Rapid advances in aging research have identified several stressful stimuli (e.g. food/oxygen availability, temperature) that can enhance health and longevity across taxa. Many of these longevity pathways act through cell non-autonomous signaling mechanisms. These pathways utilize sensory cells, frequently neurons, to signal to peripheral tissues and promote survival during the presence of external stress. Importantly, this neuronal activation of stress response pathways is often sufficient to improve health and longevity in the absence of stress.
Multiple studies, including our own, implicate serotonin (5-HT) as a signal within several longevity pathways. 5-HT is one of the best studied neuromodulators with numerous drugs targeting its actions, yet our understanding of the complex actions of 5-HT signaling is still incomplete. 5-HT is released upon food perception, therefore we posited that a decrease in 5-HT release during dietary restriction (DR) may also result in downstream signaling changes. This hypothesis is bolstered by data showing that the perception of food is sufficient to abrogate DR-mediated longevity. Using an intestinal reporter for a key gene induced by DR but suppressed by attractive smells, we identify three compounds that block food perception, thereby increasing longevity as DR mimetics. These compounds clearly implicate serotonin and dopamine in limiting lifespan in response to food perception.
We further identify an enteric neuron in this pathway that signals through the serotonin receptor 5-HT1A/ser-4 and dopamine receptor DRD2/dop-3, and critically, aspects of this pathway are conserved in the vinegar fly D. melanogaster and in mammalian cells. These studies present compelling evidence that reward circuitry is tied to the perception of food across taxa and may be a viable area of research to discover pro-longevity treatments.
Similar to our food availability experiments, we find temperature can modulate longevity interventions outside the laws of thermodynamics. Our data suggest that genetics play a major role in temperature-associated longevity and are consistent with the hypothesis that while aging in C. elegans is slowed by decreasing temperature, the major cause(s) of death may also be modified, leading to different genes and pathways becoming more or less important at different temperatures. These data shed light on the complex interplay of stress response signaling and suggest some act in a temperature-dependent manner.
Collectively, the findings in this thesis enhance our understanding of conserved signaling pathways that modify aging while advancing the fields long-term goal to develop therapeutics that increase human health/lifespan.PHDCellular & Molecular BiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/169956/1/millhill_1.pd
