Sirtuin protein family is found to be involved in aging process in yeast and D. melanogaster, while their role in higher organisms is less explored. Sirtuin3 (SIRT3) is the only member of sirtuin family linked to longevity in humans. In addition, important cellular and mitochondrial processes, including reactive oxygen species (ROS) generation are integrated through SIRT3. The excessive production of ROS leads to oxidative stress, a crucial event that contributes to mitochondrial dysfunction and age-related pathologies. Females show lower incidence of some age-related diseases that is attributed to protective effect of sex hormones. Estrogen (E2), a female sex hormone, has well established cytoprotective effect during oxidative stress. However, the mechanisms by which E2 is protective remains elusive. Although E2-dependent protection includes improvement of mitochondrial function, it is not clear whether SIRT3 participates in these events. We propose that sex-related resistance to oxidative stress occurs by E2-dependent improvement of mitochondrial function, mediated by SIRT3. We aim to define the role of SIRT3 on mitochondrial function in E2-dependent resistance to oxidative stress both in vitro and in vivo. To validate this hypothesis we will utilize pharmacological, dietary and genetic approaches to establish role of SIRT3 in E2-dependent resistance to oxidative stress. These informations will indicate if direct link between E2, SIRT3, mitochondrial function and resistance to oxidative stress exists. Successful completion of these specific aims will contribute to mechanistic understanding of the role of mitochondrial fidelity protein SIRT3, as a potential pharmacological target. Moreover, distinguishing the pathways involved in beneficial and detrimental effects of E2 is crucial for developing drug therapies that will help to retard aging with only minimal deleterious effects caused by E2.