Discoveries that affect the lifespan and health of fruit flies are typically tested in mice before being considered potentially relevant in humans, a process that is expensive and time-consuming. A pioneering approach taken at the Buck Institute surpasses that standard methodology.
Using state-of-the-art systems biology and machine learning, researchers analyzed and correlated huge data sets from flies and humans to identify key metabolites that affect the lifespan of both species. The results were published online at Nature Communicationssuggest that one of the metabolites, threonine, may show promise as a potential therapeutic for anti-aging interventions.
“These results would not have been possible without this pioneering approach,” says Professor Pankaj Kapahi, PhD, lead author of the paper. “There is a lot of data available that is not correlated across species. I think this approach could be a game-changer when it comes to identifying potential interventions to improve human health.”
Threonine has been shown to protect against diabetes in mice. The essential amino acid plays an important role in the production of collagen and elastin and is also involved in blood clotting, fat metabolism and immune function.
The method – simplified
The work began with former Buck postdoc Tyler Hilsabeck, PhD, analyzing data (involving metabolomics, phenotypes, and genomics) to analyze 120 metabolites in 160 strains of fruit flies on normal and restricted diets. The goal was to reveal how different genotypes responded to diets to influence lifespan and health. “This allowed us to find ‘needles in the haystack’ in identifying relevant metabolites,” says Hilsabeck.
Vikram Narayan, PhD, a postdoctoral fellow, compared the findings with human data from the huge UK Biobank. “Using human data allowed us to focus on interesting metabolites that are conserved in both species. It also allowed us to discover the impact of those metabolites in humans,” he says. Importantly, the team then put those relevant metabolites back into the fly to validate the results.
The results
In flies, threonine extended lifespan in a strain- and sex-specific manner. People with higher levels of threonine-related metabolites had longer, healthier lives. “We’re not saying threonine is going to work in all conditions,” Kapahi says. “Our research shows that it works in subsets of both flies and people. I think most of us have stopped hoping to find a ‘magic bullet’ intervention for aging. Our method provides another way to develop precision medicine for geroscience.” “.
The results also include findings that were not as positive for both species. Orotate, which is relatively understudied and has been linked to fat metabolism, was negatively associated with aging. In flies, orotate counteracted the positive impact of dietary restriction in all animal strains. In humans, orotate was linked to a shorter lifespan.
Most important implications
Kapahi hopes that the broader research community will begin to employ this method. “Many times we find things that work in worms and flies and then we don’t have the resources to advance basic science. This approach allows us to say with much more certainty that the discoveries will be relevant in humans.” Kapahi says this method can reduce the need to carry out studies in mice, something he welcomes.