Abstract
Research into how protein restriction improves organismal health and lengthens lifespan has largely focused on cell-autonomous processes. In certain instances, however, nutrient effects on lifespan are independent of consumption, leading us to test the hypothesis that central, cell non-autonomous processes are important protein restriction regulators. We characterized a transient feeding preference for dietary protein after modest starvation in the fruit fly, Drosophila melanogaster, and identified tryptophan hydroxylase (Trh), serotonin receptor 2a (5HT2a), and the solute carrier 7-family amino acid transporter, JhI-21, as required for this preference through their role in establishing protein value. Disruption of any one of these genes increased lifespan up to 90% independent of food intake suggesting the perceived value of dietary protein is a critical determinant of its effect on lifespan. Evolutionarily conserved neuromodulatory systems that define neural states of nutrient demand and reward are therefore sufficient to control aging and physiology independent of food consumption.
Highlights
The availability of dietary protein elicits rapid and significant effects on behavior and lifespan across taxa
We used a newly designed continuous feeding monitor (FLIC) and a novel dietary paradigm to show that in the fruit fly, Drosophila melanogaster, serotonin signaling is part of a reward circuit that is important during meal choice for assessing the value of ingested protein and inducing changes in behavior and aging
We used genetic tools that are specific to serotonergic synthesis in the CNS (Trh-GAL4; Daubert et al, 2010) and loss-of-function mutants for tryptophan hydroxylase (Trh) itself (Neckameyer et al, 2007) and 5HT2a (Nichols, 2007) to reveal significant spatial specificity of serotonin signaling in the brain for these effects
Summary
The availability of dietary protein elicits rapid and significant effects on behavior and lifespan across taxa. Availability of specific nutrients, rather than overall caloric value, may be the driving force for this effect under some circumstances, and dietary protein is important (Kamata et al, 2014; Mair et al, 2005; Mayntz et al, 2005). Many of the effects of diet manifest independently of food consumption, likely through global integration of nutrient signals and cell non-autonomous responses to those signals directed by the nervous systems (Linford et al, 2011; Mair et al, 2005; Taylor et al, 2014). Sensory neurons in Drosophila melanogaster and Caenorhabditis elegans can promote or limit lifespan depending on the specific neurons involved (Alcedo and Kenyon, 2004; Apfeld and Kenyon, 1999; Libert et al, 2007), and the first instance of sensory modulation of lifespan in mice was recently reported (Riera et al, 2014)
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