Serotonin or 5-hydroxytryptamine (5-HT) is an important neurotransmitter in the central nervous system and the periphery. Most 5-HT (~99%) is found in the periphery where it regulates the function of the gastrointestinal (GI) tract and is an important regulator of platelet aggregation. However, the remaining 1% that is found in the central nervous system (CNS) can regulate a range of physiological processes such as learning and memory formation, mood, food intake, sleep, temperature and pain perception. More recent work on the CNS of invertebrate model systems has shown that 5-HT can directly regulate lifespan.This chapter will focus on detailing how CNS 5-HT signalling is altered with increasing age and the potential consequences this has on its ability to regulate lifespan.