Oxidative Stress in Brain Aging. Implications for Therapeutics of Neurodegenerative Diseases

Age has a powerful effect on enhanced susceptibility to neurodegenerative diseases, including susceptibility to stroke and cognitive impairment (CI) even in optimally healthy individuals. We critically evaluated the notion that oxidative stress increases in aging brain. Rigorous studies show logarithmic age-dependent increases in oxidized proteins and oxidized DNA lesions. Decreased activity of antioxidant protective enzymes does not account for the observed increases. The reactivity of the lipid oxidation product 4-hydroxy-2-nonenal (HNE) with key mitochondria enzymes may be important in the age-dependent loss in energy generation and enhanced susceptibility of neurons to apoptosis. Age-dependent enhanced neuroinflammatory processes may play an important role in toxin generation that causes death or dysfunction of neurons in neurodegenerative diseases. Non-steroidal anti-inflammatory drugs (NSAIDs) show significant promise. Vitamin E supplementation did not show major beneficial effect on cognitive functions. Major clinical trials for Alzheimer's disease (AD) involving cycloxygenase-II (COX II) inhibitors and amyloid-beta vaccination have been discontinued. Novel therapeutics based on blocking neuron damaging neuroinflammatory processes show great promise for abating dementia progression although they have yet to make it to clinical practice.