Drosophila melanogaster, or fruit flies, are convenient research tools. It is easy and inexpensive to raise large numbers of them, they develop quickly, scientists know all about their genome and how to manipulate it, and they have many analogues to human genes that cause disease. Scientists have found that fruit flies also become more forgetful as they get older, similarly to humans. The lifespan of a fruit fly, however, is typically about two months.
Researchers have now used fruit flies to show that the buildup of a common structural protein found in most cell types, known as filamentous-actin or F-actin, can disrupt an important process in cells that removes unimportant or aberrant stuff. The disruption of that pathway, known as autophagy, can lead cellular waste to quickly accumulate. This seems to promote cognitive decline in the flies. The findings have been reported in Nature Communications.
This study also showed that when certain genes were manipulated in the neurons of fruit flies, the buildup of F-actin was prevented, leading to the restoration of normal autophagy pathways. The lifespan of these flies was extended by about 30 percent.
Actin is a well known protein that helps give cells their structure and form. Actin proteins are very common and important to a variety of cells.
Researcher Edward (Ted) Schmid, PhD, now of Arkansas State University, observed that F-actin was accumulating in the brains of fruit flies as they aged. Flies that were kept on a restricted diet not only lived longer, they also had lower levels of F-actin in their brains compared to flies that ate normally. A lifespan-extending drug called rapamycin was shown to reduce F-actin buildup in fruit fly brains as well.
"But that's correlation, not a direct demonstration that F-actin is detrimental to aging of the brain," noted senior study author David Walker, a professor at the University of California Los Angeles (UCLA). "To get at causality, we turned to genetics."
Since the fruit fly genome has been well characterized, the researchers targeted genes known to be involved in actin accumulation. One of them is known as Fhos, and this gene expresses one of a group of proteins that are related to the extension and organization of actin filaments.
"When we reduced Fhos expression in aging neurons, it prevented the accumulation of F-actin in the brain," said Schmid. "This really allowed us to expand our study because now we had a direct way to target F-actin accumulation in the brain and study how it affects the aging process."
Only neurons were affected by this Fhos reduction, but the lifespan of flies was still extended by 25 to 30 percent. An assessment of biomarkers suggested that brain function was also improved.
"Flies get more forgetful as they age, and their ability to learn and remember declines in middle age, just like it does in people," Walker said. Since good results are achieved in fruit fly learning and memory when the buildup of F-actin is prevented, the study authors noted that such F-actin accumulation is not a harmless process.
While autophagy pathways are known to decline with age, the reasons why have been unclear. This work has indicated that when the buildup of F-actin is prevented, autophagy mechanisms become more active. If autophagy was halted while F-actin was eliminated, aging processes continued. As such, the researchers suggested that F-actin promotes aging in the brain by disrupting autophagy.
When F-actin in aged brains was eliminated, autophagy was restored, and brain aging seemed to be reversed.
While these findings have yet to be confirmed in humans, they might help provide new answers about the reasons for cognitive decline as people age.
Sources: University of California Los Angeles, Nature Communications
