The potential explanation for why exercise helps in maintaining youthful brains could lie in blood proteins.
Platelet factor 4 (PF4), a substance found in the blood, has been associated with the mental enhancements derived from exercise, the advantages of blood transfusions, and a protein connected to longevity in three distinct studies. These processes promote cognitive improvements, making PF4 a notably influential blood factor. The research was conducted by two teams from the University of California San Francisco (UCSF) in the US and the University of Queensland in Australia.
Platelets, fragments of cells crucial in the clotting process, not only serve as physical plugs to stop bleeding but also contain granules releasing chemicals that encourage aggregation. Among these factors, PF4 contributes to the immune system’s response to injury and infection.
Now, its role extends to anti-aging mechanisms, orchestrated by an enzyme known as klotho, abundantly expressed in the brain, liver, and kidneys.
“PF4, along with young blood, and klotho, seems to communicate a message to the brain, prompting it to enhance its function. We are starting to decipher the language behind this rejuvenation.”
– UCSF anatomist Saul Villeda,
In the young blood study, PF4 injections administered to older mice displayed a reduction in brain inflammation and an enhancement in the animals’ memory. Essentially, some of the age-related decline was reversed through this process.
This study extends prior research on parabiosis, which explores the rejuvenating effects of blood from younger humans or other animals. A notable characteristic of younger blood is its higher PF4 content, as evidenced in this research.
In the second study involving mice, scientists successfully linked PF4 to the membrane protein klotho, previously known for its cognitive enhancement properties. It appears that PF4 assists in transmitting this cognitive enhancement to specific brain regions.
After klotho injections, both young and old mice showed improvement in behavioral tests, subsequently triggering PF4 release. This augmentation facilitated the formation of new connections in the hippocampus, the brain area responsible for memory formation.
Lastly, the third study revealed that exercise prompts an increased release of PF4 into the bloodstream of mice. PF4 was observed to play a role in generating new brain cells and enhancing memory functions in older mice.
We are aware that exercise contributes to maintaining mental sharpness, and PF4 seems to be involved in this process. In the future, there might be opportunities to develop therapies that harness the benefits of exercise for individuals unable to engage in regular physical activity.
Although these studies were conducted on mice, it is anticipated that these findings will likely apply to the human body as well. This suggests that PF4, as a “messenger of brain health,” could potentially offer multiple avenues for future treatments.
“Realizing that three separate interventions coincidentally converged on platelet factors left us astounded. This truly underscores the validity and reproducibility of this biological discovery.”
UCSF neurologist Dena Dubal
Abstract
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 population1. 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.