Nagoya University researchers found that excessive neuronal activation, not decreased activity, drives age-related cognitive decline.
Researchers at Nagoya University in Japan have discovered that age-related cognitive decline is primarily caused by excessive activation of certain neurons over time, rather than a reduction in neuronal activity. Their study, published in the Proceedings of the National Academy of Sciences, suggests that interventions aimed at limiting neuronal hyperactivation—such as dietary modifications—may help slow cognitive decline associated with aging.
Healthy brain function relies on a well-connected network of neurons that communicate efficiently. Traditionally, age-related cognitive decline has been attributed to a gradual decrease in neuronal activity. However, this study challenges that view, highlighting overactivation as a key factor in neurological aging.
However, in humans, some types of neurons have been reported to become hyperactive with age. A research group led by Associate Professor Kentaro Noma of Nagoya University conducted experiments on nematodes to determine the cause-and-effect relations between the hyperactivation of neurons and the decline in brain function with age.
Using Nematodes to Study Cognitive Decline
“In this study, we used the nematode Caenorhabditis elegans, which is only one millimeter long and has a lifespan of only two weeks. The nematodes exhibit a variety of behaviors with their 302 neurons,” Noma said. “C. elegans shares many genes and mechanisms with humans. So, we thought that the cause of the decline in brain function over time in C. elegans may apply to humans.”
This study took advantage of the ability of C. elegans to learn by association in a behavior called thermotaxis. In this behavior, C. elegans kept in an environment with food at 23 degrees Celsius will move toward 23 degrees when placed in an environment with a temperature gradient from 17 to 23 degrees. However, the animals will choose not to do so if kept in an environment where there is no food. This suggests that C. elegans learns to associate the presence or absence of food with the temperature of their environment.
“Our previous studies found that the brain function for associative learning in C. elegans declines over time, and we thought this was due to a decline in neuronal activity with age,” said Binta Maria Aleogho, first author of the study. “In our latest study, however, we found that the activities of AFD sensory neurons and AIY interneurons, both of which are thought to be essential for associative learning, have barely changed with age.”
The Role of Neuronal Hyperactivation in Aging
The researchers then studied the behavior of C. elegans when each of six types of neurons thought to be involved in associative learning—the sensory neurons AWC and ASI, and the interneurons AIZ, AIB, RIA, and AIA—was removed from the brains of nematodes. Surprisingly, after removing AWC or AIA from their brains, the nematodes could move to the 23-degree location.
The researchers also measured the activities of the neurons in aged nematodes. They found that AWC and AIA are spontaneously and excessively activated with age. “This finding suggests that the hyperactivation of these two types of neurons with age disrupts the normal neuronal network, rendering them unable to carry out the thermotaxis behavior,” Noma said.
“In addition, we were able to suppress neuronal hyperactivation and prevent behavioral decline in aged nematodes by changing the type of bacteria as their food source. So, we humans might be able to prevent the aging of our brains by changing our diet.”
He concluded: “So far, we have tended to focus on the decline in neuronal activity with age. Our findings may lead people to focus on the hyperactivation of neurons. We will continue to study C. elegans to determine how to reduce the hyperactivation of neurons to improve brain function. We believe this will help us understand the basis of aging in brain function.”
Reference: “Aberrant neuronal hyperactivation causes an age-dependent behavioral decline in Caenorhabditis elegans” by Binta Maria Aleogho, Mizuho Mohri, Moon Sun Jang, Sachio Tsukada, Yana Al-Hebri, Hironori J. Matsuyama, Yuki Tsukada, Ikue Mori and Kentaro Noma, 31 December 2024, Proceedings of the National Academy of Sciences.
DOI: 10.1073/pnas.2412391122
