The aging brain undergoes profound changes, many of which can lead to cognitive decline and increased susceptibility to diseases like Alzheimer’s and epilepsy. One underexplored area of research is the role of the brain’s endocannabinoid system in brain aging and disease. Often referred to as the brain’s natural “chill-out” system, endocannabinoids help regulate neural activity and prevent over-excitation. However, as we age, disruptions in this system may trigger inflammation by generating molecules called prostaglandins, which have been linked to cognitive decline.
With support from a Knight Initiative Catalyst Grant, Stanford research teams led by neuroscientists Ivan Soltesz and Katrin Andreasson are investigating how this pathway might be harnessed to promote brain resilience. By exploring whether targeting links between the endocannabinoid system and prostaglandins can restore cognitive function, this research could open doors to novel therapies for aging-related brain conditions.
We spoke with members of the research team for the latest in our video series on new approaches promoting healthy aging and resilience against neurodegenerative disease. We also followed up with Peter Klein, Ph.D., of the Soltesz lab, to learn more about the lab's hypothesis, findings, and potential therapeutic implications of this work.
Q&A with Peter Klein
Can you elaborate on the hypothesis behind this research?
Sure. Generally, in the brain, the more active neurons become, the more you tend to get the release of endocannabinoids.
These are short-lived signaling molecules, similar to some compounds found in marijuana, like THC, but made by the brain. They bind to incoming neurons and act like a brake on subsequent stimulation. Our lab has been studying circuits that dampen excessive neural activity, including the role of endocannabinoids, for decades.
So, our initial hypothesis was that in aging—and potentially in brain diseases like epilepsy—neurons become hyperactive, releasing more endocannabinoids. These endocannabinoids are then converted into prostaglandins, another type of signaling molecule, which triggers inflammation in the brain. This inflammation might contribute to the cognitive decline commonly observed even during healthy aging. Our hypothesis was initially developed with former post-doc Jordan Farrell, who now has his own lab at Boston Children’s Hospital.
How are you testing this hypothesis?
We’re studying healthy aging in animals [at ages] that are roughly equivalent to humans in their late 60s to 80s. We use cutting-edge approaches to peer directly into the brain to measure neural activity and observe endocannabinoid release in real time. We can also look at markers of inflammation in the body and perform behavioral tests of the animals’ cognitive function.
What have you observed in your experiments with aged mice?
One of our most striking findings is that elevated prostaglandin levels, particularly PGE2, correlate with cognitive deficits in aged mice. By injecting a drug to block the enzymes responsible for converting endocannabinoids into prostaglandins, specifically PGE2, we’ve been able to reduce inflammation and observe significant improvements in spatial memory tasks.
How could targeting the endocannabinoid system or prostaglandins lead to new treatments for aging-related cognitive decline?
What’s cool is that this approach isn’t just about prevention—it’s aiming to be restorative. By targeting the pathways involved in converting endocannabinoids into prostaglandins, we’ve shown that it’s possible to reverse cognitive decline in aged mice, restoring their brains to a more youthful state. Again, these are mice that are at an age where they already have these deficits. We’d love to see some of this research eventually translated into a restorative therapy for use in humans.
Could this approach also have implications for conditions like epilepsy?
Yes. While our focus is on aging, the same pathways are also potentially implicated in conditions like epilepsy, where inflammation and hyperexcitability are major factors. In fact, we know that as people age and reach a later stage in life, they are more likely to start having seizures. Our research might also open doors to new treatments for other neurological conditions.
How has working with Kati Andreasson’s lab enhanced your ability to tackle brain aging?
We were drawn into aging research by the great research community fostered at Stanford by the Knight Initiative. Our collaboration with Kati Andreasson’s lab has been essential because our lab is new to aging research. Their expertise in aging models and inflammatory pathways complements our work on neural activity and endocannabinoid imaging. We can peer into the brain and look at how these different molecules are released in real time as the brain is actually functioning. There’s a really nice synergy between the labs that has allowed us to explore how inflammation and brain health intersect in aging.
What are the next steps for this research?
We’re interested in looking at how therapies targeting this pathway affect neural circuits, and whether we can hone in on specific circuits disrupted in aging and rescue them. Our goal is to figure out if we can target specific brain areas to have the maximum benefit and minimize side effects.
