Posted on Oct 03, 2023, 8 p.m.
The anti-aging hormone klotho has been studied for years, as well as infusions of young blood and exercise, each helping to improve brain function in older mice, but scientists don’t know exactly why. Now working in collaboration, researchers from UC San Francisco and the University of Queensland have identified platelet factor 4 (PF4) as a common denominator behind all three. Their findings have been published in a trio of papers appearing in Nature, Nature Aging, and Nature Communications.
Platelets are blood cells that normally release the small protein, PF4, to alert the immune system and clot blood at wounds. But PF4 has now been found to also rejuvenate the old brain and boost young brains, which could potentially open new paths to therapies designed to restore brain function.
“Young blood, klotho, and exercise can somehow tell your brain, “Hey, improve your function,” said Saul Villeda, Ph.D., associate director of the UCSF Bakar Aging Research Institute and the senior author of the Nature paper. “With PF4, we’re starting to understand the vocabulary behind this rejuvenation.”
In 2014 Villeda found that blood plasma from young mice restored brain function in old animals. His team then discovered that young plasma contained much more PF4 than old plasma. Injecting PF4 into old animals was as restorative as young plasma, calming down the aged immune system and the brain, with the older animals performing better on a variety of memory and learning tasks.
“PF4 actually causes the immune system to look younger, it’s decreasing all of these active pro-aging immune factors, leading to a brain with less inflammation, more plasticity, and eventually more cognition,” Villeda said. “We’re taking 22-month-old mice, equivalent to a human in their 70s, and PF4 is bringing them back to function close to their late 30s, early 40s.”
Dena Dubal, MD, PhD, UCSF, previously showed that klotho enhances brain function in both young and old animals and also makes the brain more resistant to age-related degeneration. On its own klotho is not able to reach the brain, but the team was able to find that one connection was PF4 which is released by the platelets after a klotho injection.
According to Dubal, PF4 had a dramatic effect on the hippocampus, particularly enhancing the formation of new neural connections at the molecular level, and giving both old and young brains boosts in behavioral testing. Other findings show that klotho’s benefits depend on platelets releasing PF4 and other molecules, which could each have their own anti-aging benefits.
“Ideally, we’ll have multiple shots on goal for one of our biggest biomedical problems, cognitive dysfunction, with the fewest side effects and the most benefit,” Dubal said.
Exercise can help to keep the mind sharp, and in 2019 Tara Walker, PhD, senior research associate in neuroscience at the University of Queensland found that platelets released PF4 into the bloodstream after exercise, when she tested PF4 alone it was found to improve cognition in older animals.
“For a lot of people with health conditions, mobility issues or advanced in age, exercise isn’t possible, so pharmacological intervention is an important area of research,” Walker said. “We can now target platelets to promote neurogenesis, enhance cognition, and counteract age-related cognitive decline.”
The team committed to releasing their findings separately at the same time to make the case for PF4 from three different angles, that all connect.
“When we realized we had independently and serendipitously found the same thing, our jaws dropped,” said Dena Dubal, MD, PhD, UCSF professor of neurology. “The fact that three separate interventions converged on PF4 truly highlights the validity and reproducibility of this biology.”
Saul Villeda, Ph.D., led the study on young blood published in Nature. Dena Dubal, MD, PhD, UCSF professor of neurology and David A. Coulter Endowed Chair in Aging and Neurodegenerative Disease, led the study on klotho published in Nature Aging. Tara Walker, PhD, senior research associate in neuroscience at the University of Queensland, led the study on exercise published in Nature Communications.
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