PF4 Released by Platelets a Common Factor in Multiple Interventions Known to Reduce Neuroinflammation

Chronic inflammation of brain tissue is characteristic of aging and neurodegenerative conditions. The worse the inflammation, the worse the outcome. Lasting, unresolved inflammation in the absence of the usual causes of inflammation such as injury or infection occurs in aged tissues for a variety of reasons, including the pro-inflammatory signaling of senescent cells and triggering of innate immune responses by the mislocalization of mitochondrial DNA that occurs as a result of mitochondrial dysfunction. Current methods of suppressing inflammation are crude, a matter of blocking specific inflammatory signals passing between cells. This affects both excessive chronic inflammatory signaling and necessary inflammatory signaling involved in defense against pathogens, regeneration from injuries, and so forth. It is hoped that more sophisticated means can be found.

One approach to finding better ways to downregulate inflammation is to decipher the signaling produced during interventions that are known to reduce age-related inflammation without greatly affecting the normal inflammatory response. That is the thrust of today's research materials, in which scientists identify a common signal molecule and regulatory path to dampen inflammation that is triggered during heterochronic parabiosis, in which the circulatory systems of an old mouse and a young mouse are joined, during exercise, and as a result of increased levels of the longevity-associated protein klotho. This is interesting work, as is usually the case whenever commonalities are found in divergent types of treatment.

A Secret in the Blood: How PF4 Restores Youth to Old Brains

For years, scientists have known that the anti-aging hormone klotho, infusions of young blood, and exercise each improve brain function in older mice. But they didn't know why. Now, researchers have identified platelet factor 4 (PF4) - a small protein released by blood platelets - as a common denominator behind all three. Platelets are blood cells that normally release PF4 to alert the immune system and clot blood at wounds. The researchers found that PF4 also rejuvenates the old brain and boosts the young brain, potentially opening the door to new therapies that aim to restore brain function, if not tap into a fountain of youth.

In 2014, researchers found that blood plasma from young mice restored brain function in old animals. His team then found that young plasma contained much more PF4 than old plasma. Moreover, just injecting PF4 into old animals was about as restorative as young plasma. It calmed down the aged immune system in the body and the brain. Old animals treated with PF4 performed 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. 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."

A decade ago, researchers showed that the hormone klotho enhances brain function in young and old animals and also makes the brain more resistant to age-related degeneration. But klotho, injected into the body, never reached the brain. So, how? Researchers found that one connection was PF4, released by platelets after an injection of klotho. PF4 had a dramatic effect on the hippocampus, where memories are formed in the brain. In particular, PF4 enhanced the formation of new neural connections at the molecular level. It also gave both old and young animals a brain boost in behavioral tests.

Exercise can keep the mind sharp for decades. In 2019, researchers found that platelets released PF4 into the bloodstream following exercise. When they tested PF4 on its own, it improved cognition in old animals. "We can now target platelets to promote neurogenesis, enhance cognition, and counteract age-related cognitive decline."

Platelet factors attenuate inflammation and rescue cognition in ageing

Identifying therapeutics to delay, and potentially reverse, age-related cognitive decline is critical in light of the increased incidence of dementia-related disorders forecasted in the growing older population. Here we show that platelet factors transfer the benefits of young blood to the ageing brain. Systemic exposure of aged male mice to a fraction of blood plasma from young mice containing platelets decreased neuroinflammation in the hippocampus at the transcriptional and cellular level and ameliorated hippocampal-dependent cognitive impairments.

Circulating levels of the platelet-derived chemokine platelet factor 4 (PF4) (also known as CXCL4) were elevated in blood plasma preparations of young mice and humans relative to older individuals. Systemic administration of exogenous PF4 attenuated age-related hippocampal neuroinflammation, elicited synaptic-plasticity-related molecular changes and improved cognition in aged mice. We implicate decreased levels of circulating pro-ageing immune factors and restoration of the ageing peripheral immune system in the beneficial effects of systemic PF4 on the aged brain. Mechanistically, we identified CXCR3 as a chemokine receptor that, in part, mediates the cellular, molecular and cognitive benefits of systemic PF4 on the aged brain. Together, our data identify platelet-derived factors as potential therapeutic targets to abate inflammation and rescue cognition in old age.


"Moreover, just injecting PF4 into old animals was about as restorative as young plasma. It calmed down the aged immune system in the body and the brain. Old animals treated with PF4 performed better on a variety of memory and learning tasks."

Interesting. Does this put some doubt into the dilution argument for plasma transfusions?

Posted by: KV at August 30th, 2023 4:22 PM
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