Serotonin is a monoamine neurotransmitter, which is phylogenetically conserved in a wide range of species from nematodes to humans. In mammals, age-related changes in serotonin systems are known risk factors of age-related diseases, such as diabetes, faecal incontinence and cardiovascular diseases. A decline in serotonin function with aging would be consistent with observations of age-related changes in behaviours, such as sleep, sexual behaviour and mood all of which are linked to serotonergic function. Despite this little is known about serotonin in relation to aging. This review aims to give a comprehensive analysis of the distribution, function and interactions of serotonin in the brain; gastrointestinal tract; skeletal; vascular and immune systems. It also aims to demonstrate how the function of serotonin is linked to aging and disease pathology in these systems. The regulation of serotonin via microRNAs is also discussed, as are possible applications of serotonergic drugs in aging research and age-related diseases. Furthermore, this review demonstrates that serotonin is potentially involved in whole organism aging through its links with multiple organs, the immune system and microRNA regulation. Methods to investigate these links are discussed.