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Can the Brain-Boosting Benefits of Exercise Be Bottled?

Exercise-induced irisin helps cognitive functions and has therapeutic potential.

Key points

  • FNDC5 is an exercise-induced membrane protein commonly referred to as irisin or the "exercise hormone."
  • Since its discovery in 2012, numerous studies have found that exercise-induced irisin is neuroprotective.
  • A new study reports that peripheral delivery of FNDC5 confers the benefits of exercise on cognitive function.
Source: iQoncept/Shutterstock

Almost a decade ago, in 2012, Bruce Spiegelman of Dana-Farber Cancer Institute and Harvard Medical School first discovered the so-called "exercise hormone" (FNDC5) and named it irisin, after the Greek goddess Iris.

In addition to its exercise-induced ability to protect against neurodegeneration and cognitive decline, previous research has shown that irisin—which is produced in skeletal muscles during exercise—fights fat and has many other powerful health benefits.

This week, Spiegelman and colleagues at Harvard's Massachusetts General Hospital announced that a recent study in mice suggests that the cognitive benefits of exercise may be regulated by irisin and that FNDC5 shows potential as a therapeutic agent for treating dementia and other neurodegenerative diseases. These findings (Islam et al., 2021) were published on August 20 in the peer-reviewed journal Nature Metabolism.

"Identifying secreted mediators that drive the cognitive benefits of exercise holds great promise for the treatment of cognitive decline in aging or Alzheimer's disease (AD)," the authors write in the paper's abstract. "Here, we show that irisin, the cleaved and circulating form of the exercise-induced membrane protein FNDC5, is sufficient to confer the benefits of exercise on cognitive function."

"Irisin is a crucial regulator of the cognitive benefits of exercise and is a potential therapeutic agent for treating cognitive disorders including AD," they sum up.

How Does Irisin Protect the Brain?

"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," senior author Christiane Wrann of MGH's Program in Neuroprotection in Exercise said in an August 2021 news release. "[Our recent findings] could have implications for intervention in humans with Alzheimer's disease where therapy typically starts after patients have become symptomatic."

"What makes this study particularly strong is that we show irisin's effect on cognitive function in not one but four different mouse models," Spiegelman added.

For this study, Wrann et al. started by using a mouse model to show how genetic deletion of irisin in FNDC5 knock-out mice impaired the ability of exercise to improve cognitive functions during aging and in an Alzheimer's mouse model. In these knock-out mice, delivering irisin directly into the dentate gyrus rescued adult-born neurons that were "morphologically, transcriptionally, and functionally abnormal."

Irisin Protects Against Neuroinflammation

"Another important finding of the study is that irisin protects against neuroinflammation by acting directly on glial cells in the brain," the authors explain in the news release.

Using another moused model, the MGH researchers found that the elevation of circulating irisin levels in the bloodstream via a peripheral delivery of FNDC5 reduced neuroinflammation and improved cognitive deficits and neuropathology in their AD mouse model.

"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," co-author Rudy Tanzi noted.

"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," Wrann concluded.


Mohammad R. Islam, Sophia Valaris, Michael F. Young, Erin B. Haley, Renhao Luo, Sabrina F. Bond, Sofia Mazuera, Robert R. Kitchen, Barbara J. Caldarone, Luis E. B. Bettio, Brian R. Christie, Angela B. Schmider, Roy J. Soberman, Antoine Besnard, Mark P. Jedrychowski, Hyeonwoo Kim, Hua Tu, Eunhee Kim, Se Hoon Choi, Rudolph E. Tanzi, Bruce M. Spiegelman & Christiane D. Wrann. "Exercise Hormone Irisin Is a Critical Regulator of Cognitive Function."Nature Metabolism (First published: August 20, 2021) DOI: 10.1038/s42255-021-00438-z

Mychael V. Lourenco et al. "Exercise-Linked FNDC5/Irisin Rescues Synaptic Plasticity and Memory Defects in Alzheimer's Models." Nature Medicine (First published: January 07, 2019) DOI: 10.1038/s41591-018-0275-4

Bruce M. Spiegelman & Stanley J. Korsmeyer. "Irisin and the Therapeutic Benefits of Exercise" BMC Proceedings (First published: June 01, 2012) DOI: 10.1186/1753-6561-6-S3-O23

Pontus Boström, Jun Wu, Mark P. Jedrychowski, Anisha Korde, Li Ye, James C. Lo, Kyle A. Rasbach, Elisabeth Almer Boström, Jang Hyun Choi, Jonathan Z. Long, Shingo Kajimura, Maria Cristina Zingaretti, Birgitte F. Vind, Hua Tu, Saverio Cinti, Kurt Højlund, Steven P. Gygi & Bruce M. Spiegelman. "A PGC1-α-Dependent Myokine That Drives Brown-Fat-Like Development of White Fat and Thermogenesis." Nature (First published: January 11, 2012) DOI: 10.1038/nature10777