Old age takes a toll on our brains. This isn’t surprising, given their immense cellular complexity and the innumerable calculations and ruminations that we put them through over a long lifetime. But a new study has unraveled how age affects even the most basic of nervous systems: the 302 cells that constitute the “brain” of the nematode worm C. elegans. Findings from this tiny organism may hold lessons for how we treat the aging human brain.
C. elegans: A model “without competition”
“The first function of the nervous system that declines with age is the ability of the nervous system to update information that is already stored in it,” says Dr Emanuel Busch, a chancellor's fellow at the University of Edinburgh and senior author of the study, which was published in eLife.
Whilst this might not be surprising to older people or their families, the lack of knowledge around why our brains do not learn as well in older age is startling, says Busch.
The millimeter-long C. elegans, which lives on average for just a few weeks, might seem like an odd candidate to tease out the mysteries of the human brain. Busch explains that this veteran model organism, which is used by teams around the world to study the brain and remains the only model to have had its entire connectome (a “wiring map” of all neural connections) charted, is an ideal tool to study aging. “C. elegans is almost without competition in the field of aging at the moment, because they age so fast,” says Busch. “It makes it much easier to study principles of how the brain ages and how lifespan is regulated.”
Busch and colleagues looked at the intrinsic plasticity of their worms’ brains in response to changes in their environment. Intrinsic plasticity is the alteration of neurons’ electrical properties in response to changes in their firing rate. C. elegans has a set of neurons that enable the worm to seek out oxygen sources. By exposing their nematodes to a high oxygen environment over the first 10 days of life, the researchers were able to show that these neurons became overstimulated and unable to adapt to subsequent changes in oxygen concentration. Interestingly, this state of sensory stiffness was reversible. By lowering the activity of the oxygen-sensing cells, the team restored flexibility to the worms’ simple nervous system.
A causal role for calcium
Working with C. elegans, Busch’s team interrogated the genetic and molecular basis for these findings in unprecedented detail. “Their gene expression in the cells is shifted. Basically, the cells shift their resources from factors that maintain plasticity to those that maintain a higher firing rate,” says Busch.
Busch’s team identified disruptions in the delicate balance of calcium that enables normal neuronal function as a causal factor in this loss of plasticity. Alterations to proteins that had not been previously linked with aging, such as the calcium-potassium exchanger NCKX, were shown to be essential to this disruption.
"These are basic mechanisms that are conserved across species," says Busch. His team’s findings chime with similar work conducted in humans, which examined how the brain is affected by neurodegenerative disease. Whilst low activity of both body and brain is widely recognized as a risk factor for these diseases, Busch suggests that there are more nuances involved than just encouraging older adults to take up sudoku: “That’s not the whole story. As we show here, there is another risk factor. Hyperactivity is very bad as well. There is circumstantial, but quite clear evidence that the parts of humans brain that show hyperactivity in early life are those that in later life fall prey to neurodegeneration.”
Ultimately, Busch sees many aspects of the study to be optimistic about. He says that future research on overstimulation in the brain should examine whether reduce hyperactivity would help restore cognitive plasticity to aging brain. For now, he simply says that a worn-out brain could benefit most from a rest.
“If you chronically stress your brain, it impairs its ability to learn new things. I think it’s important to take a break as well.”