Population aging will become one of the most dramatic challenges in public health faced by the western world in the near future. Aging affects the organism systemically even though its consequences on the brain are of particular importance because of the progressive decline of cognitive functions. Aging impacts not only individuals; it will exert profound effects on the entire society because it causes decrease in labor productivity as well as increase in health-care costs. In this regard, it is critical to develop effective treatments to ameliorate the quality of life of the elders. Ideally, successful treatments will target those early mechanisms that are responsible for initiating the molecular cascade leading to the aging phenotype. Oxidative stress – and its consequences on DNA damage - has been indicated as a major player in the process and antioxidant treatments received ample consideration. However, such treatments have been rather unsuccessful and it is still unclear whether oxidative stress really represents an initiating factor in aging. In fact, generic induction oxidative stress is not necessarily associated to an aging phenotype. On the contrary, genetic disruption of some DNA repair mechanisms accurately mimics this physiological process. The goal of this grant is to provide insights about the causative mechanisms of aging in the brain and to generate information useful to develop effective antioxidant therapies. For this purpose, we will use genetic mice models of aging – where the DNA repair machinery is impaired – to understand if oxidative stress is causative of DNA damage or vice versa. To discover new biomarkers, studies on mitochondrial physiology will be paralleled by analyses of protein oxidation to understand which proteins specifically undergo oxidation while the physiological functions are declining. In conclusion, our final goal is to generate information that will improve quality of life in a growing portion of the European society.