Multi-pronged research approach aims to understand aging at human and molecular levels

Understanding how motor neurons change over time could reveal the keys to better aging. Researcher W. David Arnold, MD, and his team at The Ohio State University Wexner Medical Center are studying these specialized spinal cord cells — the final link between the nervous system and muscle for motor control — to unlock more of these mysteries of aging.

The scientists hypothesize, based on previous research, that aging results in reduced numbers and function of motor neurons, and that these losses drive loss of muscle function.

“Historically, people have largely looked at age-related loss as a muscle issue and have ignored the nervous system,” says Arnold, a physician-scientist with specialty training in physical medicine and rehabilitation and neuromuscular medicine. “It’s becoming clearer that the loss of physical function may be more of a neuron than a muscle problem.”

A $2.9 million, multi-principal investigator R01 grant from the National Institutes of Health will allow Arnold and his team at the Ohio State Wexner Medical Center, along with research teams at Ohio University and Wright State University, to further explore this.

“Loss of muscle function is a major contributor to loss of physical function and mobility and risk of falls in older adults,” Arnold says. “There is no known mechanism of replacing motor neurons once they are lost.”

Arnold’s studies under this grant will investigate the mechanisms of reduction of motor neuron numbers and excitation during aging.

A three-pronged approach

Arnold’s interest in motor neurons and aging began about nine years ago, when he started studying spinal muscular atrophy (SMA). Arnold was part of a team at the Ohio State Wexner Medical Center and Nationwide Children’s Hospital that developed a gene therapy for patients with SMA that is now used clinically. His interest in motor neurons and aging was based on the fact that motor neurons are nondividing cells with no known mechanism of replacement when lost during aging. Importantly, the number of motor neurons that activate the muscle and how fast these motor neurons fire can modulate the force produced by a muscle.

The work funded by the five-year R01 will explore mechanisms of age-related motor neurons dysfunction in three research prongs:

  • Clinical studies
  • Longitudinal in vivo studies with mice
  • Cellular and molecular studies

Arnold’s long-time collaborator Brian Clark, PhD, will lead the clinical human studies, while Arnold performs in vivo studies in mouse models. The clinical work will occur at the Ohio Musculoskeletal and Neurological Institute at Ohio University, where Arnold serves as the medical director.

Simultaneously, intracellular and cellular mouse studies will take place at Wright State University, led by Sherif Elbasiouny, PhD.

Additional “bolt on” studies have been added by Arnold’s lab to apply similar approaches in models of Alzheimer’s disease. There’s potential, Arnold says, for deeper future studies such as an examination of Alzheimer’s patients with muscle loss that occurs before cognitive decline.

“We are trying to understand the motor neuronal mechanisms,” Arnold says. “There may be some cross talk with muscles and the nervous system.”

Leveraging mouse models

Arnold’s team has developed and optimized repeatable in vivo assessments of motor neuron function that can be applied clinically and in animal models. Arnold’s prior work has shown mice that are 20 months old begin to show a decline in motor function associated with motor neuron dysfunction.

He and his team will perform a longitudinal aging study with comprehensive assessments of muscle mass, motor function and a battery of electrophysiological assessments of motor neuron number and excitability in a large group of mice between the ages of 12 and 27 months. In humans, this timeline would equate to roughly 30 to 90 years of age.

“That is the power of the model system,” Arnold says. “It would take the majority of a lifetime to do this study in humans, but with these sophisticated approaches with mice, we can get the equivalent of five to six decades of data condensed down to a year and a half.”

Delving into the molecular mechanisms of resilience

Findings and data from the R01 study will lay the groundwork for future studies, such as why some mice (and humans) age better than others. By investigating mice longitudinally, Arnold’s team will gain insight into drivers of resilience during aging. His team is interested in changes that occur with aging, but even more so in what changes occur in mice that age more “successfully” (with stronger resilience), which Arnold says is especially intriguing.

He plans to complete RNA sequencing to better understand the molecular mechanisms of resilience.

“If we manipulate a certain gene, does it change the resilience? These are the targets that we are trying to understand,” Arnold says. “That’s the next step.”

For example, Arnold and his colleagues know that as mice get older, they run less. But the team wants to know what drives resilience, and what interventions and lifestyle factors impact motor neuron function. A postdoctoral researcher in Arnold’s lab is currently studying aging, diet and motor function.

“We know diet and exercise have a positive impact in aging, but we don’t fully understand the mechanisms and how these interventions might specifically impact the motor neuron,” Arnold says.

Learning how to optimize aging

Everything Arnold and his colleagues learn fits into his overall goal of finding ways to improve function of the nervous system over time.

He is launching a new research center focused on translational studies to do just that.

The center, housed within Ohio State’s Neuroscience Research Institute, focuses on improving the health span and function in older adults and patients with neurological disorders by developing approaches to increase quality of life.

With the help of five new faculty members, the center will develop community engagement plans and work with older adults to understand what’s important to them as they age.

The center provides a way for Arnold and his colleagues to bring together all their research in one place. He’ll be able to combine learnings from the R01 research now underway and other studies that address:

  • Understanding the neuromuscular connection
  • Ways to medically modulate the rate of excitability of motor neurons

“We want to understand healthy aging and take a novel approach to finding ways to improve resilience, like bouncing back from an injury and preventing decline over time,” Arnold says.

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