Abstract
Age-associated rises in oxidative damage are assumed to be a central phenomenon of aging. Their attenuation is an aim for both healthy aging and life extension. This review intends to critically discuss the potential of anti-oxidant actions, but even more to direct the attention to the modes of radical avoidance and to regulatory networks involved. Mitochondria seem to play a decisive role in radical formation and cellular decline. Avoidance and repair of disruptions in the electron transport chain reduce electron leakage and, thus, oxidative damage. Several low molecular weight compounds, such as melatonin, its metabolite N1-acetyl-5-methoxykynuramine, resveratrol, α-lipoic acid, and various mitochondrially targeted nitrones are capable of supporting mitochondrial electron flux. Some of them have been successfully used for extending the lifespan of experimental animals. Importantly, chemopreventive effects of these substances against cancer development should not be confused with a slowing of the aging process. We also focus on connections between these compounds and mitochondrial biogenesis, including the roles of sirtuins and signaling via peroxisome proliferator-activated receptor-γ coactivator-1α, the participation of the circadian oscillator system in radical avoidance, as well as the potentially beneficial or detrimental effects of NO, as either a regulator or a source of mitochondrial dysfunction. Especially in the central nervous system, anti-excitatory actions by melatonin, kynurenic acid and theanine are discussed, which seem to prevent calcium overload that results in mitochondrial dysfunction. New findings on direct binding of melatonin to the amphipathic ramp of Complex I may indicate an additional regulatory role in the avoidance of electron leakage.
Highlights
Aging is a complex phenomenon, in which slow, lingering processes of steady declines in metabolism and physiological functions are superimposed by single events of deterioration, which are caused by diseases and followed by secondary impairments
The supply with anti-oxidants may favor a healthy aging, one should not expect to arrive at substantial extensions of lifespan by only detoxifying free-radicals and other oxidants formed, even not when this comprises upregulations of anti-oxidant enzymes
With regard to the crucial roles of mitochondria in the generation of free radicals and other oxidants, as well as in the aging-related metabolic decline, the support of mitochondrial function turns out to be of highest relevance
Summary
Aging is a complex phenomenon, in which slow, lingering processes of steady declines in metabolism and physiological functions are superimposed by single events of deterioration, which are caused by diseases and followed by secondary impairments. Macrophages and other oxidant-producing leukocytes can contribute to the damage of epithelial surfaces, and atherosclerotic incrustations lead to further damage by nitric oxide (NO) derived free radicals, especially radical pairs formed from peroxynitrous acid (ONOOH NO2 and OH, i.e., nitrogen dioxide and hydroxyl radical) or from the peroxynitrite-CO2 adduct (ONOOCO2– NO2 and CO3–, i.e., nitrogen dioxide and carbonate radical) [15,16] In this scenario, superoxide anions (O2–) required for peroxynitrite formation are generated at high rates in cells compromised by insufficient oxygen supply, whereas NO is produced in the partially unsuccessful attempts of causing vasodilation, and CO2 is present in supranormal concentrations because of the. The new questions to be answered are those of how mitochondrial function can be supported and maintained in the long run, how electron dissipation can be avoided, and which molecules may be suitable for this purpose
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