The hormone irisin is found to confer benefits of exercise on cognitive function

BOSTON – >The novel hormone irisin has the ability to drive the cognitive benefits of exercise, and therefore holds great promise for treating cognitive decline in Alzheimer’s disease, scientists at Massachusetts General Hospital (MGH) have found. In a study published in Nature Metabolism, the team reported that irisin, secreted by the muscles during exercise, could be an effective therapeutic for addressing deficits of the brain that result from Alzheimer’s disease. 

“Preserving cognitive function is a major challenge in an increasingly aging population,” says Christiane Wrann, DVM, PhD, leader of the Program in Neuroprotection in Exercise at MGH and senior author of the study. “Exercise is known to have positive effects on brain health, which is why identifying key mediators of those neuroprotective benefits, like irisin, has become such a critical goal of research.” 

Using mouse models, the team showed that genetic deletion of irisin impairs cognitive function in exercise, aging and Alzheimer’s disease, which was in part caused by alterations of newborn neurons in the hippocampus. The hippocampus is the compartment of the brain that stores memories and is the first to show signs of Alzheimer’s disease. At the same time, the MGH study found that elevating irisin levels in the bloodstream improved cognitive function and neuroinflammation in mouse models for Alzheimer’s disease. 

“For the first time, we showed that soluble irisin, and not its full-length parent protein FNDC5, is sufficient to confer the benefits of exercise on cognitive function,” explains Wrann, who is also an assistant professor of Medicine at Harvard Medical School. “These effects can possibly go well beyond what exercise itself can bring. This is particularly important inasmuch as irisin, a small natural peptide, would be much easier to develop into a therapeutic than the much larger membrane-bound protein FNDC5.” While previous research used the parent protein FNDC5, she adds, scientists this time delivered only the irisin portion through an adeno-associated viral vector approach to the liver, similar to gene replacement therapy, and discovered irisin was able to cross the blood-brain barrier and directly affect the brain.

“What makes this study particularly strong is that we show irisin’s effect on cognitive function in not one but four different mouse models,” states Bruce Spiegelman of Dana-Farber Cancer Institute and Harvard Medical School, who discovered irisin in 2012 and is a co-author of the current paper. Researchers were further encouraged by the fact that irisin treatment was effective in Alzheimer’s disease mouse models even after the development of significant pathology. “This could have implications for intervention in humans with Alzheimer’s disease where therapy typically starts after patients have become symptomatic,” Wrann says.

Another important finding of the study is that irisin protects against neuroinflammation by acting directly on glia cells in the brain. Co-author Rudy Tanzi, co-director of the McCance Center for Brain Health at MGH, explains: “It’s hard to imagine anything better for brain health than daily exercise, and our findings shed new light on the mechanism involved: protecting against neuroinflammation, perhaps the biggest killer of brain neurons as we age.” Adds Wrann: “Since irisin does not specifically target amyloid plaques, but rather neuroinflammation directly, we’re optimistic it could have beneficial effects on neurodegenerative diseases beyond just Alzheimer’s.”

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Wrann is a faculty member at MGH’s Cardiovascular Research Center and McCance Center for Brain Health. Co-lead authors Mohammad Islam, PhD, and Sophia Valaris, PhD, are post-doctoral fellows in the Cardiovascular Research Center at MGH. Co-author Spiegelman is professor of Cell Biology and Medicine at the Dana-Farber Cancer Institute and Harvard Medical School. Co-author Rudolph Tanzi, PhD, is co-director of the MassGeneral Institute for Neurodegenerative Disease. Other co-authors include Michael Young, Erin Haley, Renhao Luo, Sabrina Bond, Sofia Mazuera, Robert Kitchen, Barbara Caldarone, Luis Bettio, Brian Christie, Angela Schmider, Roy Soberman, Antoine Besnard, Mark Jedrychowski, Hyeonwoo Kim, Hua Tu, Eunhee Kim and Se Hoon Choi.

The study was funded by the National Institutes of Health, the Cure Alzheimer’s Fund, the Alzheimer’s Association, the McCance Center for Brain Health, a Hassenfeld Clinical Scholar Award, a Claflin Distinguished Scholar Award, the JPB Foundation, the Harvard NeuroDiscovery Center, the MSFHR, the FRAXA, the FXRFC, the NSERC, the CIHR and the Harvard Brain Science Initiative Young Scientist Travel Award. 

The authors declare the following competing interests: Wrann and Spiegelman hold a patent related to irisin and are academic co-founders of Aevum Therapeutics. Wrann has a financial interest in Aevum Therapeutics, a company developing drugs which harness the protective molecular mechanisms of exercise to treat neurodegenerative and neuromuscular disorders. Wrann’s interests were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict-of-interest policies. 

About the Massachusetts General Hospital
Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The Mass General Research Institute conducts the largest hospital-based research program in the nation, with annual research operations of more than $1 billion and comprises more than 9,500 researchers working across more than 30 institutes, centers and departments. In August 2021, Mass General was named #5 in the U.S. News & World Report list of "America’s Best Hospitals."