A new screening approach developed by a lab at The Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology is offering a new way to study the biology of aging.
Using worm and fruit fly models, William Ja, Ph.D., a neuroscientist at the institute, and collaborators, developed a test to identify compounds that mimic the life-extending effects of dietary restriction and mild cold exposure. The findings were published in The Journals of Gerontology: Series A in June.
As we age, the process cells use to build proteins becomes less efficient and more error-prone, contributing to cellular damage over time, Ja said. Scientists have long known that interventions such as dietary restriction and mild cold exposure can slow this process, but recreating those benefits with medicine has remained a challenge.
To address this challenge, Ja’s team developed a laboratory test that searches for compounds capable of “reprogramming” how cells build proteins, imitating the effects of dietary restriction and mild cold exposure. Ja said the approach they developed could one day help reduce the risk of many age-related conditions by slowing the underlying biology of aging, rather than targeting a single disease.
His tests successfully rediscovered some known longevity compounds and identified a new candidate, fluspirilene. Fluspirilene is an antipsychotic compound used in Canada and other countries to treat schizophrenia. It works by reducing excess dopamine activity in the brain and inhibiting certain calcium channels, which could affect communications between nerve cells. In Ja’s tests, the compound extended lifespan and helped preserve mobility in aging fruit flies. With roughly 60% of fruit fly genes conserved in humans, flies offer an efficient and cost-effective research tool.
When hypothesizing why an antipsychotic compound could have antiaging properties, Ja said that many widely used compounds hit more than one target in the body. “Antipsychotics, for example, primarily work by changing brain signaling through dopamine and related receptors, but many also have additional effects on cellular stress pathways. In the case of fluspirilene, others have previously shown that it can activate autophagy, a cell’s recycling and cleaning process, and influence other signaling networks beyond its psychiatric action,” said Ja. “Our best guess is that it is one of these non-psychiatric pathways, particularly autophagy and stress‑response signaling, that is responsible for the aging benefits.”
Although further research is needed, the results demonstrated the potential of the new screening strategy to uncover compounds that promote healthy aging and pointed to a possible new direction for further development.
Ja said the findings highlight the value of simple model organisms in aging research. “Simple models such as worms and flies are powerful tools for discovering pathways and candidate drugs for healthy aging,” said Ja. “Many of the most promising interventions we know today were first found in these short-lived organisms.”
While fluspirilene has, so far, only been tested in flies and worms in Ja’s research, the findings provide a foundation for future studies exploring the compound’s influences on aging. Ja said his next steps include determining how fluspirilene changes protein translation in living tissues and evaluating its effects in more complex animal models. Ultimately, Ja said the work highlights the therapeutic potential of targeting the biology of aging itself as a strategy for promoting longer and healthier lives.
The study, “Cell-based screen identifies translation state modulators that extend lifespan in Drosophila melanogaster and Caenorhabditis elegans,” was also authored by Binbin Wu, Li-Jie Wang, Adwait A. Godbole, Ji Heon Han, Erin S. Keebaugh and Gisselle Chavez of The Wertheim UF Scripps Institute. Collaborators included Catherine A. Sedore, Anna L. Coleman-Hulbert, Erik Johnson and Patrick C. Phillips of the University of Oregon; Gordon J. Lithgow of The Buck Institute for Research on Aging in Novato, Cal.; Monica Driscoll from Rutgers University; and Matthew S. Gill of the University of Minnesota.