Sirtuin-targeting drugs: Mechanisms of action and potential therapeutic applications

The sirtuins are NAD(+)-dependent histone/protein deacetylases that are similar to Saccharomyces cerevisiae silent information regulator 2 (Sir2). Sirtuins regulate various normal and abnormal cellular and metabolic processes, including tumorigenesis, neurodegeneration, and processes associated with type 2 diabetes and obesity. Several age-related diseases, such as Alzheimer's disease, and longevity have also been linked to the functions of sirtuins. A thorough understanding of the mechanisms of action of the sirtuins may therefore yield novel therapeutic strategies targeting these processes; several small-molecule and naturally occurring inhibitors and activators of these enzymes have been identified. This review describes the mechanisms regulating sirtuin activity, as well as how these modes of regulation may be exploited to manipulate activity in the context of various pathological states (ie, metabolic diseases, cancer and neurodegenerative diseases). The possible metabolic outcomes of the pharmacological manipulation of sirtuins are also discussed.