Wikimedia Commons, GENSATMouse neurons can far outlive their mouse hosts—if transplanted into longer-lived rats, according to new research published today (February 25) in Proceedings of the National Academy of Sciences. Researchers demonstrated that certain mouse neurons—which often die off well before the end of a mouse’s life—could survive twice as long if transplanted into rats, despite showing signs of decreased function. The findings suggest that neuronal survival is not pre-programmed, but strongly influenced by the brain microenvironment.
The study suggests that the “whole aging milieu of an organism” affects a cell’s function and survival, said Judith Campisi, a cell and molecular biologist at the Buck Institute for Research on Aging who was not involved in the study. “There’s nothing intrinsic in a mouse cell that says thou shalt live 18 months and then no longer exist,” she noted, adding that the data supports other studies suggesting that “non-cell autonomous” factors are important in aging.
The study on neuron lifespan arose from previous transplantation studies designed to examine both intrinsic and environmental cues neurons heed during development, said first author Lorenzo Magrassi, a neurosurgeon at the University of Pavia in Italy. The transplanted mouse neurons developed normally in young rat brains, the researchers didn’t know how long the neurons would survive in the longer-lived rats. “The question was, Are the neurons going to die when [death] is supposed to occur in the life of the mice, or do they survive?” Magrassi explained.
In order to test whether mouse neurons could outlive mice, Magrassi and his colleagues Ferdinando Rossi and Ketty Leto at the University of Turin expressed green fluorescent protein (GFP) in neuron precursors from a strain of mice that lives an average of 18 months and transplanted the cells into GFP-negative Wistar rats that can live twice as long. The mouse cells differentiated into various neuron types and integrated normally in their new environments. Magrassi’s concentrated on a specific derivative cell type, called Purkinje cells (PCs), about 40 percent of which die off in mice well before the animals succumb to old age. In contrast, Wistar rats retain about 90 percent of their PCs until death.
The researchers found that instead of dying in droves like mouse PCs, the transplanted neurons survived like rat PCs, suggesting that factors in the microenvironment of rodents’ brains are driving their survival or death. There is no “predetermined genetic clock,” said Magrassi.
In other ways, the mouse neurons retained some mouse-like characteristics—such as a smaller size—and also appeared to age as the rats aged, losing many of the protrusions seen in healthy young neurons. This makes sense, said Campisi, because the mechanisms driving aging and death are not necessarily the same.
The research suggests that changes to the neuronal environment can improve PC lifespan, Gilbert Bernier, a molecular biologist at the University of Montreal who was not involved in the research, wrote in an email to The Scientist. It’s not clear what causes mice to lose PCs in the first place, noted Bernier, who speculated that other types of neurons or immune cell-mediated inflammation could be involved. Magrassi and his collaborators are currently comparing the proteomes of host and transplanted mouse neurons to understand the differences in PC lifespan between mouse and rat.
Regardless of the mechanism, Magrassi is excited about the findings’ implications. “It means you can extend the maximum lifespan of an animal, and you don’t worry that the neurons are going to die before the death of the animal,” he said.
L. Magrassi et al., “Lifespan of neurons is uncoupled from organismal lifespan,” Proceedings of the National Academy of Sciences, doi: 10.1073/pnas.1217505110, 2013.