A single molecule may play a central role in ruvenating aging brains, albeit in multiple ways, new research suggests.
Studies in mice of three different techniques for combating the cognitive decline that accompanies aging found that they all increase levels of a protein called platelet factor four, or PF4. This in turn improved cognitive performance and biological signs of brain health, three research groups report August 16 in Nature Aging, Nature and Nature Communications.
“PF4 may be an effective factor, and this kind of work will help bring it toward a therapeutic agent” for age-related cognitive decline, says bioengineer Michael Conboy of the University of California, Berkeley, who wasn’t involved in the work.
One of the research groups, led by neuroscientist Dena Dubal of the University of California, San Francisco, was studying klotho, a hormone linked to longevity. Injecting the hormone into mice boosts cognition, but since klotho is too large to cross the blood-brain barrier, it must act on the brain indirectly via a messenger.
To search for this intermediary, Dubal’s team injected mice with klotho and measured changes in the levels of six proteins in the blood. PF4 increased the most, the team reports in Nature Aging.
Platelets are known for their role in wound healing and clotting, and they release proteins — including PF4-called platelet factors into the blood. “My first reaction was, what do platelets have to do with cognitive enhancement? This is crazy,” Dubal says. Follow-up work in mice found that PF4 enhanced neural connections in the hippocampus, a region crucial for memory.
Another UC San Francisco team, led by neuroscientist Saul Villeda, had previously shown that blood plasma from young mice rejuvenates the brains of elderly mice. A look at how young plasma differs from old revealed that young plasma contains much more PF4, the team reports in Nature. Injecting PF4 into old mice returned the immune system to a more youthful state, lowering levels of inflammatory proteins and reducing inflammation in the brain.
Separately, neuroscientist Tara Walker, of the University of Queensland in Brisbane, Australia, and colleagues found that exercise boosts PF4 in mice. Delivering PF4 directly to mice’s brains spurs new nerve cell growth in the hippocampus, the team reports in Nature Communications.
The new studies all show that PF4, on its own, improves cognition. More and more research is pointing toward a link between the immune system, cognitive decline and diseases like Alzheimer’s,” Villeda says.
The main limitation of these studies is that few findings in mice translate into safe and effective therapies in people. But in humans, as in mice, PF4 declines with age.
In July, Dubal and colleagues reported that klotho improves cognition in aging monkeys, whose brains are much more similar to ours. But whether that improvement involves PF4 is not known.
Researchers plan to start testing treatments based on PF4 in humans within the next few years, Villeda says.
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