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A Molecule Transfers Neurologic Benefits of Exercise to the Sedentary

Article In Brief

Researchers reported that sedentary mice who received serum from exercising mice exhibited many of the neurological benefits of exercise, noting that the protein clusterin appeared to mediate most of the benefits of the serum. Some researchers believe it is premature to focus on clusterin or any of the other blood factors identified so far as being responsible for the neuroprotective benefits of exercise.

Another molecule adds to the growing list of proteins and hormones that appear to be able to transfer the benefits of exercise to the sedentary.

In a series of experiments, reported in Nature, researchers at Stanford first replicated earlier work showing that sedentary mice who receive serum from exercising mice show many of the neurological benefits of exercise. The Stanford team then screened the plasma to find which of its constituents conferred those benefits.

They found that the protein clusterin, long known to have a variety of effects on inflammation and coagulation, appeared to mediate most of the benefits of the serum from exercising mice. When they removed clusterin from the exercise serum given to sedentary mice, most of the benefits disappeared. On the other hand, intravenously injecting clusterin into the brain of sedentary mice reduced neuroinflammatory gene expression in a model of acute brain inflammation as well as in a model of Alzheimer's disease.

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“They showed that the anti-inflammatory effect of exercisers' serum went away when they removed clusterin. It would have been nice to see how big an impact it had on cognition. That's obviously the next step.”—DR. SAUL VILLEDA

Finally, in a clinical study involving US military veterans with mild cognitive impairment, they found that six months of physical exercise increased their plasma levels of clusterin.

Zurine De Miguel, PhD, the first author of the paper, told Neurology Today that the findings support the view that factors circulating in the peripheral system are somehow conferring the benefits of exercise on the brain.

“It's not just a single factor—it's likely to be a set of factors that activate many pathways in the brain,” said Dr. De Miguel, who was a postdoctoral researcher in the Stanford laboratory of Tony Wyss-Coray, PhD, during the study. (She has since become an assistant professor of psychology at California State University in Monterey Bay.)

Other recent papers have identified some of those other potential factors. In August of last year, a paper in Nature Metabolism identified the hormone irisin as being critical in conferring the neurocognitive benefits of exercise. A year earlier, a paper in Science identified the liver enzyme GPLD1 as playing a key role. Yet another hormone that appears to transduce the cognitive benefits of exercise, klotho, was first discovered in 1997.

Researchers involved in the search for such exercise-associated factors said they found the new study extremely well done and convincing. They noted, however, that while the study showed that the serum of exercising mice improved memory in their sedentary counterparts, no such direct measure was included of clusterin's effect on memory.

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“This discovery really begins to address how exercise staves off and counters cognitive decline.”—DR. DENA DUBAL

“They showed that the anti-inflammatory effect of exercisers' serum went away when they removed clusterin,” said Saul Villeda, PhD, who led the 2021 study of GPLD1 as assistant professor in the University of California at San Francisco's department of anatomy. “It would be nice to see how big an impact it had on cognition. That's obviously the next step.”

Study Details

Dr. Wyss-Coray's group's made headlines in 2014 with a paper in Nature Medicine, which showed that giving blood from young mice to old reversed their age-related impairments in cognitive function and synaptic plasticity.

The new paper, published in December, cited previous research showing that physical exercise slows cognitive ageing and neurodegeneration, at least in part due to increased plasticity and reduced inflammation in the hippocampus. But, the paper noted, “little is known about the factors and mechanisms that mediate these effects.”

Although many of the previous studies have focused on the effects of giving exercisers' serum to older, sedentary mice, the Stanford team sought to test the effects on sedentary mice that are young.

They began by measuring the neurologic effects of exercise on young mice. Compared with their sedentary litter mates, 28 days of running increased overall cell survival in the hippocampus, including neurons, the number of neural stem and progenitor cells and astrocytes.

After intravenously injecting the sedentary mice with serum from the runners, they observed similar results with those seen in the runners, including a significant increase in total proliferating cells and neuroblasts. In particular, they saw twice as many surviving neural stem and progenitor cells, and a doubling of survival of newly produced astrocytes.

The runners' serum also resulted in improved contextual learning and memory in the sedentary mice, both in the fear conditioning paradigm and in the Morris water maze. The serum did not, however, affect their activity in a light–dark arena or anxiety levels in the activity chamber.

To tease out the molecular underpinnings of the effects, Dr. Wyss-Coray's group analyzed the hippocampal transcriptome of mice treated with runner's serum using RNA sequencing.

“We observed 1,952 significant differentially expressed genes, of which 61 percent were down-regulated and 39 percent were up-regulated,” the study reported. Among the up-regulated genes were those implicated in hippocampal learning and memory, as well as in the immune system and plasticity.

Upon finding that neuroinflammation was reduced in the active mice, the researchers sought to identify the factor in their serum responsible for the anti-inflammatory effect. “Plasma proteomic analysis,” they reported, “revealed a concerted increase in complement cascade inhibitors, including clusterin.”

They then depleted four of the most up-regulated proteins, including clusterin, from the runners' plasma before giving it to sedentary mice. While the depletion of clusterin eliminated the anti-inflammatory effect of the runners' plasma, eliminating the other three proteins had no such effect.

Finally, to test the clinical translatability of their observations, Dr. Wyss-Coray's group measured eight of the proteins involved in complement and coagulation among 20 veterans with mild cognitive impairment. After six months of a three-days-a-week exercise program, their level of clusterin was significantly increased, while complement factor 3, coagulation factor II, and other proteins involved in the complement and coagulation cascades fell.

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“It's not just a single factor—it's likely to be a set of factors that activate many pathways in the brain.”—DR. ZURINE DE MIGUEL

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“It's important to know whether the clusterin they added ends up in the hippocampus. They didn't show that. There's a whole literature on clusterin, and some of the previous findings argue for a detrimental effect of clusterin on the aging brain.”—DR. MARK MATTSON

Although not reported in the current paper, verbal and episodic memory were tested in the veterans before and after the six months of exercise, and were significantly improved, according to Kaci Fairchild, PhD, a geropsychologist and associate director of the Department of Veterans Affairs Sierra Pacific Mental Illness Research, Education, and Clinical Center in Palo Alto. Those results, she told Neurology Today, are in a paper now under review.

Expert Commentary

Some researchers believe it is premature to focus on clusterin or any of the other blood factors identified so far as being responsible for the neuroprotective benefits of exercise.

“Of course, we do not know the magic molecule yet,” said Ulrik Wisloff, PhD, professor and leader of the Cardiac Exercise Research Group at the Norwegian University of Science and Technology. “If it's just one factor, the person who discovers it will get the Nobel Prize.”

His group is currently running a clinical trial involving 60 patients with mild cognitive impairment or early Alzheimer's disease, who will receive either 12 transfusions of runner's plasma, 12 of plasma from standard blood plasma, or 12 of saline, delivered over the course of a year.

“Our hypothesis is that several of these factors affect each other somehow, that there is a far more complex interplay between them than is known today,” said Dr. Atefe Tari, the first author of the study in Dr. Wisloff's lab. “We don't assume that just one of these factors will be enough to mimic the benefits of exercise.”

The senior author of last year's paper on irisin agreed that it's hard to know which of the various molecules so far associated with the neurocognitive benefits of exercise is most important.

“It's one of the questions we always get asked: Which is the one and only one?” said Christiane D. Wrann, DVM, PhD, leader of the program in neuroprotection in exercise at Massachusetts General Hospital and assistant professor of medicine at the Harvard Medical School. “There has not yet been a study that compared them head-to-head, so it's really hard to say if one is better than another.”

Her studies of irisin have found that it not only helps restore cognitive function in brain-injured mice, but it also improves performance in healthy mice as well. It crosses the blood-brain barrier, Dr. Wrann said, and is identical in mice and humans.

“It's a very promising candidate,” she said. “Irisin checks a lot of the boxes.”

Dr. Villeda said the results of the clusterin study appear to be consistent with the effects he found for GPLD1 in his 2021 paper.

“Our paper also showed complement going down,” Dr. Villeda said. “And both GPLD1 and clusterin are produced primarily by the liver. It's always nice to see this convergence of findings.”

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“Of course, we do not know the magic molecule yet. If it's just one factor, the person who discovers it will get the Nobel Prize.”—DR. ULRIK WISLOFF

Dena Dubal, MD, PhD, an associate professor of neurology and David A. Coulter Endowed Chair in Ageing and Neurodegenerative Disease at UCSF, called the new study “very exciting.”

“This discovery really begins to address how exercise staves off and counters cognitive decline,” she said.

Dr. Dubal has been studying the role of klotho, a protein first identified 25 years ago as having a strong effect on aging. In a 2017 paper, she reported that increasing naturally occurring levels of the protein improves cognitive function in young and old mice alike.

She said it's possible that the various molecules, given together, might enhance each other's effects. “Could irisin increase klotho?” she wondered. “Could clusterin increase GPLD1? Is there a master regulator of exercise-related brain enhancement? We have so much to learn.”

She currently has another paper in review about the neurocognitive effects of klotho. “We're so excited,” she said. “Stay tuned.”

Mark Mattson, PhD, adjunct professor of neuroscience at Johns Hopkins and the former chief of the neuroscience laboratory at the National Institute of Aging, said the study of clusterin could have included more data.

“It's important to know whether the clusterin they added directly affects hippocampal plasticity,” he said. “They didn't show that.”

He added, “There's a whole literature on clusterin, and some of the previous findings argue for a detrimental effect of clusterin on the aging brain.”

Indeed, a 2016 paper in Alzheimer's & Dementia found that clusterin “was significantly associated with increased risk of dementia among elderly persons.”

Disclosures

Dr. De Miguel had no disclosures. Dr. Dubal is an associate editor for JAMA Neurology and has consulted for Unity Biotechnology. Dr. Mattson has no disclosures. Dr. Villeda has consulted for Alkahest Biotech. Dr. 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. Dr. Wrann's interests were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict of interest policies.

Link Up for More Information

• De Miguel Z, Khoury N, Betley MJ, et al. Exercise plasma boosts memory and dampens brain inflammation via clusterin https://www.nature.com/articles/s41586-021-04183-x. Nature 2021; 600(7889):494–499.
    • Horowitz AA, Fan X, Bieri G, et al. Blood factors transfer beneficial effects of exercise on neurogenesis and cognition to the aged brain https://www.science.org/doi/10.1126/science.aaw2622. Science 2020;369(6500):167–173.
    • Islam MR, Valaris S, Young MF, et al. Exercise hormone irisin is a critical regulator of cognitive function https://www.nature.com/articles/s42255-021-00438-z. Nature Med 2021;3(8):1058–1070.
      • Leon J, Moreno AJ, Gary BI, et al. Peripheral elevation of a klotho fragment enhances brain function and resilience in young, aging and-synuclein transgenic mice https://www.cell.com/cell-reports/fulltext/S2211-1247(17)30990-7?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2211124717309907%3Fshowall%3Dtrue. Cell Rep 2017;20(6):1360–1371.
        • Dubal DB, Yokoyama JS, Zhu L, et al. Life extension factor klotho enhances cognition https://www.cell.com/cell-reports/fulltext/S2211-1247(14)00287-3?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2211124714002873%3Fshowall%3Dtrue. Cell Rep 2014;7(4):1065–1076.
          • Villeda SA, Plambeck KE, Middeldorp J, et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice https://www.nature.com/articles/nm.3569. Nat Med 2014;20(6):659–663.
          • Weinstein G, Beiser AS, Preis SR, et al. Plasma clusterin levels and risk of dementia, Alzheimer's disease, and stroke https://alz-journals.onlinelibrary.wiley.com/doi/full/10.1016/j.dadm.2016.06.005. Alzheimers Dement (Amst) 2016;3:103–109.