Due to improvements in lifestyle and healthcare, the proportion of aged people is rising steadily, especially in developed countries. With aging, some physiological functions are altered and resemble those occurring in disease conditions such as hypertension, chronic coronary disease and diabetes. Thus, there is the urge to better understand molecular and cellular mechanisms underlying aging and aging-related diseases. In rodents and possibly primates, calorie restriction is an effective approach to extend lifespan by reducing free radical-induced damage. Increased production of oxygen-derived free radicals plays an important role in the process of aging. Reactive oxygen species are generated by different intracellular molecular pathways principally located in the cytoplasm and in the mitochondria. The mitochondrial protein p66(Shc) is considered a longevity assurance gene since its genetic deletion extends the lifespan of rodents and displays protective effects in several models of cardiovascular disease. Silent mating type information regulation 2 homolog 1 Saccharomyces cerevisiae (SIRT1) is a nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase that may also be involved in aging and diseases. SIRT1 also deacetylates a number of nonhistone target proteins, including p53, endothelial nitric oxide synthase and forkhead box protein. This review focuses on the latest scientific advances in understanding aging as well as delineates the possible therapeutic implications of p66(Shc) and SIRT1 in this process.