Blood Factor Responsible for Brain Rejuvenation

Platelets may explain how young blood transfusion, physical activity, and the longevity hormone klotho could improve cognitive function and contribute to brain rejuvenation in mice, studies suggest.

A trio of studies conducted by researchers from the University of California San Francisco (UCSF) and the University of Queensland, Australia, found that a blood factor called platelet factor 4 (PF4) may be behind the well-known interventions against cognitive decline.

PF4 is made by platelets, small cell fragments in the blood that form clots and stop or prevent bleeding. As a cognitive enhancer, PF4 helped to improve cognitive function in young mice and recover the sharpness of middle age in old mice.

"The fact that three separate interventions converged on platelet factors truly highlights the validity and reproducibility of this biology. The time has come to pursue platelet factors in brain health and cognitive enhancement," says Dena Dubal, M.D., Ph.D., professor at the University of California, San Francisco.

Overwhelming evidence shows that physical activity can positively affect brain aging and protect against neurodegenerative diseases such as Alzheimer's. Scientists think this may be due to exerkines, the biological compounds released into the bloodstream during exercise.

In a study published in Nature Communications, researchers at the University of Queensland discovered that PF4, which is released from platelets after exercise, results in regenerative and cognitive improvements when injected into old mice. The authors say findings could be used for the development of drug interventions.

"For a lot of people with health conditions, mobility issues or of advanced age, exercise isn't possible, so pharmacological intervention is an important area of research," lead researcher Tara Walker from UQ's Queensland Brain Institute said in a statement.

Injection reduced cognitive deficits

Klotho hormone has been long known for its longevity and cognition-enhancing properties, as well as the ability to increase brain resistance to age-related degeneration. However, when injected into the body, klotho molecules never reach the brain, suggesting that its effects are indirect.

New research published in Nature Aging indicates that PF4 may be the mediator. In the study, administration of klotho hormone in mice increased the levels of multiple platelet factors in plasma, including PF4.

In young mice, PF4 enhanced the formation of new brain connections and cognition, whereas, in old animals, PF4 decreased cognitive deficits. Moreover, it gave both old and young animals a brain boost in behavioral tests. The authors now hope that the klotho hormone could be used therapeutically for cognitive dysfunction.

Researchers at UCSF have previously shown that young mice's plasma— a part of the blood that carries platelets — contains much more PF4 than the plasma of older animals. When injected into old mice, young blood plasma was restorative.

In their new study published in Nature, injecting PF4 into old animals had similar restorative effects as young plasma: it calmed down the aged immune system in the body and the brain. Moreover, old animals who received PF4 performed better on various 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," said Saul Villeda, Ph.D., associate director of the UCSF Bakar Aging Research Institute and the senior author on the paper.

"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," he added.

Identification of PF4 as a cognitive enhancer shows promise in developing new treatments for brain rejuvenation, although further research is necessary to determine if the findings could be applied to humans.