Scientists Move One Step Closer to “Exercise in a Bottle”

The brain benefits of exercise may be linked to a single protein called “GPLD1.”

Posted Jul 10, 2020

Source: LANBO/Shutterstock

Groundbreaking new research by scientists at the University of California, San Francisco (UCSF) zeroes in on an exercise-induced protein called "GPLD1" that is produced in the liver and enters the bloodstream after cardio workouts; this single protein appears to have remarkable brain-boosting benefits. As the authors explain: "Reversing brain aging may be possible through systemic interventions such as exercise. We found that administration of circulating blood factors [GPLD1] in plasma from exercised aged mice transferred the effects of exercise on adult neurogenesis and cognition to sedentary aged mice."

In this study, a cohort of older, sedentary "couch potato mice" who were given a transfusion of GPLD1 quickly grew new "adult-born neurons" in the hippocampus and experienced the cognitive benefits of exercise without exercising. These findings (Horowitz et al., 2020) were published on July 10 in the journal Science.

For decades, brain-derived neurotrophic factor (BDNF) has been associated with the birth of new adult-born neurons (via neurogenesis) in the hippocampus. BDNF is widely thought to be one reason that aerobic exercise is like "Miracle-Gro" for the brain and why regular cardio workouts help to offset cognitive decline.

Now, for the first time, a research team led by Alana Horowitz of UCSF's Villeda Lab has identified that GPLD1 also appears to trigger neurogenesis in the hippocampus of mice and is associated with better cognitive functioning in the "aged brains" of laboratory mice.

Although human adults show an uptick of GPLD1 in their blood after cardio workouts, it's way too early to know if the results of this study in mice will result in therapies that might benefit humans. That said, the researchers are optimistic that this discovery could lead to an "exercise pill" that increases neurogenesis in the hippocampus and provides neuroprotective benefits in the aging human brain for anyone who can't (or won't) exercise regularly for whatever reason.

"If there were a drug that produced the same brain benefits as exercise, everyone would be taking it. Now our study suggests that at least some of these benefits might one day be available in pill form," senior author Saul Villeda of UCSF said in a news release

Only About One in Six U.S. Adults Meet Current Physical Activity Guidelines

Another recent study (Zhao et al., 2020) found that avid walkers and "cardio fanatics" may reap similar survival benefits if they meet the recommended physical activity guidelines of doing a total of 150 minutes of moderate-to-vigorous physical activity (e.g., casual walking) or 75 minutes of vigorous exercise (e.g., jogging) per week.

Unfortunately, Min Zhao and colleagues also found that only 15.9 percent of people achieve these weekly physical activity recommendations. On the flip side, 84.1 percent of U.S. adults could be classified colloquially as "chronic couch potatoes."

Unlike most humans, if mice are given access to a running wheel in their laboratory environment, the majority of them will voluntarily run for miles and miles every night. Most mice seem like they're "born to run," not born to be couch potatoes.

For the latest study on GPLD1, the researchers denied one cohort of older mice access to a running wheel and forced them to become so-called "couch potato mice." Conversely, another group of older mice was housed in a lab environment with lots of running wheels in their laboratory habitat. As expected, these mice ran all the time and reaped the brain benefits of staying active. 

Much to their surprise and amazement, Horowitz et al. found that just three weeks of the GPLD1-infused blood plasma treatments produced brain benefits that were similar to six weeks of daily aerobic exercise. Below is a one-minute video that sums up the significance of this research: 

In an editorial commentary, "Exercising Your Mind," (Ansere & Freeman, 2020), that accompanies the publication of the new GPLD1 mouse study in the July 10 issue of Science, Victor Ansere and Willard Freeman write: "Although the beneficial effects of exercise on the brain and cognition are generally accepted, the mechanisms by which physically active people remain mentally sharp later in life have been unclear."

Ansere and Freeman acknowledge that the new UCSF study provides "compelling evidence that the positive effects of exercise on brain aging are at least partially mediated through hepatic mechanisms." However, Freeman also cautions that "we have a lot to learn" and stresses the importance of conducting more research.

CLIPAREA l Custom media/Shutterstock
Source: CLIPAREA l Custom media/Shutterstock

Brain-Boosting "Exercise Pills" and the Cautionary Tale of "Flowers for Algernon"

Whenever a new scientific discovery shows promise for leading to a "magic pill" that may boost brainpower or offset cognitive decline, my first reaction is one of healthy skepticism. This knee-jerk reaction is partly inspired by the tragic outcome for "Charlie" in the dystopian science-fiction novel, Flowers for Algernon by Daniel Keyes. 

In this cautionary tale, the protagonist, Charlie, is a janitor with an IQ of 68 who is the first "human guinea pig" to undergo a medical procedure (akin to a plasma transfer) that initially shows intelligence-enhancing benefits in a laboratory mouse named Algernon.

At first, both Charlie and Algernon respond well to the brain-boosting procedure. However, just as Charlie's intelligence is reaching a peak and his IQ scores are zooming off the charts, Algernon's intelligence goes into a rapid decline and his cognitive performance nosedives. Soon thereafter, the lab mouse dies from what appears to be the equivalent of rapid-onset Alzheimer's disease.

At the time of Algernon's death, Charlie is still a genius who doesn't suffer from the Dunning-Kruger effect and is smart enough to know that his superior intelligence is temporary. He sees the writing on the wall and knows that he's in a race against time to identify the fatal flaw of the intelligence-enhancing procedure before his superhuman IQ evaporates. Just before Charlie's intelligence completely regresses, he discovers the defect in the brain-boosting procedure and coins it "The Algernon-Gordon Effect."

The reason I bring up the fictional "Algernon-Gordon Effect" in the context of the recent discovery of GPLD1 blood factor transfers possibly leading to an "exercise pill" that could boost neurogenesis and offset cognitive decline is to highlight the importance of proceeding with caution.

The benefits of exercise go far beyond neurogenesis. As a public health advocate, I have concerns that any pharmaceutical pills that might be marketed or perceived by the general public as a "substitute for exercise" could backfire in the long run. For now, the preliminary research on GPLD1 shows promise, but let's not forget that being able to put "exercise in a bottle" could demotivate people to stay physically fit and could have many unforeseen negative consequences on our psychological and physical well-being.


Lana M. Horowitz, Xuelai Fan, Gregor Bieri, Lucas K. Smith, Cesar I. Sanchez-Diaz, Adam B. Schroer, Geraldine Gontier, Kaitlin B. Casaletto, Joel H. Kramer, Katherine E. Williams, Saul A. Villeda. “Blood Factors Transfer Beneficial Effects of Exercise on Neurogenesis and Cognition to the Aged Brain.” Science (First published: July 10, 2020) DOI: 10.1126/science.aaw2622

Accompanying commentary by Victor A. Ansere and Willard M. Freeman. "Exercising Your Mind." Science  (First published: July 10, 2020) DOI: 10.1126/science.abc8830