Fruitful insights on the brain from research on flies

China Byrns of Nancy M. Bonini’s lab led research on 'zombie-like' cells, findings that could offer insights into neurodegenerative disease and aging.

Microscopy images of fly brains with lipid deposits.
Lipids accumulate in the fly brain with age (left, young brain; middle, aged brain), likely contributing to cell dysfunction and disease protein aggregation. The authors show that targeting zombie-like neuronal support cells prevents lipid accumulation (right). (Image: Courtesy of China N. Byrns)

Senescent cells, often described as zombie-like, are ones that have stopped dividing but are still alive. They do not function as effectively they used to; instead, they resist death and linger in the body, causing trouble.

“These cells can be beneficial in the short term, as in wound healing,” explains University of Pennsylvania neuroscientist and geneticist Nancy M. Bonini. “But over time, they accumulate and release noxious pro-inflammatory signals that can contribute to cognitive declines, increase frailty, and weaken the immune system.”

A bottleneck in research on senescence is identifying and manipulating naturally occurring senescent cells in vivo. Most insights into senescence have come from in vitro studies or induced models, leaving a gap in understanding how these cells form and function naturally in living organisms.

In a new paper published in Nature, research led by China N. Byrns of the Bonini lab discovered that senescent cells naturally occur in the brain of a fruit fly (Drosophila melanogaster) with age. By isolating these cells, they found that a subset of support cells in the brain, glia, express specific genes that indicate their senescence status. The researchers found that neurons’ power stations, mitochondria, decline with age, experimentally reproducing this decline in young neurons triggers a senescence response in glia, signaling a link between neuronal health and the glial senescent state.

“Our ability to experimentally reproduce these cells as they appear in aging hints that we have found one mechanism by which these cells occur naturally, paving the way for prevention,” Byrns says.

“We can use the fly’s powerful genetics,” Bonini says, “to understand how these cells impact brain function and potentially develop strategies to slow down age-related cognitive decline in humans."

TBI in the fly

Bonini explains that this study originated from an unexpected discovery during Byrns’ earlier research on traumatic brain injury (TBI) in Drosophila: A specific pathway was activated not in the neurons, but in the glial cells.

Photograph of researcher, China Byrns, in front of monitor showing microscopy images of fly brain
China Byrns used high-magnification confocal microscopy to visualize senescent glia (red) in Drosophila brains as part of a multidisciplinary approach to define the origin and effects of senescent cells in brain aging. (Image: Courtesy of Riya Anand)

This pathway, controlled by a regulatory transcription factor AP1, was significantly activated in glial cells, suggesting these cells played a protective or reactive role to the injury.

That fortuitous finding shifted Byrns’ focus towards further investigating the role of the AP1 pathway in the natural aging process. She found that the same pathway activated by TBI in young flies also became activated as the flies aged and then that it was associated with the development of senescent cells.

“We were looking at the effects of TBI, but what we found was that the trauma seemed to accelerate processes that occur naturally as the flies age,” Bonini says. “This led us to hypothesize that there might be a connection between the brain’s response to injury and the natural aging process, mediated through the activation of this specific pathway.”

Molecular insights

For their new study, Byrns and a team of scientists used a combination of transcriptomic and metabolomic profiling, genetic tools, and advanced imaging techniques to identify and analyze senescent cells in the fly brain, such as specific markers to isolate senescent glial cells, and performed gene expression analyses to confirm their senescence status. They also then experimentally induced mitochondrial dysfunction in neurons to monitor the effects on nearby glial cells.

Mitochondrial dysfunction in neurons led to the activation of the AP1 pathway in glial cells, which triggered them to enter senescence, Bonini says. In addition, the scientists discovered that these senescent glial cells upregulate lipid-synthesizing genes, leading to the accumulation of small, spherical vesicles that store fat in non-senescent glial cells.

These vesicles, called lipid droplets, are small and are thought to sequester reactive oxygen molecules that can damage cells, potentially protecting the brain. However, while mitigating senescent glial cells can extend lifespan and improve some aspects of brain function in the flies, it also resulted in increased oxidative damage. This suggests that senescent glial cells may have some beneficial functions alongside their detrimental effects.

“China tried to mitigate the senescent cells,” Bonini says. “In the fly, we can do that by knocking down the transcription factor that is driving the senescence. China found that if you knock that down completely, it’s deleterious to the animal. But if we knocked it down just a little bit, the animals have an extended lifespan.

“Our findings highlight the complexity of cellular senescence, as these cells seem to have a double-edged sword,” Bonini says. “Understanding the signals between neurons and glia and how to manipulate this pathway to mitigate the negative effects of senescence while preserving its potential benefits are important areas for future research.”

The researchers believe their findings pave the way for further exploration of senescence as a potential target for developing therapies to delay age-associated pathologies and potentially extend the health span of the brain.

Nancy M. Bonini is the Florence R.C. Murray Professor of Biology in the School of Arts & Sciences at the University of Pennsylvania and holds secondary appointments in the Cell & Developmental Biology Department and Neuroscience at the Perelman School of Medicine.

China N. Byrns is a former postdoctoral researcher in the Bonini Lab at Penn Arts & Sciences and currently a student of medicine at Penn Medicine.

Other authors are Alexandra E. Perlegos, V Sai Chaluvadi, Shirley L. Zhang, Frederick C. Bennett, and Amita Sehgal of Penn Medicine; Zhecheng Jin, Faith R. Carranza, Ananth R. Srinivasan of Penn Arts & Sciences; Karl Miller and Peter D. Adams of Sanford Burnham Prebys Medical Discovery Institute; and Palak Machandra, Connor H. Beveridge, Caitlin E. Randolph, and Gaurav Chopra of Purdue University.

This research received support from grants from the National Institutes of Health (T32-AG000255, F31-NS111868, F32-AG066459-02, K99-AG073450-01, K99HL147212, T32-GM007179-47, NIH P40OD018537, RF1-MH128866, and R01-NS120960), Paul Allen Frontiers Distinguished Investigator Program (GRT-00000774), Kingenstein-Simons Foundation (R01-AG031862-13 and R01-AG071861-01), Howard Hughes Medical Institute, United States Department of Defense (award no. W81XWH2919665,) and Arnold O. Beckman Foundation (award U18TR004146).