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

The researchers not only determined how a common cellular protein affects aging, but also altered the genes that produce it in fruit flies, extending healthy lifespan by 25 to 30%. This discovery opens the door to healthier aging for people.

The cytoskeleton provides most cells with shape, structure, and internal organization. In turn, the cytoskeleton relies on a type of actin protein called filamentous or F-actin. It forms networks of thin, flexible filaments that influence the shape, stiffness and movement of cells. Research found that aging alters actin expression, disrupting cytoskeletal functions, which can lead to age-related diseases, including cancer and neurodegenerative diseases.

A new study by researchers at UCLA examined the role of actin in brain aging and found that when F-actin accumulates in the brain, it interferes with cell clearance and leads to the accumulation of waste, which reduces neuronal function and promotes cognitive decline. However, they also found that changing certain genes in fruit flies prevented the accumulation of F-actin and extended the flies’ healthy lifespan by about 30%.

“Flies become more forgetful as they age, and their ability to learn and remember declines in midlife, just like in humans,” said David Walker, study author and professor in the Department of Integrative Biology and Physiology at UCLA. “If we prevent the accumulation of F-actin, it will help the flies learn and remember as they get older, which tells us that the accumulation is not harmless.”

Autophagy (from the ancient Greek “self-eating”) 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 growing evidence that autophagic activity declines with age, including in the brain.

The researchers conducted an experiment on Drosophila – the fruit fly is a model studying F-actin in the brain 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.

To determine whether the F-actin levels they observed reflected age or were observed across the board over time, the researchers then examined flies on diet and/or protein restriction. This approach has been shown to slow aging and promote longevity. They found that flies fed a low-protein diet had significantly longer lifespans than those fed a high-protein diet. They also found F-actin in the brains of flies fed a rich diet in early middle age, which was not found in the brains of flies fed a diet-restricted diet.

The flies were then given rapamycin, a small molecule that has been shown to extend lifespan. Feeding flies rapamycin significantly extended their lifespan compared to the control group. In addition, older flies treated with rapamycin had significantly less F-actin in their brains than age-matched controls. Taken together, the results suggest that age-related F-actin reflects healthy aging in fruit flies, and this can be counteracted by lifespan extension strategies.

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

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

“When we cut Phos expression in aging neurons, it prevents the accumulation of F-actin 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 “tuning” only targeted neurons, the researchers saw that it improved the flies’ overall health. They lived 25–30% longer and showed signs of improved brain function and markers of improved health in other organs. Preventing F-actin accumulation protects cognitive function, suggesting that this accumulation drives age-related cognitive decline.

A more thorough study showed that F-actin disrupted the cell recycling system. The researchers found that preventing the accumulation of F-actin resulted in increased autophagy in the brains of aged fruit flies. If F-actin were removed And turned off autophagy, aging did not slow down. It turned out that the main mechanism by which F-actin causes brain aging is impaired autophagy. The researchers also showed that disrupting F in the aged brain restored brain autophagy to levels seen in youth and reversed certain cellular markers of brain aging.

Of course, these results need to be translated into humans, which may be more challenging. But researchers are here to solve problems, right?

“Most of us in the field of aging are focused on the transition from life span to what we call health span,” Walker said. “We want to help people achieve good health and a high quality of life while extending life expectancy. Our study improved cognitive and gut function, activity levels and overall healthspan in fruit flies – and gives hope for what we could achieve in humans.”

The study was published in the journal Natural communications.

Source: UCLA