In a new editorial, researchers discuss interconnected mechanisms of neuronal functionality and available tools to investigate neuronal aging and longevity.
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Neurons, the building blocks of the nervous system, play a vital role in our body’s function and longevity. Unlike other cells, neurons do not undergo replicative aging. However, they are still susceptible to various sources of damage throughout life, leading to neuronal death. Understanding the mechanisms behind aging and neuronal death is crucial for uncovering the secrets of brain longevity and developing potential interventions to promote healthy aging.
In a new editorial, researchers Fang Fang, Robert Usselman and Renee Reijo Pera from University of Science and Technology of China, Florida Institute of Technology and McLaughlin Research Institute discussed new interconnected mechanisms of neuronal functionality and available tools to investigate neuronal aging and longevity. On December 13, 2023, their editorial was published in Aging’s Volume 15, Issue 23, entitled, “Aging and neuronal death.”
Neuronal Durability, Differentiation & Maintenance
Neurons, born during embryonic development, must function in the body for the entire lifespan of the organism. They are incredibly durable cells, but they are not immune to damage. Neurons require a significant amount of oxygen and glucose to carry out their activities, making them vulnerable to ischemia. Ischemia occurs when the blood supply to a particular tissue is restricted, leading to oxygen and nutrient deprivation.
Neurons can accumulate damage over time, which may result in cell death linked to reactive oxygen species (ROS). Neurons may also die due to ion overload and swelling caused by the malfunction of voltage-gated ion channels on their membranes. High concentrations of neurotransmitters and the accumulation of misfolded proteins are also implicated in neuronal death, observed in various neurodegenerative diseases.
To gain insights into the factors that promote neuron differentiation and maintenance, researchers have developed innovative screening methods. For example, Cui and colleagues described a high-throughput screening method using a luciferase reporter construct inserted downstream of the endogenous tyrosine hydroxylase (TH) gene. They differentiated neurons from human pluripotent stem cells and monitored their activity over time. This approach allows for the modeling of cell survival and demise, providing valuable information about the factors that influence neuronal longevity.
The Role of ROS in Survival & Death
Reactive oxygen species (ROS) are molecules produced during normal cellular metabolism. They play a crucial role in various biological processes but can also lead to oxidative stress when their levels exceed normal functional levels. Recent research has shed light on the distinction between global and local ROS balances and imbalances in cell phenotyping and mitochondrial energy management.
While global ROS homeostasis is essential for overall cellular health, ROS signaling pathways are driven locally by cellular microdomain-specific ROS production and degradation. Neurons have developed mechanisms to control ROS production and combat oxidative stress. For example, they express neurotrophic proteins that enhance mitochondrial activity, promoting the overall health of neurons.
“A sustained disruption of ROS balance can result in desirable enhanced cell signaling or undesirable oxidative stress, which can either improve function or diminish performance, respectively.”
Mechanisms for Longevity
Neurons have evolutionarily developed intricate mechanisms to maintain their longevity. They possess a distinct transcriptome signature that represses genes related to neural excitation and synaptic function. By preventing neurons from experiencing ion overload, this mechanism contributes to their long-term survival.
These brain cells have also developed specific DNA repair mechanisms to correct errors induced by active transcription. Neurons can turn off pro-apoptotic genes through alternative splicing, avoiding apoptosis and promoting long-term survival. These interconnected mechanisms work together to reduce the accumulation of aging-related damage in neurons. Understanding the fundamental mechanisms that enable the longevity of neurons is crucial for developing interventions that promote healthy brain aging. Researchers can use novel tools, including cell-based models, imaging techniques and animal studies, to investigate these mechanisms.
Conclusions
Neurons, although durable cells, are susceptible to various forms of damage that can lead to their demise. By studying the interplay between ROS, neuronal excitation, DNA repair, and apoptosis, researchers aim to uncover the secrets of brain longevity and develop strategies to mitigate the effects of aging on neurons. By understanding these mechanisms, researchers aim to develop interventions that promote healthy brain aging and enhance our overall understanding of brain health.
“Together, these findings suggest that neurons have evolved a set of intrinsically interconnected mechanisms to reduce long-term accumulations of aging-related damages. Disruption in these mechanisms may tip the neuron homeostasis off-balance and drive the neurons into the path of degeneration. We have a plethora of tools to probe the fundamental mechanisms with hopes of translation to clinical applications.”
Click here to read the full editorial published in Aging.
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