Key Points:
- Fisetin reduces the number of senescent neurons in the brain.
- Supplementing with fisetin lowers the number of microglia and astrocytes — brain cells with roles in nervous system inflammation and immunity — that are senescent.
- Fisetin reduces a blood marker protein for brain and nervous system injury called S100B.
Fisetin, a naturally-occurring flavonoid found in fruits and vegetables like strawberries, cucumbers, apples, and onions, has been shown to enhance rodent cognition and promote neuron survival. Fisetin’s cognition enhancing effects in rodents have mainly been attributed to its antioxidant and antiinflammatory activities. However, whether fisetin acts as a senolytic agent to reduce senescent neurons and enhance cognition hasn’t been clearly defined. Moreover, because it can be difficult to extrapolate findings from small organisms like rodents, testing whether fisetin eliminates senescent neurons in larger animals like sheep could carry more meaning for humans.
Published in Antioxidants, Huard and colleagues from the Steadman Philippon Research Institute in Colorado show that fisetin injections lower senescent neurons in a key brain region for cognition called the cortex in aged sheep. Fisetin also reduces other senescent brain cells involved in neuroinflammation and brain immunity called microglia and astrocytes. Additionally, fisetin significantly lowers a blood protein marker for brain injury and disease called S100B. These findings suggest that fisetin’s cognition-enhancing capabilities may arise from lowering nervous system senescent cells and reducing age-related nervous system damage.
Fisetin Reduces Senescent Brain Cells and Blunts Age-Related Brain Injury
To find whether fisetin diminishes senescent cortex neurons, Huard and colleagues measured a protein senescence marker, p16, in neurons of aged sheep. The researchers found that treatment with fisetin significantly reduced senescent neurons. These results suggest that fisetin reduces brain senescent neurons to possibly enhance cognition.
Other cells involved in neuroinflammation and brain immunity, microglia and astrocytes, may become senescent and contribute to age-related cognitive decline. Along those lines, Huard and colleagues tested whether fisetin reduces senescent microglia and astrocytes in the cortex of aged sheep. Interestingly, they found that injecting the sheep with fisetin significantly reduced the abundance of senescent microglia and astrocytes. These data show that fisetin reduces brain senescent cells, including senescent microglia and astrocytes, which potentially improves the brain’s immune response and reduces brain inflammation.
Because chronic inflammation from senescent brain cells can facilitate age-related damage to neurons, Huard and colleagues measured how fisetin affects a blood protein marker for brain damage, S100B. The researchers found that fisetin more than cut in half S100B levels in blood. These findings provide evidence that fisetin can enhance brain function by reducing age-related brain deterioration.
The study’s findings showed that fisetin reduces senescent brain cells, namely, neurons, microglia, and astrocytes in aged sheep. Reducing microglia and astrocyte senescence may alleviate neuroinflammation, which could enhance brain health and improve cognition. The study’s main limitation was that it didn’t examine how fisetin affects cognition in the aged sheep. If the researchers tied reduced senescent cells to improved cognition, the results could have provided evidence that fisetin improves brain function in larger animals.
The study also examined whether fisetin reduces senescent gene activity in organs like the lung, spleen, heart, and liver. The data show that fisetin reduces senescent gene activity in the livers and lungs of aged sheep, but results for the other organs were mixed. Future research should confirm the effectiveness of fisetin in different organs for a better picture of benefits against age-related diseases.
Questioning Whether Sheep Research Surpasses the Benefits of Rodent Research
The study’s authors claimed that this study has high value, because it was based on larger animals like sheep that have better applicability to human research than smaller mammals like rodents. While this proposition is interesting, based on evolutionary science, rodents are more closely related to humans than sheep, which could actually make rodent research more pertinent to humans. At any rate, the study did confirm for the first time that fisetin reduces brain senescent cells, which may help explain how it protects healthy neurons and improves cognition in other aged animals like rodents.
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