As we grow older, our cognitive abilities begin to wane. We forget names and places, lose trains of thought, and become creatures of habit. A key to overcoming these ageing-induced cognitive deficits may be exercise.
“Exercise improves cardiovascular fitness, glucose metabolism, insulin sensitivity, blood pressure, lipid profiles, sleep, mood, and immune function,” Atefe Tari, a researcher studying exercise and brain health at the Norwegian University of Science and Technology and St. Olav’s University Hospital, said.
“While all of these can influence brain health, exercise also affects the brain more directly by many different processes, including changes in signaling molecules.”
A new study published in Cell has reported how a signal released by the liver after exercise reduces cognitive decline due to ageing and Alzheimer’s disease in mice.
Exerkines to the rescue
After exercise, small molecules called exerkines are released by the liver, skeletal muscles, heart, and brain into the bloodstream. These include peptides, lipids, hormones, and nucleic acids. These exerkines mediate the beneficial effects of exercise, including promoting cardiovascular fitness and improving metabolism, throughout the body.
In the study, Gregor Bieri and colleagues at the University of California, San Francisco, examined the mechanism of action of one such exerkine produced by the liver: GPLD1.
The researchers increased the levels of GPLD1 in the livers of older mice that had exercised — voluntarily running on wheels, like a treadmill. Old mice that could not exercise because their wheels had been locked had lower levels of GPLD1 in their livers.
Next, the researchers tested the cognitive abilities of young and old mice. Young mice performed better at a spatial memory test compared to old mice. The test was to find a platform hidden in a pool of water. Young mice made fewer errors and found the platform sooner compared to their older peers. The young mice also preferred novel objects instead of familiar ones and would readily explore novel locations, while old mice showed no such preferences.
Importantly, these cognitive deficits were reduced in old mice whose livers were injected with GPLD1, showing that GPLD1 could mitigate ageing-induced cognitive decline.
Protective barrier
GPLD1 is an enzyme that breaks down hundreds of proteins on cell surfaces. Based on this function, the authors focused on the blood-brain barrier in mice – a network of blood vessels and specialised cells that surround the brain.
“The blood-brain barrier tightly regulates the signals and nutrients that get shuttled between the brain and blood,” Dr. Bieri, the lead author of the study, explained.
As we age, the barrier accumulates proteins that make it leaky. The authors found one such protein, called TNAP, to be highly enriched in the blood-brain barriers of old mice, notably even around the hippocampus, the learning and memory centre of the brain.
“While we do not fully understand its role, we observed that TNAP drives inflammation and impairs the transport of factors from blood to brain,” Dr. Bieri said.
He and his colleagues performed three experiments to tie the roles of TNAP and GPLD1. First, the scientists found that old mice that have more TNAP in their barriers also had leaky blood vessels. Next, young mice in which TNAP levels were artificially increased in the barrier surrounding the hippocampus showed leaky blood vessels and cognitive defects similar to old mice. Third, injecting GPLD1 in the livers of old mice, while also artificially increasing TNAP in the blood-brain barrier, nullified the beneficial effects of GPLD1 on cognitive function.
“A strength of this study is the combination of approaches that provides mechanistic evidence that TNAP is functionally involved in blood-brain barrier dysfunction and cognitive decline,” Dr. Tari said.
Overall, these experiments showed that TNAP, which accumulates on the blood-brain barrier due to ageing, is broken down by GPLD1, an enzyme released by the liver after exercise.
Therapeutic potential for Alzheimer’s
Given that ageing is a risk factor for neurodegenerative disorders like Alzheimer’s disease and dementia, the authors next tested whether the GPLD1 intervention could reduce cognitive decline in a mouse model of Alzheimer’s disease.
Dr. Tari, who was not involved in the study, exercised caution on this count, noting that “mouse models of Alzheimer’s do not fully reproduce the complexity of the disease in humans, which develops over decades and involves vascular dysfunction, inflammation, metabolism, genetics, and lifestyle factors.”
“When the blood-brain barrier becomes leaky, several things can happen that are relevant to Alzheimer’s development,” Dr. Tari said. “First, inflammatory molecules and other blood-derived factors can enter the brain more easily and activate immune responses. This causes chronic inflammation in the nerve cells which can accelerate disease processes.”
“Secondly, if the blood-brain barrier function is impaired, the brain may become less efficient at clearing toxic proteins and maintaining its internal environment.”
Alzheimer’s disease is characterised by the accumulation of toxic amyloid protein, which clump together to form plaques, leading to neurodegeneration and cognitive decline. These features are modelled in genetically modified mice by expressing human genes with multiple mutations that force the rapid buildup of amyloid protein.
The team allowed the Alzheimer’s-modelled mice to run on wheels voluntarily for three months, after which their GPLD1 levels were higher, and their cognitive performance was notably improved, compared to Alzheimer’s-modelled mice that did not exercise.
In another experiment, GPLD1 was injected into the livers of Alzheimer’s-modelled mice. In these mice, TNAP levels in the blood-brain barrier were lower, the blood vessels were less leaky, there were fewer amyloid plaques, and cognitive dysfunction was reduced.
Experts said these results are encouraging and have clinical implications for Alzheimer’s disease.
Dr. Bieri noted that “while a lot of research and potential therapeutic strategies have focused on the brain, recent antibody-based interventions are associated with side effects resulting from a breakdown of the blood-brain barrier. Thus, improving blood-brain barrier function could also improve the treatment efficacy of other therapeutic interventions.”
“This study identifies a promising pathway that may become relevant for drug development or biomarker work,” Dr. Tari added. “But it does not mean we are close to replacing exercise with a pill yet.”
Parallel and convergent pathways
Exercise affects different parts of the body simultaneously. Brain function is also influenced by multiple factors. Recently, in another study, researchers from Seoul National University and the Korea Brain Research Institute found that exerkines secreted by skeletal muscles could improve cognitive performance by crossing the blood-brain barrier, unlike GPLD1. This exerkine was found to boost new neuron formation within the hippocampus.
“The benefits of exercise are unlikely to be explained by a single molecule or pathway alone,” Dr. Tari noted, adding that “the strength of exercise likely lies in its ability to trigger a coordinated, whole-body response.”
Dr. Bieri said he sees clinical opportunity in the possibility of multiple exerkines working in tandem: “As potential new therapeutic strategies keep expanding, [the] discovery of complementary mechanisms will allow for a more personalised medicine approach. Future treatments will likely be combinatorial, tackling different cell types and hallmarks of ageing and disease.”
Sheetal Potdar is a freelance science journalist with a PhD in neuroscience.