Longevity Briefs: An ‘Exercise Molecule’ That Improves Memory In Old Mice

Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

Why is this research important: Exercise is one of the most important things anyone can do to improve their health and wellbeing. Better yet, research suggests that you can gain significant benefits from exercise at any age. We like to say that it’s never too late to get fit, but unfortunately that’s not entirely true – some people are too elderly and frail to exercise effectively, resulting in a vicious cycle of health decline. A drug that could mimic some of the beneficial effects of exercise would be incredibly useful for such people.

One benefit of exercise is the formation of new neurons in the brain, as well as improved memory and learning. Molecules called exerkines, which are released by various organs during exercise, are thought to be partly responsible for these benefits. In this study, researchers investigate a specific exerkine called PF4 (platelet-derived factor 4). As its name implies, this exerkine is released by platelets.

What did the researchers do: In this study, researchers first injected young adult mice with PF4 and studied the effects on neuron formation and development in the brain, and on the genes involved in these processes. They also tried genetically altering mice so that they would not produce PF4, or gave them antiplatelet drugs, to see if this would have the opposite effect in the brain.

Finally, researchers investigated whether PF4 injections could improve cognitive function in 23 20 month-old mice, which are roughly equivalent to 70 year-old humans. In all cases, mice injected with saline solution were used as controls.

Key takeaway(s) from this research:

• PF4 treatment was associated with neuron development in the hippocampus, but not with an increase in stem cell numbers or synaptic plasticity
• Genetically altered mice lacking PF4 or mice whose platelets were depleted through drugs had fewer developing neurons and did not benefit from exercise as much as controls
• PF4 treatment in old mice was associated with improved learning and memory.

Young adult mice who received PF4 had more developing neurons in the part of the hippocampus involved in memory formation, but did not have more neural stem cells than those injected with saline. This could mean that PF4 works by helping stem cells to develop and survive, rather than by stimulating their multiplication. This was consistent with the genetic sequencing, which showed that genes involved in stem cell differentiation and development were upregulated. PF4 didn’t have a significant effect on synaptic plasticity (the ability of neurons to strengthen or weaken their connections with other neurons), suggesting that this established effect of exercise is down to other mechanisms.

Mice lacking the ability to produce PF4 showed the opposite effects in the brain – fewer developing neurons in the hippocampus. This defect wasn’t improved by exercise, suggesting that PF4 plays an important role in the health of this brain region. Similar results were observed in mice given antiplatelet drugs – 18 month old mice given antiplatelet drugs didn’t benefit as much as control mice. One point of note is that platelet counts generally decline among elderly humans.

Finally and most importantly, researchers found that 20 month old mice treated with PF4 had significantly improved performance in various memory tests when compared with controls. They were more willing to explore new locations and learnt to associate locations with negative stimuli more rapidly than control mice. Diphtheria toxin, which selectively kills new neurons, abolished these benefits, suggesting that neuronal development was responsible for said benefits rather than some other effect of PF4.

How can we apply this knowledge today:

These are exciting results if you’re a mouse, but what do they mean for humans? It’s far too early to tell, but one thing that is clear in humans is the relationship between exercise and brain health. Research suggests that if you exercise more, you will not only protect yourself against neurodegenerative diseases, but also experience day-to-day improvements in memory and learning.