Understanding the origins of age-related disease

By 2040, approximately one in five people in the U.S. will be 65 years old or older. As Americans are increasingly dealing with age-related diseases such as diabetes, heart disease, stroke, and Alzheimer’s, Brown researchers are trying to understand why aging occurs in an attempt to meet the country’s growing health care needs.

Kaitlyn Hajdarovic, a Ph.D. candidate in the Neuroscience Graduate Program at Brown, is investigating the details of cellular aging with the goal of paving the way for treatments for age-related diseases. She conducts her research in the laboratory of Ashley Webb, the Richard and Edna Salomon Assistant Professor of Molecular Biology, Cell Biology and Biochemistry.

Hajdarovic is developing a novel cell reprogramming platform, called "direct reprogramming," to study aging in the hypothalamus brain region. The hypothalamus controls critical processes, such as sleep, temperature regulation, eating, and metabolism, that can become dysregulated with aging. With direct reprogramming, Hajdarovic is able to convert a skin cell, for example, into a brain cell that maintains the hallmarks of aging.

"I am developing a strategy to recreate, in a dish, a type of brain cell that controls feeding," Hajdarovic said.

Starting from mouse skin cells, Hajdarovic aims to generate specific hypothalamic brain cells, called POMC neurons. Normally, these cells trigger satiety (the feeling of being full), but they lose the ability to do so as they age.

"My project specifically will uncover the mechanisms that underlie changes in feeding behavior during aging, and how those changes can be ameliorated to improve function," she said. "As we age, we lose lean body mass and gain fat. Most aging humans gain weight, especially around the midsection."

Hajdarovic's research could be useful to others studying obesity and diabetes, even in patients who aren't at an advanced age. She is one of four students who received this year's Graduate Awards in Brain Science from Brown's Robert J. and Nancy D. Carney Institute for Brain Science. The awards recognize graduate students who have made outstanding research progress and demonstrate strong potential for successful lifelong scientific careers. Recipients get stipend and tuition support for a full year, as well as additional funds to present their work at a scientific meeting, meet with collaborators, or attend special workshops.

Fueling research into the brain

Hajdarovic's graduate award was supported by the Robin Chemers Neustein ’75 Graduate Fellowship Fund. Neustein, a Brown trustee emerita, established this fund in 2013 to support students and initiatives that are at the forefront of discovery.

At the time, she was struck by the achievements of BrainGate, a research program spearheaded by Professor John Donoghue at Brown that focused on developing brain-computer interface technologies to restore the communication, mobility, and independence of people with neurologic disease, injury, or limb loss. After meeting with Professor Donoghue and John Davenport, managing director of what is now the Carney Institute for Brain Science, she was convinced that support for outstanding graduate students would elevate research across all areas of brain science.

"I find research scientists to be among the most creative people in the world, and that is what inspired me to create the fellowship," Neustein said. "These young scientists may be early in their careers, but they have already demonstrated high-impact accomplishments and the probability of doing science that is novel and elegant."

Over the last 20 years, Neustein has been a supporter of basic scientific research at Brown and beyond the University. She admires the entrepreneurial aspect of scientists' work: "Consider the fact that they think up something new; then they fund it, staff it, execute it, and propagate it into general knowledge. And, in the process, they help humanity."

Exploring the hypothalamus

Hajdarovic first demonstrated that her method could work by implementing the novel cell reprogramming strategy in brain cells from embryonic mice. She is now ready to apply the same approach in order to reprogram fibroblasts—biological cells that play a critical role in wound healing—from young and old mice to create POMC neurons.

The goal, she said, is to try to understand how young and aged POMC neurons differ in function and to translate that knowledge into gene editing or pharmacological interventions that restore aged POMC neurons to a youthful phenotype.

She emphasizes that the Carney Institute was instrumental in getting this project off the ground. Professor Webb, who leads the laboratory in which she works, received a Zimmerman Innovation Award in 2018 from the Carney Institute to collect initial data for the project. Hajdarovic was then able to use that data to apply for a graduate award to continue the research.

"With this support, we have been able to perform more in-depth and technical analyses, such as single-cell RNA sequencing," she said. "This project would not have existed without the help of the Carney Institute."

After graduation, Hajdarovic plans to continue studying the hypothalamus as a postdoctoral researcher.

"As a scientific community, we have developed new tools to study this region, and I plan to make good use of them," she said.

Neustein is proud to continue supporting the work of graduate students at Brown, who are full of potential. Brunonians, she said, are driven to seek truth and solve problems. "That passion is what attracted me to Brown in 1973, and it is even more important in today's incredibly fluid and ever-changing world."

For more information on the work of the Carney Institute for Brain Science, please visit the institute’s website at https://www.brown.edu/carney.