Aging is believed to be a primary risk factor for cancer. Interestingly, the sirtuin family of class III histone deacetylases (HDACs) has been implicated in the regulation of longevity and may be a lost link between aging and cancer. SIRT1, a nicotinamide adenine dinucleotide (NAD(+))-dependent sirtuin, has been shown to promote cell survival by inhibiting apoptosis or cellular senescence in mammalian cells. Recent studies have provided a link between the cellular metabolic function of SIRT1 and the circadian rhythm (controlled by a clock machinery), which, if deregulated, may lead to an increased risk for some cancers. Interestingly, the loss of the pineal hormone melatonin, a known regulator of circadian rhythm, has been shown to cause deregulation in the circadian rhythm machinery and an increase in susceptibility to cancer. On the basis of scientific evidence, we propose a hypothesis that SIRT1 inhibition will impart an antiproliferative response in age-related cancers via resynchronization of deregulated core clock circuitry at the cellular level. If this hypothesis is found valid, it may ultimately lead to the development of novel approaches toward management of age-related malignancies and possibly other diseases.