Humans and fruit flies both may become forgetful as they age. But because fruit flies have a lifespan of only about two months, they can be a useful model for understanding the cognitive decline that comes with aging.
Research in the fruit fly Drosophila by scientists at the University of California, Los Angeles (UCLA) has now found that buildup of a common cell structural protein, filamentous actin (F-actin), in the brain inhibits a key process that removes unnecessary or dysfunctional components within cells, including DNA, lipids, proteins and organelles. The resulting accumulation of waste diminishes neuronal functions and contributes to cognitive decline.
UCLA professor of integrative biology and physiology David Walker, PhD, and colleagues, in addition showed that tweaking a few specific genes in aging fruit flies’ neurons prevented this F-actin buildup, maintained cellular recycling and extended the healthy lifespan of fruit flies by approximately 30%. “Most of us in the aging field are focused on moving beyond lifespan into what we call the healthspan,” said Walker. “We want to help people enjoy good health and a high quality of life while extending the lifespan. Our study improved cognitive and gut function, activity level, and overall healthspan of fruit flies—and offers hope for what we might be able to achieve in humans.”
Walker is senior author of the team’s published paper in Nature Communications, titled “Accumulation of F-actin drives brain aging and limits healthspan in Drosophila,” in which the researchers concluded, “Our data identify excess actin polymerization as a hallmark of brain aging, which can be targeted to reverse brain aging phenotypes and prolong healthspan.”
Actin proteins are abundant throughout the body and help to give cells their shape. “The actin cytoskeleton dictates the shape and polarity of a cell and is essential in numerous and diverse fundamental processes including cellular division, motility, phagocytosis, organelle trafficking, and signaling,” the authors explained. Actin can be found in two forms, monomeric (G-actin) and filamentous (F-actin). The latter forms filaments that are essential for maintaining cell structure and many other functions.
The assembly and disassembly of actin filaments are processes regulated by a large number of actin-interacting proteins, and maintenance of the actin cytoskeleton is “highly susceptible to disruption caused by aging,” the team noted. “In fact, aging is associated with not only changes in the expression of actin genes but also disruption of actin cytoskeletal dynamics. However, they pointed out, the interplay between actin dynamics and neuronal aging hasn’t been characterized in any species.”
For their reported study the team we set out to examine the role of actin dynamics in brain aging. Led by former postdoctoral scholar Edward (Ted) Schmid, PhD, in David Walker’s lab, the researchers first identified F-actin buildup in the brains of aging fruit flies, and questioned whether this contributed to brain aging and overall loss of organismal health. They made an initial correlation, on the finding that flies on a restricted diet both lived longer and had less F-actin buildup in their brains. “Flies fed a low-protein diet had a significantly longer lifespan compared to those provided a high-protein diet,” they commented. The investigators also showed that, when treated with rapamycin, a drug known to extend lifespan, aged flies had less F-actin buildup in the brain. “Together, these findings suggest that age-associated F-actin polymerization in Drosophila brains reflects aging health and can be counteracted by prolongevity strategies,” the team stated.
As Walker further pointed out, “But that’s correlation, not a direct demonstration that F-actin is detrimental to aging of the brain … To get at causality, we turned to genetics.”
The fruit fly genome has been thoroughly mapped, and the investigators targeted in aging fruit flies genes that are known to play important roles in the accumulation of actin filaments. That included knocking down a gene called Fhos, a member of a family of proteins known to elongate and organize actin filaments. “Fhos promotes actin nucleation and is important for filament assembly,” they commented.
“When we reduced Fhos expression in aging neurons, it prevented the accumulation of F-actin in the brain,” said Schmid, now an investigator at the Arkansas Biosciences Institute and assistant professor at Arkansas State University. “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.”
They found that even though the genetic intervention was targeted to just neurons, it improved the flies’ overall health. These animals lived 25–30% longer, while showing signs of improved brain function as well as markers of improved health in other organ systems. Preventing F-actin accumulation protected cognitive function, indicating that the buildup was a driver of age-onset cognitive decline. The authors stated in their report, “Here, we show that disrupting actin polymerization in the brains of middle-aged animals robustly improves a well-established paradigm of olfactory learning: the ability of flies to associate an odor with an aversive stimulus.”
Walker added, “Flies get more forgetful as they age, and their ability to learn and remember declines in middle age, just like it does in people … If we prevent accumulation of F-actin, it helps the flies learn and remember when older—which tells us the buildup is not benign.”
Further investigation showed the F-actin was interfering with a cellular “garbage disposal” system. Damaged or superfluous proteins and other components inside a cell are broken down in a process called autophagy. Aging research has established that autophagy pathways become less active with age, but no one knew exactly why. “A growing body of evidence indicates that autophagic activity declines with age, including in the aged brain,” the team pointed out. Also, they noted, “the interplay between actin dynamics, autophagy and brain aging remains unexplored.”
The newly reported study showed that preventing F-actin accumulation led to much more active autophagy in the brains of aged fruit flies. The authors found that if they removed F-actin but also disabled autophagy, it did not slow aging. Their results collectively indicated that the primary mechanism by which F-actin drives brain aging appears to be by impairing autophagy. The team also showed that disrupting F-actin in aged brains can restore brain autophagy to youthful levels and reverse certain cellular makers of brain aging. Describing the results of one set of experiments, the team noted, “These findings imply that therapeutic targeting of age-associated actin polymerization, in aged animals, may reverse both cellular hallmarks of brain aging and improve brain function.”
The researchers findings may be good news for the elderly fruit flies with reduced F-actin in their brains. But it has not yet been demonstrated in humans, and developing interventions to prevent F-actin accumulation might prove more challenging. “… in order to translate these findings to benefit human health, future work could focus upon identifying cell-type and tissue-specific approaches to target actin polymerization in aged organisms,” they wrote.
Nevertheless, the discovery directs researchers in a fruitful new direction for healthier aging in people. “Our findings reveal that inhibiting actin polymerization in aged animals can slow or even reverse aspects of brain aging,” they concluded. “Cumulatively, these data are consistent with a model in which age-associated F-actin polymerization in Drosophila brains disrupts autophagy and, thereby, drives paradigms of brain and organismal aging.”
