Brain iron deposition and the free radical-mitochondrial theory of ageing

The central hypothesis of this paper states that oxidative stress, augmented iron deposition, and mitochondrial insufficiency in the ageing and degenerating CNS constitute a single neuropathological ‘lesion’, and that the advent of one component of this triad obligates the appearance of the others. Evidence in support of this unifying perspective is adduced from human neuropathological studies, experimental paradigms of ageing-associated neurological disorders, and a comprehensive model of astroglial senescence. A pivotal role for the enzyme, heme oxygenase-1 (HO-1) in consolidating this tripartite lesion in the ageing and diseased CNS is emphasized. The data are discussed in the context of a revised ‘free radical-mitochondrial-metal’ theory of brain ageing, and some scientific and clinical implications of the latter are considered.