Overview: Drugs that block serotonin and dopamine enable the life-prolonging effect of the FMO protein in C. elegans, even in the presence of the odor of food.
Source: University of Michigan
It is well known that a healthy diet is the key to a healthy life. And while many people follow specialized diets to reduce or improve their overall health, researchers interested in aging have been actively studying the life-prolonging effects of dietary restrictions and fasting.
“There’s a concept called hormesis in biology, where the idea is what doesn’t kill you makes you stronger,” says Scott Leiser, Ph.D., an assistant professor of Molecular & Integrative Physiology and Internal Medicine at the University of Michigan Medical School.
“One of the strains that has been most studied is dietary restriction, shown in many different organisms to extend lifespan and in humans to improve health.”
But as anyone dieting to lose weight can attest, the smell of delicious food can be enough to break a person’s willpower. A previous study by Leiser’s colleague Scott Pletcher, Ph.D., also of the Department of Molecular & Integrative Physiology, found that in fruit flies, attractive food odors are enough to attenuate the life-prolonging effect of a restricted diet.
In a new study published in nature communicationLeiser, lead authors Hillary Miller, Ph.D., and Shijiao Huang, Ph.D., and their team are building on that research to find out why this is the case and whether the phenomenon can be blocked with a drug.
In the roundworm C. elegans, the extension of lifespan 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 see levels of FMO proteins in real time.
When worms were limited in the amount of food they could eat, the FMO protein, which was marked with a fluorescent marker, glowed “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, leading to a loss of life extension.
One of the main problems with dietary restriction as a possible approach to life extension in humans is how difficult it is. But, Leiser said, “what if you could give yourself a drug that confuses your body into thinking you were restricting your diet?”
Building on previous research showing that neurotransmitters regulate longevity as a result of dietary restrictions, the team screened 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 antipsychotics used to treat schizophrenia, both of which block the neurotransmitter dopamine.
“We know that serotonin and dopamine are important players in the reward part of the brain and are often involved in satiety and food response signals,” 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-prolonging effect of FMO, even in the presence of the odor of food.
However, these particular drugs are unlikely to be prescribed for this effect, given their many potentially dangerous side effects. But they provide important clues about the activation pathway of fmo-2 and its effect on life extension.
About this neuroscience research news
Original research: Open access.
†Serotonin and dopamine modulate aging in response to food odor and availabilityby Hillary A. Miller et al. nature communication
Serotonin and dopamine modulate aging in response to food odor and availability
An organism’s ability to sense and respond to changes in its environment is critical to its health and survival.
Here we reveal how the most well-studied intervention for longevity, dietary restriction, works in part through a non-autonomous cell signaling pathway that is inhibited by the presence of attractive odors.
Using a gut reporter for a key gene induced by dietary restrictions but suppressed by attractive odors, we identify three compounds that enhance the effects of food odor in C. elegansthereby extending lifespan as mimetics of dietary restrictions.
These compounds clearly implicate serotonin and dopamine in limiting lifespan in response to food odor.
We further identify a chemosensory neuron likely to sense food odor, an enteric neuron signaling via the serotonin receptor 5-HT1A/SER-4, and a dopaminergic neuron signaling via the dopamine receptor DRD2/DOP-3. Aspects of this route are preserved in D. melanogaster†
Thus, blocking food odor signaling by antagonism of serotonin or dopamine receptors is a plausible approach to mimic the benefits of dietary restriction.
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