Exercise-Linked Irisin May Protect Against Neurodegeneration

A new study by an international team of researchers reaffirms the potential neuroprotective power of exercise-induced irisin. Since the hormone irisin was first discovered less than a decade ago, there’s been some debate about whether or not irisin is, in fact, the powerful exercise-induced messenger that the pioneering researchers at Harvard Medical School led by Bruce Spiegelman initially speculated back in 2012.

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The recent study by first author Mychael Lourenco et al., “Exercise-Linked FNDC5/Irisin Rescues Synaptic Plasticity and Memory Defects in Alzheimer’s Models,” adds to a growing body of evidence that exercise-induced irisin may protect against neurodegeneration and boost memory in both humans and mice. This paper was published January 7 in Nature Medicine.

An accompanying commentary in this issue of Nature Medicine by Xu Chen and Li Gan—who were not involved in the Lourenco et al. (2019) study—sums up the significance of this research: “An exercise-linked hormone, FNDC5/irisin, mediates the benefit of exercise in Alzheimer’s disease models by enhancing synaptic plasticity and memory.”

The first notable aspect of this three-pronged study is that post-mortem analysis of samples from human brain banks revealed that irisin molecules make their way into the human hippocampus and that hippocampal levels of irisin are significantly reduced in individuals with Alzheimer's disease (AD).

The second phase of this study used mice to investigate if irisin rescues synaptic plasticity and helps to preserve memory in an animal model. Notably, the researchers found that if they disabled or "knocked out" the effects of irisin in mice, synaptic function and memory both weakened. On the flip side, if they boosted levels of irisin, synaptic plasticity and memory both improved.

The third part of this study explored the effect of aerobic exercise on irisin levels in the mouse brain. For this arm of the three-part study, the researchers had one cohort of mice swim for 60 minutes/five days a week for five weeks. In comparison to a control group that didn’t swim regularly, the researchers found clear evidence of exercise-linked irisin production.

Additionally, when the swimming mice were infused with a beta-amyloid (that is implicated in AD) the exercise-linked irisin provided neuroprotection. For example, if the researchers administered a drug that blocked irisin, the brain benefits of swimming became nonexistent. Irisin-blocking substances wiped away any exercise-related improvements on memory tests.

The multi-faceted findings of this research suggest that exercise-induced irisin may help prevent certain types of dementia in humans. The next phase of ongoing irisin research will be to explore possible pharmaceuticals that can increase levels of irisin in the brain without the need to exercise.

“In the meantime, I would certainly encourage everyone to exercise, to promote brain function and overall health," co-author Ottavio Arancio of Columbia University said in a statement. "But that's not possible for many people, especially those with age-related conditions like heart disease, arthritis, or dementia. For those individuals, there's a particular need for drugs that can mimic the effects of irisin and protect synapses and prevent cognitive decline."

The Brief (and Somewhat Controversial) History of Exercise-Induced Irisin

Seven years ago, Bruce Spiegelman and colleagues at the Dana-Farber Cancer Institute in Boston first reported their discovery of an exercise-induced messenger that seemed to have amazing potential for communicating with various tissues throughout the body and brain.

Spiegelman and co-authors reported on these findings in a January 2012 study (Boström et al., 2012) published in the journal Nature. In this paper, the authors explain the novelty of their discovery: “Here we show in mouse that PGC1-α expression in muscle stimulates an increase in expression of FNDC5, a membrane protein that is cleaved and secreted as a newly identified hormone, irisin.”

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Spiegelman coined the name “irisin” for this newly discovered hormone as a shout-out to Iris, who is a messenger of the gods in Greek mythology and Homer's Iliad. Early on, Spiegelman had a hunch that isolating and naming irisin was an important first step for advancing our understanding of how aerobic exercise triggers a chain reaction of benefits throughout the body and brain.

I first learned about the ability of a relatively unknown exercise-induced molecule called “irisin” to improve cognitive function and protect the brain against neurodegeneration in mice six years ago.

In an October 2013 post, “Scientists Discover Why Exercise Makes You Smarter,” I reported on more cutting-edge research (Wrann et al., 2013) from Spiegelman's lab published in the journal Cell Metabolism.

Christianne Wrann and co-authors explained the significance of this paper, “Exercise can improve cognitive function and has been linked to the increased expression of brain-derived neurotrophic factor (BDNF). However, the underlying molecular mechanisms driving the elevation of this neurotrophin remain unknown. Here we show that FNDC5, a previously identified muscle protein that is induced in exercise and is cleaved and secreted as irisin, is also elevated by endurance exercise in the hippocampus of mice."

Soon after this paper was published, some controversy erupted. Other experts questioned the protocol and validity of Spiegelman’s research methods and his team’s subsequent findings. These naysayers raised some doubts about whether levels of irisin actually increase via aerobic exercise.

In 2015, Spiegelman and his team addressed these concerns in a paper, "Detection and Quantitation of Circulating Human Irisin by Tandem Mass Spectrometry," which confirmed the existence of exercise-linked irisin. The authors (Jedrychowski et al., 2015) said, "In this paper we have identified and quantitated human irisin in plasma using mass spectrometry with control peptides enriched with heavy stable isotopes as internal standards. These data unequivocally demonstrate that human irisin exists, circulates, and is regulated by exercise." (See "The 'Exercise Hormone' Irisin Is NOT a Myth.")

Hopefully, the latest study on irisin by Lourenco et al. (2019) will serve as another source of motivation for people of all ages to sit less and exercise more. But again, for those who are unable to exercise for whatever reason, irisin-based pharmaceuticals may offer new hope in the ongoing fight against Alzheimer’s disease and other forms of dementia in the near future.