G protein-coupled receptors (GPCRs), the largest and the most versatile family of membrane receptors, respond to a wide range of extracellular stimuli and control various physiological functions. The potential role of GPCRs in lifespan control has been highlighted by the study in Drosophila with mutations in a class B GPCR encoded by methuselah (mth). Downregulation or mutation of mth increases the lifespan and stress resistance of Drosophila (Lin et al., 1998). Stunted (Sun) is the first reported endogenous ligand of Mth, and the mutation of sun gene also leads to increased lifespan (Cvejic et al., 2004). Two additional activators of Mth have been identified: Drosophila sex peptide (SP) and a novel peptide designated SPAM (Ja et al., 2009). The minimal sequence homology among these peptide activators demonstrates the promiscuity of Mth. Also, the fact that mth mutants exhibit no defects in behaviors elicited by SP leads to the doubt whether these peptide agonists are suitable for dissecting Mth signaling pathway. In this study, we took a different approach—screening for specific small molecule ligands of Mth receptor. Using these new tools in combination with the mth1 mutant strain, we identified that the target of rapamycin (TOR) pathway is the major effector underlying Mth's function in lifespan control.