Changing the gene for a common cellular protein increases healthy lifespan by 30%

Scientists have not only identified how a common cellular protein affects aging, but also modified the genes that produce it in fruit flies, extending healthy lifespan by 25% to 30%. The discovery opens the door to healthier aging in people.

The cytoskeleton provides most cells with shape, structure, and internal organization. In turn, the cytoskeleton is based on a type of actin protein called filamentous or F-actin. It creates networks of thin, flexible fibers that influence the shape, stiffness and movement of cells. Studies I found it aging changes actin expression, disrupting cytoskeletal functions, which may lead to age-related diseases, including cancer and neurodegenerative diseases.

A new study by UCLA researchers examined the role of actin in brain aging and found that the accumulation of F-actin in the brain hinders cell cleansing and leads to the accumulation of waste that impairs neuronal function and contributes to cognitive decline. However, they also found that modifying certain fruit fly genes prevented the accumulation of F-actin and extended the lifespan of the flies by about 30%.

“As flies age, they become increasingly forgetful, and their ability to learn and remember declines in middle age, just as it does in humans,” said David Walker, corresponding author of the study and professor in the Department of Integrative Biology and Physiology at the University of California, Los Angeles. “If we prevent the accumulation of F-actin, it helps the flies learn and remember when they are older, which tells us that the accumulation is not benign.”

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

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

Nature communication / Edward Schmid

To determine whether the observed F-actin levels reflected age or occurred universally over time, the researchers next examined flies on dietary and/or protein restriction – an approach that has been shown to slow aging and promote longevity. They found that flies fed a low-protein diet had a significantly longer lifespan than flies fed a high-protein diet. Moreover, they observed F-actin in the brains of flies on the high diet during young middle age, which was not observed in the brains of flies on the restricted diet.

The flies were then given rapamycin, a small molecule that has been shown to prolong life. Feeding flies with rapamycin significantly extended their lifespan compared to flies fed the control group. Additionally, older rapamycin-fed flies had significantly less F-actin in the brain than age-matched controls. Taken together, these findings suggest that age-related F-actin reflects healthy aging in fruit flies and may be countered by lifespan extension strategies.

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

Because the Drosophila genome has been fully mapped, researchers could target genes in aging flies that are known to play a role in the accumulation of actin filaments. They discovered that it was a knockdown Formin homology 2 domain containing the ortholog (Fos) in fruit fly neurons prevented the accumulation of F-actin in the brain.

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

Although the genetic modification only affected neurons, the researchers observed that it improved the overall health of the flies. They lived 25% to 30% longer and showed signs of improved brain function and improved health of other organs. Preventing the accumulation of cognitive function protected by F-actin, suggesting that the accumulation causes age-related cognitive decline.

Closer examination revealed that F-actin disrupted the cell’s recycling system. The researchers found that preventing F-actin accumulation increased autophagy in the brains of older fruit flies. If they removed F-actin AND autophagy turned off, aging was not slowed down. It turned out that the main mechanism by which F-actin causes brain aging is impairment of autophagy. The researchers also showed that disrupting F function in older brains restored brain autophagy to levels seen in youth and reversed certain cellular markers of brain aging.

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

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

The study was published in the journal Nature communication.

Source: University of California