A tiny worm just revealed a big secret about living longer

Some of the approaches most strongly supported by scientific evidence, such as strict dieting for health and longevity, can be difficult to follow consistently.

Exploring How Environment Shapes Longevity

New work from the laboratory of Scott Leiser, Ph.D., in the Molecular and Integrative Physiology Department at the University of Michigan Medical School, highlights notable links between a longevity-associated gene, environmental influences and behavior.

These findings help researchers move closer to uncovering the biological pathways that might be used to lengthen life while avoiding the uncomfortable aspects of current strategies.

Worm Studies Reveal How Cues Affect Lifespan

The first study, published in PNAS, uses the model organism C. elegans (a widely studied worm species) to investigate how environmental signals and access to food influence longevity.

"Believe it or not, most of the central ideas and types of metabolism we study are conserved from worms to people," said Leiser.

He explained that both humans and worms release hormones, including adrenaline or dopamine, in response to what they sense around them. Neurons in worms react to their surroundings in much the same way, triggering physiological changes.

Past research has shown that stress related to limited food availability can increase survival.

Earlier work in flies by Scott Pletcher, Ph.D., Leiser's colleague at U-M, revealed that simply smelling food can counteract this survival benefit.

Touch Interferes With Longevity Pathways

Leiser, project leader Elizabeth Kitto, Ph.D., and contributor Safa Beydoun, Ph.D., questioned whether other sensory experiences, such as touch, might also reduce the life-extending outcomes of dietary restriction and, if so, what mechanisms might be involved.

To explore this, they placed worms on a layer of beads that mimicked the feel of the E. coli they normally encounter while feeding.

This gentle tactile cue was enough to suppress the activity of a longevity-related gene in the intestine (fmo-2) and reduced the lifespan extension usually produced by dietary restriction.

Leiser had previously shown in 2015 that fmo-2 is both necessary and sufficient for lifespan extension in response to dietary restriction.

"The fmo-2 enzyme remodels metabolism, and as a result increases lifespan," he explained. "Without the enzyme, dietary restriction does not lead to a longer lifespan."

Their experiments revealed that touch activates a neural circuit that alters signals from cells releasing dopamine and tyramine. This lowers the induction of intestinal fmo-2 and reduces the longevity benefits of restricted diets.

Potential to Manipulate Longevity Mechanisms

According to Leiser, the most significant implication for human health is that these circuits can potentially be adjusted.

"If we could induce fmo-2 without taking away food, we could activate the stress response and trick your brain into making you long-lived."

Before that is possible, however, researchers need to understand other roles that fmo-2 plays in living organisms.

Behavioral Effects of the fmo-2 Enzyme

In a separate study published in Science Advances, the team found that the enzyme influences behavior in clear and measurable ways.

Worms engineered to overexpress fmo-2 showed little reaction to positive or negative changes in their surroundings. They did not retreat from potentially dangerous bacteria, and after a short fast, they did not pause to feed the way typical worms would.

Worms that lacked fmo-2 entirely also explored their environment less frequently than normal worms. Both of these behavioral changes stemmed from altered tryptophan metabolism.

"There are going to be side effects to any intervention to extend life-and we think one of the side effects will be behavioral," said Leiser.

"By understanding this pathway, we could potentially provide supplements to offset some of these negative behavioral effects."

Future Research Directions

Leiser plans to continue investigating how the brain, metabolism, behavior and health interact, with the goal of supporting the development of drugs that target these natural pathways.

"Investigating all of the individual signals that our brain is responding to from the gut is a hot but not well understood area."

Additional authors: Ella Henry, Megan L. Schaller, Mira Bhandari, Sarah A. Easow, Angela M. Tuckowski, Marshall B. Howington, Ajay Bhat, Aditya Sridhar, Eugene Chung, Charles R. Evans