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Brain & Neurons

Latest Findings: Fisetin Confers Anti-Aging Impact Against Brain Senescence

Researchers find that fisetin cuts inflammation-promoting senescent brain cells and reduces brain injury in aged sheep.

By Bennett M. Sherman

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.

"Comparison of p16 marker for senescence in neurons (NEUN) between fisetin-treated (red bar) and non-treated sheep (blue bar) in the cortex gray matter (neuron cell bodies) and cortex white matter (neuronal projections or axons). Fisetin injections significantly reduce senescent neurons.
(Huard et al., 2023 | Antioxidants) Fisetin injections significantly reduce cortex senescent neurons.A marker for senescence (p16) in neurons (NEUN) showed reduced abundance with fisetin treatment (red bar) compared to non-treated sheep (blue bar) in B) cortex gray matter — neuron cell bodies — and cortex white matter — neuronal projections (axons) that connect neurons.

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.

Comparison of senescent astrocytes and microglia in gray matter (E, H) and white matter (F, I) with and without fisetin treatment. Fisetin-treated samples are represented by red bars, while non-treated samples are represented by blue bars. Fisetin reduces the number of senescent astrocytes (GFAP labeled) and senescent microglia (labeled with p16 and IBA1) in both gray and white matter.
(Huard et al., 2023 | Antioxidants) Fisetin reduces senescent astrocytes and microglia. In gray matter (E) and white matter (F), fisetin (red bars) reduced the number of senescent (p16 labeled) astrocytes (GFAP labeled). In gray matter (H) and white matter (I), fisetin (red bars) reduced the number of senescent microglia (labeled with p16 and IBA1) out of the total microglia (IBA1 labeled) compared to non-treated microglia (blue bars).

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.

Fisetin's impact on the blood protein marker for age-related nervous system injury, S100B. Fisetin treatment (red bar) significantly reduces blood levels of the S100B protein marker associated with brain and nervous system injury, by more than half.
(Huard et al., 2023 | Antioxidants) Fisetin lowered the blood protein marker for age-related nervous system injury, S100B. Fisetin treatment (red bar) more than cut in half the blood levels of the S100B protein marker for brain and nervous system injury.

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.

Model and Dosage

Model: Six to seven-year-old female sheep

Dosage: 100 mg/kg of fisetin on two consecutive days per week for eight weeks by intravenous infusion

Source

Huard CA, Gao X, Dey Hazra ME, Dey Hazra RO, Lebsock K, Easley JT, Millett PJ, Huard J. Effects of Fisetin Treatment on Cellular Senescence of Various Tissues and Organs of Old Sheep. Antioxidants (Basel). 2023 Aug 21;12(8):1646. doi: 10.3390/antiox12081646. PMID: 37627641; PMCID: PMC10451965.

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