"One of the fundamental observations in oncology is that increasing age is the strongest statistic variable that predicts for carcinogenesis. A fact that has emerged over the last several years is that aging is a complex process that appears to be regulated, at least in part, by several signaling protein families that have been identified in multiple species, including sirtuins, a relatively new gene family that was initially identified in S. cerevisiae and C. elegans. SIrtuins have been found to both increase life span and decrease spontaneous tumor development suggesting that they may regulate both processes. They appear to function as fidelity proteins and loss or decrease of function, which may occur during aging, creates a cell environment permissive for several age-related illnesses, including cancer. The significant role played by sirtuins can be explained by accumulating evidence establishing their pivotal role in regulating post-translational modifications (PTMs) in both histone and non-histone proteins involved in diverse cellular processes. Despite recent scientific interest in this field, there is still scarcity regarding the functional consequences of the role of these PTMs in cellular homeostasis. Our proposed studies take an integrative approach to current challenges in dissecting the functional role of sirtuin-directed PTMs in tumorigenesis which may bridge the gap between the observation that tumorigenesis increases with age and the limited information regarding the specific mechanisms underlying this phenomenon. By blending classic molecular/ cellular biology, biochemistry and mouse genetics with large-scale proteomics, our ultimate research goal is to elucidate the function of sirtuins in maintaining cellular homeostasis which may provide novel mechanistic insights in different aspects of tumorigenesis."