elimination would certainly be fatal. This multiplicity of parallel pathways and side-effects illustrates why attempts to postpone aging by "cleaning up" metabolism will surely fail for the foreseeable future: we simply understand metabolism too poorly. This has led me to pursue the alternative, "repair and maintenance" approach that sidesteps our ignorance of metabolism and may be feasible relatively soon.