Discoveries that influence lifespan and healthspan in fruit flies often undergo testing in mice before being deemed applicable to humans—a process that is costly and lengthy. A groundbreaking technique developed at the Buck Institute bypasses this traditional method.
By leveraging advanced machine learning and systems biology, scientists examined and correlated vast datasets from both flies and humans to pinpoint crucial metabolites that affect lifespan in both groups. Findings published online in Nature Communications indicate that one of these metabolites, threonine, may have potential as a therapeutic target for aging interventions.
“These findings would not have been achievable without this innovative approach,” remarks Buck professor Pankaj Kapahi, PhD, the lead author of the study. “There is a wealth of data that hasn’t been analyzed across different species. I believe this method could significantly change how we identify potential health interventions for humans.”
Threonine has demonstrated a protective effect against diabetes in mice. This essential amino acid is vital for producing collagen and elastin, and it plays roles in blood coagulation, fat metabolism, and immune function.
The method — simplified
The research commenced with former Buck postdoctoral researcher Tyler Hilsabeck, PhD, who analyzed metabolomic, phenotypic, and genomic data concerning 120 metabolites across 160 fruit fly strains on both restricted and normal diets. The aim was to determine how various genotypes reacted to these diets and their effects on lifespan and healthspan. “This process enabled us to discover the ‘needles in the haystack’ regarding significant metabolites,” states Hilsabeck.
Postdoctoral fellow Vikram Narayan, PhD, then compared these findings with human data from the extensive UK Biobank. “Utilizing the human data helped us focus on metabolites that are interesting due to their conservation across both species, allowing us to explore their effects in humans,” he explains. Crucially, the team reintroduced these pertinent metabolites back into the fruit flies to confirm their findings.
The results
In fruit flies, threonine enhanced lifespan in specific strains and sexes. Those with elevated levels of threonine-related metabolites experienced longer, more robust lives. “We are not suggesting that threonine will be effective in all scenarios,” notes Kapahi. “Our study shows it is effective in certain groups of both flies and humans. Many of us have shifted away from the idea of a ‘magic-bullet’ solution for aging. This method offers another pathway for developing precision medicine in geroscience.”
However, not all findings were encouraging for both species. Orotate, which has received limited study and is associated with fat metabolism, was negatively correlated with aging. In flies, orotate mitigated the benefits of dietary restriction across all tested strains. In humans, it was connected to a reduced lifespan.
Larger implications
Kapahi hopes that the broader research community will adopt this novel method. “Frequently, we discover effective treatments in worms and flies, but we lack the resources to advance that basic research. This approach allows us to assert with greater confidence that these discoveries will be meaningful in humans.” Kapahi believes that this method may lessen the reliance on mouse studies, which he views as a positive development.
