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Researchers have long known that there are several interventions that can boost the brain function of aging mice. These include the anti-aging hormone klotho, infusions of blood from younger animals and exercise. The underlying mechanism behind these changes has remained elusive until now. Joint studies conducted by teams from the University of California San Francisco (UCSF) and the University of Queensland have highlighted platelet factor 4 (PF4) as the linked factor behind these improvements.
PF4 is a small protein typically released by blood platelets at wound sites to wake up the immune system and clot blood. In the new studies, PF4 was not only able to enhance the function of aging brains, but young ones too. It not only decreases age-associated immune factors but also results in reduced brain inflammation and enhanced cognitive functions.
Here’s how PF4 links the three interventions.
- In 2014, Saul Villeda associate director of the UCSF Bakar Aging Research Institute noted that blood plasma – whole blood that has been filtered to remove all white and red blood cells – from young mice could boost the brain function of older mice. In a new paper, Villeda showed that injections of PF4, which was enriched in young plasma, could achieve the same kind of improvement to brain function on its own. The injections improved the mice’s cognitive function and lowered levels of inflammation. “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 commented. “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.”
- Around the same time that Villega was looking into young blood, Dena Dubal, professor of neurology and David A. Coulter Endowed Chair in Aging and Neurodegenerative Disease at UCSF, was focusing on the anti-aging hormone klotho, which could help the aging brain resist decline. Her work discovered that while klotho did not directly reach the brain, it could stimulate the release of PF4 from platelets. This had profound effects on the brain’s hippocampus. Here, PF4 could increase the formation of new brain connections and boost brain function in both old and young animals. Dubal believes that other molecules released alongside PF4 could also have anti-aging potential, giving the area “multiple shots on goal” to score a win against cognitive dysfunction.
- Tara Walker, a senior research associate in neuroscience at the University of Queensland, explored how exercise affects the brain. Her lab showed that exercise resulted in the release of PF4. In her new publication, exercise-derived PF4 again was shown to improve subsequent cognition in older animals.
A new anti-aging vocabulary
The papers outlining Villeda, Dubal and Walker’s findings were published in Nature, Nature Aging and Nature Communications respectively. “Young blood, klotho and exercise can somehow tell your brain, ‘Hey, improve your function,’” said Villeda. “With PF4, we’re starting to understand the vocabulary behind this rejuvenation.”
The researchers’ simultaneous publications are designed to draw more attention to the multifaceted potential of PF4. “When we realized we had independently and serendipitously found the same thing, our jaws dropped,” Dubal said. “The fact that three separate interventions converged on PF4 truly highlights the validity and reproducibility of this biology.”
“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 concluded. “We can now target platelets to promote neurogenesis, enhance cognition and counteract age-related cognitive decline.”
Schroer AB, Ventura PB, Sucharov J, et al. Platelet factors attenuate inflammation and rescue cognition in aging. Nature. 2023:1-9. doi:10.1038/s41586-023-06436-3
Park C, Hahn O, Gupta S, et al. Platelet factors are induced by longevity factor klotho and enhance cognition in young and aging mice. Nat Aging.2023:1-12. doi:10.1038/s43587-023-00468-0
Leiter O, Brici D, Fletcher SJ, et al. Platelet-derived exerkine CXCL4/platelet factor 4 rejuvenates hippocampal neurogenesis and restores cognitive function in aged mice. Nat Commun. 2023;14(1):4375. doi:10.1038/s41467-023-39873-9
This article is a rework of a press release issued by USCF. Material has been edited for length and content.