Young Minds Tackling Old Questions

The science of aging and longevity is a rapidly growing frontier, as breakthroughs in our understanding of biological aging reveal how genetics, environmental influences, and cellular and metabolic factors shape health over the lifespan, and as new drugs emerge that may target these processes.  

Duke University School of Medicine, building on its long history as a pioneer in aging research, is a national leader in this rapidly evolving field. Duke researchers from numerous disciplines are working to uncover the secrets of aging — and many of our students are playing a vital role.  

This next generation of scientific leaders is contributing fresh perspectives to questions that span basic science, clinical innovation, and public health, all aimed at improving vitality and health throughout the lifespan.  

Here are just a few of the School of Medicine students seeking to ensure that longer lives are also healthier, more active ones.   

The Long Memories of Microglia 

In recent years, it has become increasingly clear that neuroinflammation, driven by the activation of the brain’s immune cells, plays an important role in the development and progression of Alzheimer’s disease. The brain’s immune cells, known as microglia, may actually, at different times and regions, have both beneficial and harmful effects: they help eliminate the amyloid plaques that are characteristic of Alzheimer’s, but it also appears that they can damage healthy synapses and neurons. 

Seneca Oxendine, a fifth-year MD/PhD student, is working with Staci Bilbo, PhD, the Haley Family Professor of Neuroscience and interim chair of the Department of Neurobiology, to unravel the secrets of how microglia function in health and disease, and what factors influence the different roles they play. 

Oxendine is interested in how infections early in life influence the risk of Alzheimer’s disease much later. In particular, she’s exploring how environmental stressors may produce long-lasting effects in microglia that could change how they respond in the aging brain. 

“Microglia are long-lived cells, and things that happen in early to middle adulthood that affect microglia might influence the way they function over the course of aging,” she said. “I’m very interested in how peripheral immune stressors, such as viral infections that don’t actually infect neurons, may change the way the microglia function in the long term, potentially impacting how they interact with plaques.” 

In animal models, Oxendine has found that exposure to peripheral flu-like viruses does appear to change how microglia respond to plaques. Microglia even seem to carry a sort of memory of the initial episode with them: long after they’ve returned to a normal homeostatic state, if they then encounter another infection, they respond more actively. 

“We think something called immune priming or training happens in the microglia, where if they encounter an additional insult later on, they can have an exacerbated response,” Oxendine said. “That could cause increased inflammation that could exacerbate disease.” 

Oxendine’s dual role as an MD/PhD student speaks to her passion for science in the service of improving people’s lives. “I want to help provide autonomy for people who have lost some of the control of their lives due to neurologic disease,” she said. “I want to provide hope. I think research absolutely does that.” 

How Exercise Strengthens Immune Cells 

Hannah Maclellan, a third-year MD student, worked as a public health and technology consultant for four years before applying to medical school at Duke. She enjoyed the work but decided she wanted to work directly with patients. “I’m fascinated by the immune system and passionate about helping people navigating conditions that affect their physical function,” she said. “That, plus my own health journey, convinced me to go back to school.” 

Now, working with assistant professor of medicine Brian Andonian, MD, and professor of medicine Kim Huffman, MD, PhD, Maclellan is digging into the effects of exercise on immune function in adults with rheumatoid arthritis (RA). 

Unlike osteoarthritis, which generally results from wear and tear on the joints, rheumatoid arthritis is an autoimmune disease in which the immune system attacks the joints, causing inflammation, pain, and stiffness. 

The researchers have developed exercise and diet interventions, tested them with older adults with RA, and evaluated results with measures ranging from patient self-reporting to molecular analysis.  

They found that the regimens decreased inflammation and, as one might expect, improved overall health and fitness. But they also discovered that the exercise and diet program appears to actually alter the way immune cells work. 

Maclellan and Andonian expected to see effects mostly associated with immune signaling pathways, but what they saw instead was that exercise might actually make immune cells more fit. 

If she and other researchers can identify how exercise improves immune cells and functions, they might be able to design therapies that target those pathways and processes to treat not only RA but potentially other inflammatory diseases, especially in older patients whose immune systems are less robust. 

Maclellan is also recruiting subjects for another project, to assess the effect of exercise on cognitive function in older adults who have recently been diagnosed with RA. 

“So many people with inflammatory conditions have trouble maintaining consistent exercise programs,” she said. “I want to help equip them with the knowledge and reassurance to exercise safely, and to give them evidence that it will help them in the long run. I think that’s powerful for someone dealing with musculoskeletal conditions.” 

New Clues to Neurodegeneration 

Jordan Green, a fifth-year PhD student in Chantell Evans, PhD’s lab, is revealing surprising details about the role that mitochondria — tiny organelles that generate chemical energy to power the cells in most living organisms — play in the progression of neurodegenerative diseases. 

Like many of our other parts, mitochondria wear down over time. Cells eliminate damaged and aged mitochondria in a process called mitophagy, which breaks down and clears out dysfunctional mitochondria to make way for healthy new ones. 

Mitophagy is essential for maintaining the efficient functioning of cells, including neurons, and helps prevent age-related diseases such as Alzheimer’s and Parkinson’s. 

Neurodegenerative diseases are linked to mutations that disrupt the mitophagy pathway and lead to the accumulation of damaged mitochondria in neuronal cells. However, familially inherited mutations are found in only a small fraction studying what happens when mitophagy fails in the absence of genetic mutations.  

“In hippocampal neurons, which are targeted by diseases like Alzheimer’s, we’ve found that the damaged mitochondria are not being actively removed,” Green said. “They just sort of sit there and accumulate in the cytoplasm. Our recent research showed that these damaged mitochondria eventually get turned over three days after their initial damage. This was a surprise, because other cell types seem to degrade their damaged mitochondria much faster, on the scale of hours. This prolonged accumulation seems to be unique to neurons.” 

Green and Evans speculate that the sluggish mitophagy in neurons might be a contributing factor in neurodegeneration — and that if researchers can find a way to accelerate the process and move damaged mitochondria out faster, it could potentially delay the onset of disease. 

Green is now trying to zero in on exactly where in the complex mitophagy pathway the holdup is occurring. “We originally hypothesized that something downstream in the pathway was slowing down the process,” she said. “My research was the first to show that the blockade seems to be happening further upstream. We’re trying to identify what the rate-limiting factor is. We have some hypotheses, and we have a few tools up our sleeve to test those.” 

Green was drawn to this field of study in part because, like many of us, she has seen people close to her affected by neurodegenerative diseases. “I want to make a difference and, hopefully, play some part in helping to find what causes these diseases,” she said.

Dave Hart is the editorial director in the Office of Strategic Communications at the Duke University School of Medicine. 

Eamon Queeney is the assistant director of multimedia and creative in the Office of Strategic Communications at the Duke University School of Medicine.