Provided herein are methods for diagnosis and prognosis using polymorphic variants of sirtuins. Such polymorphic may be used, for example, to identify subjects that would be responsive to treatment with a sirtuin modulating compound and/or subjects that are suffering from or susceptible to a disease mediated by a sirtuin. Also provided are methods for determining the predictive value of a sirtuin polymorphic variant, methods for evaluating sirtuin modulating compounds, and methods for determining appropriate dosage and/or treatment regimens for subjects having one or more sirtuin polymorphic variants. Screening methods for identifying sirtuin modulating compounds using polymorphic variants of a sirtuin are also provided.