Emerging research indicates that a solitary molecule could play a crucial role in revitalizing aging brains through diverse mechanisms.
A series of three studies aimed at counteracting age-related cognitive decline yielded consistent outcomes—heightened levels of a protein called platelet factor four (PF4) in mice. Consequently, cognitive performance improved in the animals, accompanied by favorable biological indications of brain health. These significant findings were collectively published on August 16 in the journals Nature Aging, Nature, and Nature Communications.
Michael Conboy, a bioengineer from the University of California, Berkeley, who was not directly engaged in the studies, noted, "PF4 may prove to be an effective factor, and this line of research will contribute to advancing it closer to becoming a potential therapeutic agent" for addressing age-related cognitive decline.
A research team led by neuroscientist Dena Dubal from the University of California, San Francisco, explored klotho, a hormone associated with longevity. Their prior investigations demonstrated that injecting klotho into mice enhanced cognition. Considering that klotho molecules are too sizable to breach the blood-brain barrier, the researchers hypothesized that the hormone's brain-related effects are mediated indirectly through a messenger molecule.
In pursuit of this mediator, Dubal's team administered klotho to mice and tracked fluctuations in protein levels within their bloodstream. Levels of platelet factors, particularly PF4, exhibited notable elevation.
PF4, linked to platelets known for their role in clotting and wound healing, puzzled Dubal: "My initial reaction was, what's the connection between platelets and cognitive enhancement? It's quite astonishing."
Another group from the University of California, San Francisco, led by neuroscientist Saul Villeda, previously demonstrated that blood plasma from young mice rejuvenated the brains of older counterparts. Upon comparing plasma from young and aged mice, Villeda's team identified significantly increased PF4 levels in the former.
Serendipitously, Dubal and Villeda exchanged insights from their individual studies and realized both converged on PF4. This mutual discovery prompted discussions with neuroscientist Tara Walker from the University of Queensland, Australia, who had unearthed the PF4-boosting effects of exercise.
Walker's team unveiled that exercise-induced PF4 elevation stimulated neurogenesis, the generation of new nerve cells, in the hippocampus—a brain region pivotal for memory. Significantly, this heightened neurogenesis corresponded to enhanced cognitive advantages.
Taken together, these studies underscored PF4's efficacy in enhancing cognition in mice. Walker's investigation indicated that administering PF4 triggered neurogenesis, subsequently yielding observed cognitive enhancements. Dubal's team additionally noted PF4's augmentation of neural connections in the hippocampus.
Villeda's group delved into the immune system's role and found that injecting PF4 into older mice revitalized their immune systems, leading to reduced levels of inflammatory proteins and diminished brain inflammation.
While PF4 holds promise, it constitutes a single piece within a complex puzzle. Neuroscientist Lida Katsimpardi from the Pasteur Institute in Paris opined that while these findings are valuable, they represent a partial step forward. She commented, "These findings substantially bolster our understanding by unveiling a single factor. While our aim is comprehending the entire puzzle, each factor contributes to the overall picture."
Katsimpardi's own research focuses on GDF11, a protein with similar restorative attributes linked to calorie restriction. The extent of these proteins' contributions remains uncertain. Katsimpardi mused, "This is the question we face daily. Is this molecule the solution? Or do we need more?"
Though primarily conducted in mice, these studies hold relevance for humans as well. Similar to mice, PF4 levels decline with age in humans, and PF4 has also demonstrated the capacity to enhance cognition in mice. In addition to this, Dubal and her team reported in July in Nature Aging that klotho improves cognition in aging monkeys, which exhibit greater brain similarities with humans. However, the exact role of PF4 in this enhancement remains uncertain.
The researchers anticipate initiating human trials centered on PF4-based treatments within the next few years. Emphasizing the significance of vigilant monitoring for potential side effects, they intend to delve deeper into the precise mechanisms underlying PF4's actions within the body and brain. Ultimately, these investigations will determine its potential incorporation into therapeutic approaches, as elucidated by Conboy.