The researchers not only identified how a common cellular protein affects aging, but they modified the genes that produce it in fruit flies, extending healthy lifespans by 25 percent to 30 percent. The discovery opens the door to healthier aging in humans.

The cytoskeleton gives most cells their shape, structure, and internal organization. In turn, the cytoskeleton is based on a type of actin protein called filamentous or F-actin. It forms networks of thin, flexible filaments that affect cell shape, stiffness, and movement. studied they found that aging alters actin expression, disrupting cytoskeleton functions, which can lead to age-related diseases, including cancer and neurodegenerative diseases.

A new study by UCLA researchers investigated the role of actin in brain aging and found that when F-actin accumulates in the brain, it impedes cellular clearance and leads to the accumulation of waste that decreases neuronal function and contributes to cognitive decline. However, they found that changing some genes in the fruit flies prevented the accumulation of F-actin and extended the healthy lifespan of the flies by about 30 percent.

“Flies become more forgetful as they age, and their ability to learn and remember declines in middle age, just like in humans,” said David Walker, the study’s corresponding author and professor in the Department of Biology and UCLA’s Integrative Physiology. “If we prevent the build-up of F-actin, it helps the flies learn and remember when they’re older—which tells us the build-up is not benign.”

Autophagy (from the ancient Greek for “self-feeding”) is the body’s cellular recycling system. This vital process breaks down and clears old, damaged or abnormal proteins and other cellular substances. There is increasing evidence that autophagic activity declines with age, including in the brain.

The researchers experimented on a Drosophila – fruit fly – model, examining F-actin in the brains of naturally aging animals. They compared the brains of young, middle-aged, and late-aged flies and observed a significant increase in total F-actin levels in the brain as they age.

Nature Communications/Edward Schmid

To determine whether the F-actin levels they observed reflected age or occurred universally over time, the researchers then examined flies with dietary and/or protein restriction, an approach that has been shown to slow aging and promotes longevity. They found that flies fed a low-protein diet had significantly longer lifespans than those fed a high-protein diet. Moreover, they saw F-actin in the brains of flies fed a rich diet in young middle age, which was not seen in the brains of flies with a food restriction.

Rapamycin, a small molecule that has been shown to extend lifespan, was administered to the flies next. Feeding flies with rapamycin significantly extended their lifespan compared to those fed a control. In addition, aged rapamycin-fed flies had significantly less F-actin in the brain than age-matched controls. All findings, taken together, suggested that age-associated F-actin reflects healthy aging in fruit flies and could be counteracted by longevity-enhancing strategies.

“But this is a correlation, not a direct demonstration that F-actin is detrimental to brain aging,” Walker said. “To get to causation, we turned to genetics.”

Because the fruit fly genome has been completely mapped, the researchers could target genes in aging flies that are known to play a role in the accumulation of actin filaments. They found that knocking down Formin homology domain 2 containing ortholog (Phos) from fruit fly neurons prevented the accumulation of F-actin in the brain.

“When I reduced Phos expression in aging neurons, prevented the accumulation of F-actin in the brain,” said Edward (Ted) Schmid, who worked in Walker’s UCLA lab and is the study’s lead author. “This really allowed us to expand our studies because now we had a direct way to target the accumulation of F-actin in the brain and study how it affects the aging process.”

Although the genetic “tweak” only targeted neurons, the researchers saw that it improved the overall health of the flies. They lived 25% to 30% longer and showed signs of improved brain function and markers of improved health in other organs. Preventing F-actin accumulation protected cognitive function, suggesting that accumulation drives age-related cognitive decline.

Closer examination revealed that F-actin destroyed the cell’s recycling system. The researchers found that preventing the accumulation of F-actin caused more autophagy in the brains of aging fruit flies. If they removed the F-actin and autophagy turned off, aging was not slowed. It appears that the primary mechanism by which F-actin drives brain aging was the impairment of autophagy. The researchers also showed that disrupting the action of F in the aging brain restored brain autophagy to levels seen in youth and reversed certain cellular markers of brain aging.

Of course, these findings need to be translated into humans, which may prove to be more of a challenge. But challenges are what researchers are here for, right?

“Most of us in the field of aging are focused on moving beyond the lifespan into what we call the health span,” Walker said. “We want to help people enjoy good health and a high quality of life while extending their lifespan. Our study improved the cognitive and gut function, activity level and overall health span of fruit flies – and offers hope for what we might achieve in humans.”

The study was published in the journal Communication of nature.

Source: UCLA