SIRT1 promotes tumorigenesis. Upon genotoxic stress, p53 is acetylated at K382, which enhanced DNA binding and transactivation activity. HIC1, miR34a, and DBC1 suppress SIRT1 activity. Multilayered inhibition of SIRT1 allows the activation status of p53 for p21, PUMA and BAX genes expression which induced cell cycle arrest, apoptosis, and senescence. Resveratrol and AROS, Along with other SIRT1 activators, enhance SIRT1 deacetylation on p53 and suppress p53 transcription-dependent cell cycle arrest and apoptosis by genotoxic stress.