Ageing, nutrition, disease, and therapy: a role for antioxidants?

Abstract This chapter reviews various theories of ageing, with a particular focus on the free-radical theory of ageing (cumulative oxidative damage by reactive species [RS] causes ageing) and the evidence supporting and challenging it. The mechanisms behind how genes (e.g. in yeast, C. elegans, and human progeroid syndromes) influence ageing are discussed, as is the role of telomeres and telomerase. The mechanisms by which caloric restriction can increase lifespan are discussed, especially the role of sirtuins and mTOR. How lifestyle (diet, exercise etc.) modulate ageing and age-related disease is also discussed. We explore whether production of RS and levels of oxidative damage in vivo increase with age (including a discussion of which proteins are special targets of damage), whether antioxidant levels (especially those of GSH) and repair or clearance mechanisms (e.g. DNA repair, the proteasome, autophagy) decline with age, and if increased antioxidant levels (administered directly, or raised by transgenic manipulations) can affect ageing. The roles of RS generated by mitochondria, and of deletions in mitochondrial DNA in modulating ageing are explored. The second part of the chapter reviews the role of antioxidants in treating disease, both agents specifically designed to decrease oxidative damage, as well as drugs targeting other mechanisms that may also have antioxidant activity (e.g. sulphasalazine, statins). Examples of the former reviewed in detail include catalase, SODs, SOD mimetics (including managanese chelates), mitochondrially targeted antioxidants, edaravone, Ebselen, nitrones, nitroxides, thiols (GSH, N -acetylcysteine, lipoate etc.), iron ion chelators, Nrf2 activators, and inhibitors of NADPH oxidases, myeloperoxidase, and xanthine oxidase.