**8. Cancer-associated fatigue, aging and oxidative mitochondrial damage**

Cancer-associated fatigue has been defined as a multidimensional sensation (McDonald et al., 1993; Milton et al., 2008; Mustian et al., 2007; Ryan et al., 2007). Most patients understand fatigue as a loss of energy and inability to perform even simple tasks without exertion (Levy, 2008; Milton et al., 2008). Cancer-associated fatigue has been described as the dysregulation of several interrelated physiological, biochemical and psychological systems (Mustian et al., 2007; Ryan et al., 2007), but at the tissue and cellular levels fatigue is related to reductions in the efficiency of cellular energy systems, mainly found in mitochondria (Agadjanyan et al., 2003; Nicolson, 2003; 2005). Damage to mitochondrial components, mainly by ROS/RNS oxidation, can impair mitochondrial function, and this can also result in oxidative damage (reviewed in Bartsch & Nair, 2004; Castro & Freeman, 2001; Kehrer, 1993). Mitochondrial membranes and DNA are major targets of oxidative stress, and with aging ROS/RNS mitochondrial damage can accumulate (Huang & Manton, 2004; Wei & Lee, 2002).

During aging and in certain medical conditions oxidative damage to mitochondrial membranes impairs mitochondrial function (Huang & Manton, 2004; Logan & Wong, 2001; Wei & Lee, 2002). For example, in chronic fatigue syndrome patients there is evidence of oxidative damage to DNA and lipids (Logan & Wong, 2001; Manuel y Keenoy et al., 2001) as well as oxidized blood markers (Richards et al., 2000) and muscle membrane lipids (Felle et al., 2000) that are indicative of excess oxidative stress (Dianzani, 1993). In chronic fatigue syndrome patients also have sustained elevated levels of peroxynitrite due to excess nitric oxide, which can result in lipid peroxidation and loss of mitochondrial function as well as changes in cytokine levels that exert a positive feedback on nitric oxide production, increasing the rate of membrane damage (Pall, 2000).
