Aging and the brain’s sugar-coated shield

What if a critical piece of the puzzle of brain aging has been hiding in plain sight? While neuroscience has long focused on proteins and DNA, a team of Stanford researchers dared to shift their gaze to sugars – specifically the complex sugar chains that cover all our cells like chain mail.

Their investigation revealed how changes in this sugary armor on the brain’s frontline cells could be key to understanding cognitive decline and diseases like Alzheimer’s.

“This is like landing on a new planet,” says Nobel laureate Carolyn Bertozzi, professor of chemistry and Baker Family Director of Sarafan ChEM-H, whose groundbreaking research on cell surface sugars and their biological roles laid the groundwork for this interdisciplinary study. “We’re stepping outside for the first time and trying to make sense of what’s out there.”

At the center of this discovery is Sophia Shi, a Stanford Bio-X Graduate Fellow, whose doctoral research bridges the labs of Bertozzi and neuroscientist Tony Wyss-Coray, professor of neurology and neurological sciences and the Director of the Phil and Penny Knight Initiative for Brain Resilience at the Wu Tsai Neurosciences Institute.

In a study in aging mice, Shi has uncovered striking age-related changes in the sugary coating – called the glycocalyx – on cells that form the blood-brain barrier, a structure that protects the brain by filtering out harmful substances while allowing in essential nutrients.

“The glycocalyx is like a forest,” Shi explains. “In young, healthy brains, this forest is lush and thriving. But in older brains, it becomes sparse, patchy, and degraded.”

These age-related changes to the glycocalyx weaken the blood-brain barrier, Shi found. As the barrier becomes leaky with age, harmful molecules can infiltrate the brain, potentially fueling inflammation, cognitive decline, and neurodegenerative diseases.

“This work lays the foundation for a new field of inquiry into how the aging brain loses its resilience,” says Wyss-Coray, the D.H. Chen Professor II of Neurology.

The study, published online in Nature on Feb. 26, was jointly supervised by Bertozzi and Wyss-Coray, with Shi as lead author.

Decline and resilience in the blood-brain barrier

While Wyss-Coray’s lab has extensively studied how aging impacts the blood-brain barrier, Shi’s project was the first to investigate how age affects its sugary armor – the glycocalyx. The results were striking: In older mice, bottlebrush-shaped, sugar-coated proteins called mucins, a key component of the glycocalyx, were significantly reduced. This thinning of the glycocalyx correlated with increased permeability of the blood-brain barrier and heightened neuroinflammation.

When the team reintroduced those critical mucins in aged mice, restoring a more “youthful” glycocalyx, they improved the integrity of the blood-brain barrier, reduced neuroinflammation, and measurably improved cognitive function.

“Modulating glycans has a major effect on the brain – both negatively in aging, when these sugars are lost, and positively, when they are restored,” Shi says. “This opens an entirely new avenue for treating brain aging and related diseases.”

Bertozzi underscores the significance of the discovery: “Biology is often about looking in the right place. This huge structural change in the glycocalyx was hiding in plain sight because no one had thought to look at it before, or had the tools to do so.”

Shi’s work also raises new questions. While the glycocalyx is traditionally viewed as a passive barrier that blocks harmful substances from entering cells, its sugars may play a more active role in the brain and how it ages.

Scientists often look to nucleic acids and proteins to understand how biological processes are precisely controlled, but they may be missing the roles that sugar molecules play, Bertozzi explains. “The glycome adds a layer of complexity that allows biological systems to achieve extraordinary fine-tuning.” This is particularly true in the brain, where many sugar molecules are uniquely expressed. Yet, until now, their roles in brain aging and disease have remained largely unexplored, she adds.

Shi’s dual expertise in chemistry and biology enabled her to tackle a problem that neither lab could have solved alone. This study also brought together the two interdisciplinary institutes that share the Stanford ChEM-H / Neurosciences Research Complex: Sarafan ChEM-H and the Knight Initiative for Brain Resilience at the Wu Tsai Neurosciences Institute.

The brain’s sugar shield and disease

Many questions remain about the glycocalyx – what drives its decline with age, and do similar changes occur in humans? “It’s hard to study human brains,” Bertozzi notes, “but understanding whether similar mechanisms are at play in humans will be crucial for translating these discoveries into therapies.”

The study also offers new opportunities to tackle neurodegenerative diseases like Alzheimer’s, a particular interest for Shi. By identifying the molecular pathways behind glycocalyx changes, the team hopes to uncover therapeutic targets that could slow or even reverse disease progression. Shi, who will soon establish her own lab at the Rowland Institute at Harvard, plans to expand this research to better understand glycans’ roles in neurodegeneration and explore their potential for developing new treatments.

Beyond aging and neurodegeneration, the findings have significant implications for effectively delivering drugs to the brain. The blood-brain barrier is notoriously difficult to penetrate, making it challenging to treat many neurological diseases. By understanding the role of the glycocalyx, scientists may discover better ways to get medicines into the brain, offering hope for conditions ranging from multiple sclerosis to brain cancer.

For now, this work represents a first step into a new field. As Shi puts it, “I’m excited to unlock the secrets of the glycocalyx in brain aging and neurodegeneration and discover how we can harness its potential to improve brain health.”

For more information

Stanford’s Office of Technology Licensing has filed for a patent on intellectual property associated with this study.

Sophia Shi, the study’s lead author, is a Stanford Bio-X Graduate Fellow and PhD student in the Department of Chemistry. She is co-supervised by Carolyn Bertozzi, PhD, and Tony Wyss-Coray, PhD. Bertozzi is Baker Family Director of Sarafan ChEM-H, Anne T. and Robert M. Bass Professor in the School of Humanities and Sciences and a professor of chemistry, while Wyss-Coray is the D.H. Chen Professor II of neurology and Director of the Phil and Penny Knight Initiative for Brain Resilience. Both are faculty affiliates of the Wu Tsai Neurosciences Institute.

Other Stanford co-authors of the study are Ryan J. Suh, D. Judy Shon, Josephine K. Buff, Micaiah Atkins, Nannan Lu and M. Windy McNerney. Researchers at the Picower Institute for Learning and Memory, Palo Alto Veterans Institute for Research, Hong Kong Center for Neurodegenerative Diseases and The Hong Kong University of Science and Technology also contributed to this work.

This research was funded by the Department of Veterans Affairs, the National Institutes of Health, the Phil and Penny Knight Initiative for Brain Resilience, the Bev Hartig Huntington’s Disease Foundation, and the JPB Foundation.