Scientists have known for years that the anti-aging hormone Klotho, infusions of young blood, and exercise improve brain function in older mice. But they didn’t know why.
Now, two research teams, one from the University of California, San Francisco, and one from the University of Queensland, Australia, have identified platelet factor 4 (PF4), a small protein released by platelets, as the common denominator in all three. .
Platelets are blood cells that normally release PF4 to alert the immune system and cause blood to clot at wounds. Researchers say PF4 rejuvenates old brains and revitalizes young brains, potentially opening the door to new treatments aimed at restoring brain function, even if they don’t tap into the fountain of youth. I discovered that there is a sex.
“Young blood, Klotho, and exercise can somehow tell the brain to ‘improve your function,'” said Bakar, vice director of the University of California, San Francisco’s Institute on Aging and senior author of the paper. said Dr. Saul Vireda. Nature paper. “With PF4, we are beginning to understand the vocabulary behind this rejuvenation.”
Details of this breakthrough are published in three papers: Nature, natural aging and nature communications Dr. Villeda led the Young Blood study, which was published on August 16, 2023. Nature. Dena Duvall, MD, PhD, professor of neurology and David A. Coulter Endowed Chair in Aging and Neurodegenerative Diseases at the University of California, San Francisco, led research on Klotho that was published in 2006. natural aging. Dr Tara Walker, a senior research fellow in neuroscience at the University of Queensland, led the exercise research. nature communications.
They promised to present their findings simultaneously to make the case for PF4 from three different angles.
“We were stunned when we realized that we had independently stumbled upon the same thing,” Duvall said. “The fact that three separate interventions converged on PF4 truly highlights the validity and reproducibility of this biology.”
Can a 70-year-old brain function the same way as a 40-year-old brain?
In 2014, Dr. Villeda discovered that plasma from young mice, with red blood cells removed, restored brain function in older mice. His team then discovered that young plasma contained much more PF4 than older plasma.
Furthermore, simply injecting PF4 into old animals had nearly the same restorative effect as plasma from young animals. Calms the aging immune system of the body and brain. Older animals given PF4 performed better in a variety of memory and learning tasks.
“PF4 actually makes the immune system look younger. It reduces all of these active age-promoting immune factors, reduces inflammation in the brain, increases plasticity, and ultimately improves cognition,” says Villeda. said. “We raise mice at 22 months of age, which is equivalent to humans in their 70s, and PF4 returns them to function more like they are in their late 30s to early 40s.”
This microscopic image shows microglia, immune cells in the brain, in red. Green and yellow areas indicate age-related inflammation in old mice.
This image shows reduced brain inflammation in old mice treated with PF4. Credit: Adam B. Schroer
Young brains are also activated
Ten years ago, Duvall, a member of the UCSF Weill Neuroscience Institute, showed that the hormone klotho enhances brain function in young and old animals and makes the brain more resistant to age-related degeneration. However, the Klotho injected into the body did not reach the brain. So how? Duvall’s team found that one link is PF4, which is released from platelets after Klotho injection.
PF4 had a dramatic effect on the hippocampus, where memories are formed in the brain. In particular, PF4 enhanced the formation of new neural connections at the molecular level. Duvall said this strengthened the brains of both young and old animals in behavioral tests, suggesting that “there is scope to improve cognitive function even in young brains.”
Other recent discoveries by Duvall support the potential therapeutic use of klotho. Klotho’s benefits depend on platelets releasing PF4 and other molecules, each of which may have their own benefits during aging.
“Ideally, we want to be able to take multiple shots on goal against one of the biggest biomedical problems: cognitive dysfunction, while minimizing side effects and maximizing effectiveness.” ,” Duvall said.
Exercise improves brain health thanks to PF4
Exercise can keep your mind sharp for decades. In 2019, Walker and her lab discovered that platelets release PF4 into the bloodstream after exercise. When she tested PF4 alone, like Duval and Villeda, it improved cognition in older animals.
“For many people who are in poor health, have limited mobility, and are older, exercise is not possible, so pharmacological interventions are an important area of research,” Walker said. “We can now target platelets to promote neurogenesis, enhance cognitive function, and counter age-related cognitive decline.”
Co-author: Other UCSF authors of the Nature paper are Dr. Adam B. Schroer, Dr. Patrick B. Ventura, MS, Juliana Sucharov, Rhea Misra, MK Kirsten Chui, Dr. Gregor Bieri, Dr. Alana M. Horowitz, and Lucas K. Smith. , Katrielle Enkabo, MD, MPH, Imelda Tengara, June M. Chan, MD, Anthony Luke, MD, MPH. His other UCSF authors on the Nature Aging paper are Cana Park, Ph.D., Shweta Gupta, Ph.D., Arturo J. Moreno, Francesca Marino, Dan Wang, MD, MS, and Saul Villeda, Ph.D. His other UCSF authors on the Nature Communications paper are Dr. Adam B. Schroer, Dr. Gregor Bieri, and Dr. Saul Villeda. See the paper for all authors.
Funding and disclosure: The research was supported in part by the National Institutes of Health (Nature: AG064823, AG081038, AG077816, and AG067740; Nature Aging: NS092918, AG068325; Nature Communications: R01AG077816) and through philanthropy. Please see the paper for full funding sources and author disclosures.
