and Good Health. Who would have thought?
A team of researchers, led by Scripps scientist Matthew Gill, recently identified a new pathway affecting lifespan. Thanks to what they’ve learned from the lowly worm, there may come a time when we humans may enjoy a healthy old age.
Gill, 38, has been working with worms, (Caenorhabditis elegans – nematodes or roundworms) for more than a dozen years and, for three years, studying the molecule, N-Acylethanolamine (NAE) in worms, and how NAEs relate to diet and lifespan.
“Despite the fact that the worm is only a millimeter long, has 959 cells and lives in the soil, actually its biology and physiology are similar to humans,” Gill said. “So, we can learn important lessons from worms that apply to human physiology.”
For example, worms have two-thirds of the genes known to be involved in human diseases, he explained. “We can look at the worm and try to understand how disease progresses and find therapeutics to address those diseases.”
Two discoveries since the 1980s laid groundwork for possible interventions in the aging process, which, Gill explained, had been considered a difficult prospect since it had so many complex angles.
But then, single gene mutations were discovered in the worm that could double and triple its life span. “Instead of 20 days, it would live 40 days or 60 days,” he said. “This was a major step forward in how we think about aging.”
Then in 1997, came a real breakthrough. “One of those genes was cloned and we found out what the protein was that was being encoded. It turned out to a receptor similar to an insulin receptor that we have in humans.
“This was not just a gene specific to worms, but the same gene affects lifespan across species. Now we have a pathway that seems to be conserved across species that affects lifespan in a profound way.”
Also, researchers had discovered through studying these genes in the worm, fruit fly, yeast and mice, that there are different methods to extend lifespan and one of the most robust ways is through dietary restriction.
For example, if researchers reduced a mouse’s dietary intake, its lifespan was extended and the occurrence of age-related diseases (cancer is a major cause of death in mice) is prevented or delayed.
But, the scientists wanted to know, how do dietary restrictions work and what physiological changes take place that allow the animal to live an extended period of time? Also, many were interested to know whether dietary restrictions extend lifespan in humans.
People are trying to figure that out, too, Gill said. But, in any case, “if we can understand the genes, processes, and pathways involved in making dietary restrictions work in a simple animal, then maybe we can discover key molecules that can act as targets for drug discovery.
“And this leads to the idea put forth by a number of people to discover a calorie restriction mimetic. This would be a drug that would give you the benefits of calorie restriction but without you reducing food intake.
“It’s not about living longer, but delaying the onset of age-related disease.”
So, Gill’s study focuses on the molecules N-acylethanolamnes (NAEs) and endocannabinoids. These signaling molecules act between cells to coordinate a cell’s response to a particular input, and they are involved in response to food. Their levels change when an animal or person has low food or high food, and the molecules can control energy use in animals, “so we thought they would be a good candidate for response in dietary restriction and also, if they were involved in dietary restriction, they may have an impact on lifespan.”
The researchers set out to find these molecules, and they found that the worm has at least 6 NAEs, two of which are similar to endocannobinoids in mammals, and that the levels of these molecules change with food availability.
“When the researchers feed the worms bacteria (its food), the levels of those molecules are high. But when they reduce the levels of food, the NAEs drop down. If they add food back, the levels go back,” he said.
“We saw these molecules are responsive to food.”
“But, if we made an animal that’s deficient in NAEs, we found that the worm was long lived, so there was a correlation between low NAEs and an extended lifespan.”
Then, with one of the worms deficient in NAEs, they added back one of the NAEs, “with exciting results,” he said.
“Just adding one of these molecules back to this worm suddenly shortened its lifespan dramatically. Instead of living 25 or 30 days. Now it was living 15 days.
“Usually with these dietary restrictions, there would be a reduced level of those molecules and that would signal to the animal that food is low, and it needs to change its physiology to use nutrients more efficiently.
“But that one molecule added back in, tricked the worm into thinking it was in an environment where there was plenty of food.”
The worm can manage up to a certain point, but then it reaches a crisis, he said. “ It tries to live its normal lifespan of 25 days, but it crashes and burns. After 15 days, it can’t go any further.
“The implication, in terms of relevance to humans: this is a pretty well known signaling pathway in response to food, but it never had been demonstrated that it had impact an aging.
This study adds another pathway and set of molecules that scientists know are involved in dietary restriction, and, therefore, potentially another target for drug discovery. “If we can manipulate the NAE pathway with a small molecule, then maybe we can find something that will act with one of these dietary restriction mimetics.”
Now, the aim at Scripps is two-fold, he said. “One is to go into more details in the mechanism of how these molecules affect lifespan in a worm, and exactly how they work. Secondly is a discovery angle. NAEs are known to interact with certain receptors in humans but we don’t know the receptors in worms, and if we find these new receptors in the worm, it might lead us to find a new receptor in humans. A new receptor in humans becomes a new target for drug discovery.
“And given the role of these pathways in food sensing, energy balance and aging, there’s a potential in the long term that we can find something that has profound impact on obesity, diabetes, age-related diseases and aging itself.”