The neurotransmitter serotonin (5HT) has been implicated to affect variation of longevity in natural Drosophila populations and age-related diseases in mammals. Based on the observations, it has been predicted that serotonin signal, perhaps at levels of serotonin biosynthesis, may control lifespan. Despite the prediction, we found that mutations in the serotonin biosynthesis genes had little or modest effects on life span. Interestingly, a deletion mutation of the
ser-1 serotonin receptor gene increased longevity by up to 46%, while a deletion mutation of another serotonin receptor gene,
ser-4, shortened early to mid lifespan [1]. The serotonin receptor genes modulate early phase of behavioral aging (locomotion, learning behavior, sensory behavior, etc.) [2; Murakami et al., unpublished] and in stress responses [3] in a different manner. The results provide several important suggestions: (a) Sarcopenia (i.e., muscle frailty) is not the only cause of behavioral aging. (b) Behavioral aging has early and late phases. Early phase occurs prior to the timing when sarcopenia is observed. Serotonin signal modulates early phase. Alterations in neurotransmitters may cause early phase of aging (or post-developmental changes in behaviors) [4]. (c) Late phase is associated with increased oxidative stress in neurons. We are currently defining the roles of oxidative stress in aging of behaviors. References: [1] Murakami H, Murakami S. (2007) Serotonin receptors antagonistically modulate C. elegans longevity. Aging Cell. In Press. [2] Murakami H, Bessinger K, Hellmann J, Murakami S. (2007) Manipulation of serotonin signal suppresses early phase of behavioral aging in Caenorhabditis elegans. Neurobiology of Aging. In Press. [3] Liang B, Moussaif M, Kuan CJ, Gargus JJ, Sze JY. (2006) Serotonin targets the DAF-16/FOXO signaling pathway to modulate stress responses. Cell Metab. 4:429-40. [4] Murakami S. (2007) C. elegans as a model system to study aging of learning and memory. Molecular Neurobiology. In Press.