Abstract: Drugs that block serotonin and dopamine enable the life-extending effect of the FMO protein in C. elegans, even in the presence of food odor.
Source: University of Michigan
It is common knowledge that a healthy diet is the key to a healthy life. And while many people undergo specialized diets to reduce or improve their overall health, researchers interested in aging are actively studying the life-prolonging effects of dietary restrictions and fasting.
“There’s a concept in biology called hormesis, the idea that what doesn’t kill you makes you stronger,” said Scott Leyser, Ph.D., assistant professor of molecular and integrative physiology and internal medicine at the University of Michigan Medical School.
“One of the most studied stresses is dietary restriction, shown in many different organisms to extend lifespan and in humans to improve health.”
However, as anyone on a diet can attest, the mere smell of delicious food can be enough to break the will. A previous study by Leiser’s colleague Scott Pletcher, Ph.D., also in the Department of Molecular and Integrative Physiology, found that in fruit flies, attractive food odors are sufficient to blunt the life-extending effect of a restricted diet.
In a new study published in Nature Communications, Leiser, first authors Hilary Miller, Ph.D., and Shijiao Huang, Ph.D., and their team build on this research to understand why this is the case and whether the phenomenon could be blocked with medicine.
In the roundworm C. elegans, lifespan extension in response to environmental stressors such as dietary restrictions involves the activation of a gene called fmo-2. The team used the transparent nature of C. elegans to be able to see real-time levels of FMO proteins.
When the worms were restricted in the amount of food they could eat, the FMO protein, which was highlighted using a fluorescent marker, lit up “like a Christmas tree … it was bright red,” Leiser noted. However, when the worms were exposed to food odors, there was significantly less activation of FMO, resulting in a loss of lifespan extension.
In the roundworm C. elegans, lifespan extension in response to environmental stressors such as dietary restrictions involves the activation of a gene called fmo-2. Credit: Justin Ross, Michigan Medicine
One of the main problems with dietary restriction as a potential approach to extending life in humans is how difficult it is. But, Lazer said, “what if you could give yourself a drug that would fool your body into thinking you’re restricting your diet?”
Based on earlier research showing that neurotransmitters regulate longevity as a result of dietary restrictions, the team screened for compounds known to act on neurons.
They found three compounds that could prevent the reversal of fmo-2 induction in the presence of food: an antidepressant that blocks the neurotransmitter serotonin, and two antipsychotic drugs used to treat schizophrenia, both of which block the neurotransmitter dopamine.
“We know that serotonin and dopamine are major players in the reward part of the brain and tend to be involved in satiety signals and response to food,” Leiser said. “The fact that the drugs we found counteracted this suggests that you are blocking aspects of these pathways.” Ultimately, the drugs enabled the life-extending effect of FMO, even in the presence of food odor.
However, these specific drugs are unlikely to be prescribed for this effect given their many potentially dangerous side effects. But they provide important clues about the pathway of fmo-2 activation and its effect on lifespan extension.
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Author: Press Office Source: University of Michigan Contact: Press Office – University of Michigan Image: Image credited to Justin Ross, Michigan Medicine
Original Research: Open Access. “Serotonin and Dopamine Modulate Aging in Response to Food Odor and Availability” by Hillary A. Miller et al. Nature Communications
Summary
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Serotonin and dopamine modulate aging in response to food odor and availability
An organism’s ability to perceive and respond to environmental changes is critical to its health and survival.
Here, we reveal how the best-studied longevity intervention, dietary restriction, works in part through a cell-nonautonomous signaling pathway that is inhibited by the presence of attractive odors.
Using an intestinal reporter for a key gene induced by dietary restriction but repressed by attractive odors, we identify three compounds that block the effects of food odor in C. elegans, thereby increasing longevity as mimetics of dietary restriction.
These compounds clearly show that serotonin and dopamine limit lifespan in response to food odor.
We further identify a chemosensory neuron that likely perceives food odor, a enteric neuron that signals through the serotonin receptor 5-HT1A/SER-4, and a dopaminergic neuron that signals through the dopamine receptor DRD2/DOP-3. Aspects of this pathway are conserved in D. melanogaster.
Thus, blocking food odor signaling by antagonizing serotonin or dopamine receptors is a plausible approach to mimic the benefits of dietary restriction.
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