Using microarray analysis, we have identified putative regulatory elements in pro-longevity genes (dwarfism and CR-response elements: DFCR-RE) [9, 35] . Using one of the DFCR-REs, we have developed a cell-and animal-based reporter screening system, named CRISP: the CR-Imitating anti-aging agent Screening Platform. Because the DFCR-REs were isolated from long-lived mice, the unidentified transcriptional regulators of this sequence may be beneficial for longevity and delay the onset of age-related diseases. We found that reporter construct transgenic mice (CRISP mice) showed increased reporter activity upon CR ( [9] and our unpublished data). Hence, compounds that activate this reporter may be CR mimetic pro-longevity drug candidates. As revealed in the ERE-Luc mice, CRISP mice may also reveal novel longevity signaling pathways and target molecules. The activity of candidate compounds can be easily studied on cells by their addition to culture medium, or in mice by their addition to food and water. In addition to isolating the activators of pro-longevity elements, our CRISP method may also identify inhibitors or negative regulators of these elements. In this respect, CRISP is advantageous compared to single molecular target screening. Therefore, a two-step screen in which a primary HTS in CRISP cells is used to identify hit compounds, followed by a secondary screen to verify the activity, metabolism and toxicology of the hits in CRISP mice, is a potentially powerful tool for identifying promising novel drug candidates.