Serotonin receptors antagonistically modulate Caenorhabditis elegans longevity

Abstract

SummaryThe neurotransmitter serotonin has been implicated in affecting the variation of longevity in natural Drosophila populations and age-related diseases in mammals. Based on these observations, it has been predicted that serotonin signal, perhaps at levels of serotonin biosynthesis, may control lifespan. Here, we investigated a variety of mutations in serotonin-signal genes, including serotonin biosynthesis genes, a serotonin transporter gene, and serotonin receptor genes. Despite this prediction, mutations in the serotonin biosynthesis genes had little or modest effects on lifespan, while the mod-5 mutation with increased availability of serotonin caused a modest life-shortening effect. In contrast, a deletion mutation of the ser-1 serotonin receptor gene increased longevity by up to 46%, likely through the insulin/insulin-like growth factor 1 pathway. This result suggests an interaction between the serotonin pathway and the insulin/insulinlike growth factor 1 pathway. A deletion mutation of another serotonin receptor gene, ser-4 , shortened early to mid lifespan. The results suggest that serotonin signal antagonistically modulates longevity through different serotonin receptors. This study may indicate serotonin receptors as a potential target for antigeric interventions.

A Genetic Survey of Fluoxetine Action on Synaptic Transmission in Caenorhabditis elegans

“…Opposing 5-HT receptors have been found to modulate other behaviors in C. elegans. For example, ser-7 and ser-1 stimulate egg laying in opposition to ser-4 ), and ser-1 and ser-4 antagonistically regulate aging (Murakami and Murakami 2007). However, SER-5 and SER-7 have not been detected in neurons directly involved in locomotion (Tsalik et al 2003;Carre-Pierrat et al 2006;Harris et al 2009) and ser-7 mutants do not exhibit defects in GLR-1-mediated nose-touch response (data not shown).…”

“…The relevance of these behaviors to endogenous 5-HT has since been validated through studies of mutants of 5-HT signaling. Importantly, multiple 5-HT receptors may function in distinct cells synergistically or antagonistically to regulate a specific behavior (Carnell et al 2005;Dernovici et al 2007;Murakami and Murakami 2007;Hapiak et al 2009). In nearly all tested paradigms, fluoxetine and imipramine induce behavioral changes similarly to exogenous 5-HT Nurrish et al 1999), implying that fluoxetine regulates 5-HT inputs to these neural circuits.…”

C. elegans dauer formation and the molecular basis of plasticity

“…Not all heterochronic activites are shown. spectively, perhaps neutralizing one another's effect (Murakami and Murakami 2007). Importantly then, serotonergic signaling converges on IIS, coupling sensory information to the stress response.…”

“…Conceivably, serotonin impacts IIS by regulating production of ILPs, but this has not yet been shown. Consistent with reduced IIS signaling, tph-1 mutants also exhibit an extended reproductive period, but surprisingly, demonstrate normal longevity (Sze et al 2000;Murakami and Murakami 2007). By contrast, the activity of two different serotonin receptors, ser-1 and ser-4, reduce and extend adult longevity, re- Figure 3.…”

Bacteria and the Aging and Longevity of Caenorhabditis elegans

“…Many of the corresponding signaling mechanisms, such as the DAF-7/TGFβ pathway and the neurotransmitter serotonin, are also implicated in the regulation of organismal longevity (60,78), illustrating how bacterial modulation of C. elegans neuronal and endocrine signaling pathways may also affect life span.…”