Competing forces of nature

oxidative Medicine and cellular Longevity 257 By their very nature, intrinsic cellular pathways form complex biological systems yet in many ways can open the door for the generation and development of novel therapeutic strategies for many disorders. Interestingly, it is the knowledge gained from examination of these pathways that provide the necessary insight and caution for the application of treatments for different disorders. For example, if one considers the vitamin B 3 (niacin) and its amide form nicotinamide, this agent may be seen initially as a necessary nutrient and therapy that is vital for cellular function and deficiency states. Lack of nicotinamide can result in fatigue, loss of appetite, pigmented rashes of the skin and oral ulcerations. More severe states of deficiency lead to pellagra that is characterized by cutaneous rashes, oral ulcerations, gastrointestinal difficulties and cognitive loss. Pellagra can occur during conditions of low nicotinamide or the inability to absorb nico-tinamide in the gastrointestinal tract. In addition, excessive alcohol consumption that is associated with poor dietary intake also can lead to severe nicotinamide loss and insufficient absorption. Supplementation with vitamin B 3 that can generate nicotinamide through the conversion of nicotinic acid in the liver or through the hydrolysis of NAD + can resolve these disorders. Interestingly, nicotinamide also is a vital cellular protectant during oxidative stress and cell injury. Administration of nicotinamide during periods of anoxia, oxygen-glucose deprivation or free radical exposure can not only block early cellular apoptotic programs, but also limit inflammatory cell activation. When one translates this work to animal studies, nicotinamide can improve cognitive function, reduce edema following cortical trauma, prevent spinal cord injury and limit disability in models of neurodegeneration and demyelinating disorders. Yet a paradox ensues upon further consideration of nicotinamide and the pathways controlled by this agent. It appears that a reduction in nicotinamide levels is required to support cellular longevity and increased lifespan. For example, physiological concentrations of nicotinamide can block the activity of the sirtuin Sirt1, a NAD +-dependent deacetylase associated with increased cellular lifespan. In some scenarios, inhibition of sirtuin (Sirt1) activity can be detrimental to cell survival during oxidative stress. As a result, nicotinamide can function as a physiological regulator of sirtuins and supplementation of nicotinamide may at times promote cellular dysfunction or death rather than enhanced cellular survival. These observations for the agent nicotinamide bring to light the complexity of biological systems and the need for …