Immunity

Japanese Researchers Show Fisetin Alleviates Depression

A new study shows that fisetin, a senolytic compound, reduces depression-like behavior in mice with brain inflammation.

By Daniel R. Miranda, Ph.D.

Highlights: 

  • Many lupus patients suffer from depression, the biological causes of which are not fully understood. 
  • Removing cells in an arrested state known as senescence from the brains of lupus mice reduces depression-like behavior. 
  • Senolytic compounds, drugs that target and remove senescent cells, could help treat depression in lupus patients.  

Senolytic compounds are an exciting new area of research as they have been shown to slow aging and prevent age-related disease by killing senescent cells. One of the most potent senolytics is fisetin, a plant-based compound known as a polyphenol found in foods like strawberries, onions, and grapes with anti-oxidant, anti-cancer, anti-bacterial, and anti-viral properties. Fisetin has been shown to increase lifespan and protect against age-related diseases like neurodegeneration and diabetes. Now, Japanese scientists have found that fisetin reduces depression.

As reported in Frontiers in Immunology, Saito and colleagues from Hokkaido University in Japan show that fisetin reduces depression-like behavior in a mouse model for lupus (lupus erythematosus). These findings give insight into the relationship between aging and neuropsychiatric disorders and how senolytics could treat both. 

Senescent Cells 

Enough stress, such as the stress caused by inflammation, will cause a normal cell to enter a senescent state, protecting the cell from DNA damage. Senescent cells can be either beneficial or harmful. They can be beneficial for embryonic development, wound healing, and tumor suppression, but things start to go wrong when there are too many of them. The accumulation of senescent cells, which occurs with aging, leads to diseases like atherosclerosis, type 2 diabetes, arthritis, lung scarring, and liver disease. 

A major downside to having too many senescent cells is that they secrete pro-inflammatory molecules, which leads to chronic inflammation. The inflammation caused by senescent cells seems to contribute to neurodegenerative diseases like Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. It is the pro-inflammatory properties of senescent cells that brought Saito and colleagues to investigate the role of senescent cells in depression. 

Lupus and Depression 

Lupus is an incurable autoimmune disorder characterized by a hyperactive immune system that damages multiple organs, including the brain. When the immune system attacks the brain, lupus patients are burdened with neuropsychiatric disorders like depression. The root cause of depression is not fully understood, but inflammation may be involved.    

Pro-inflammatory molecules are elevated in lupus patients and can contribute to depression. Since cells go into a senescent state in response to stressors like inflammation, Saito and colleagues hypothesized that lupus-induced inflammation would increase the number of senescent cells in the hippocampus, a brain region associated with depression.  

Depressed Lupus Mice 

To study what would happen in lupus patients, Saito and colleagues used a mouse model for lupus. The lupus mice (MRL/lpr) have a genetic mutation that causes systemic autoimmunity, causing the immune system to attack multiple organs, including the brain, similar to what occurs in lupus patients.

How do we know these mice are depressed? The Japanese scientists determined whether the lupus mice were depressed using a tail suspension test. The researchers held the mice by the tail and measured how long they took to give up on trying to escape. The lupus mice gave up faster than those without lupus, which was interpreted as depression-like behavior. 

Brain Inflammation and Senescence in Lupus 

To confirm that lupus leads to inflammation in brain regions associated with depression, Saito and colleagues measured markers of inflammation in the hippocampus of the lupus mice. They found that the lupus mice had higher levels of inflammation, confirming that lupus leads to inflammation of the hippocampus in mice.  

Next, the number of senescent cells in the hippocampus of the lupus mice was counted. It was found that the lupus mice had more senescent cells than the mice without lupus. This validated the hypothesis of Saito and colleagues, concurring with the idea that inflammation is linked to elevated levels of senescent cells in lupus. 

Fisetin Kills Senescent Cells 

Fisetin is a flavonoid found in many fruits and vegetables. Fisetin is also a senolytic, a molecule that induces the death of senescent cells. Saito and colleagues chose fisetin over other flavonoids/senolytics because it can get to the brain more easily (bypassing the blood-brain barrier). 

The Hokkaido University researchers induced senescence in neurons grown in a dish using radiation. They then treated the senescent neurons with fisetin. As would be expected from a senolytic, the researchers found that fisetin decreased senescent cells in a dose-dependent manner. These findings demonstrated that fisetin kills senescent cells. 


(Saito et al., 2021| Front. Immunol.) Fisetin Kills Senescent Cells. Cells not exposed to radiation (Ctrl) and cells exposed to radiation (IR) were both treated with an increasing dose of fisetin. (B) Graph showing a decrease in cell count with increasing doses of fisetin. (C) Graph showing a reduction of senescent cells with increasing doses of fisetin.  

Fisetin Alleviates Depression 

After showing that fisetin kills senescent cells in a dish, Saito and colleagues determined whether fisetin could kill the senescent cells found in the hippocampus of the lupus mice. To do this, they fed the lupus mice fisetin for four weeks, which reduced the high number of senescent cells in the lupus mice. In contrast, the lupus mice not given fisetin died before four weeks.

Next, Saito and colleagues looked at fisetin’s ability to alleviate depression in the lupus mice. The researchers again used the tail suspension test. They found that after treatment with fisetin, the mice did not give up on escaping as quickly. This demonstrated that the fisetin had alleviated depression in the lupus mice. 


(Saito et al., 2021| Front. Immunol.) Fisetin Kills Senescent Cells and Alleviates Depression in Lupus Mice. (left) Lupus mice (Ipr) fed fisetin had a reduction in immobility time (time spent not trying to escape), meaning they were less depressed after four weeks (post-treatment). (right) Fisetin treatment reduced senescent cells in the lupus mice. 

Senolytics Could Treat Depression and Slow Aging 

The data of Saito and colleagues suggest that fisetin could alleviate depression in lupus patients. They demonstrate, in mice, that fisetin alleviates depression-like behavior by killing senescent cells and reducing inflammation in the hippocampus. These findings have implications not only for depression in non-lupus patients but also for diseases related to aging. 

Chronic inflammation is associated with aging and age-related diseases, including neurodegenerative disease. The findings of Saito and colleagues help reveal that it may be possible that senescent cells are contributing to age-related inflammation. Some scientists even consider senescent cells as the root cause of aging, which could be linked to the pro-inflammatory molecules they secrete. 

Inflammation is also related to depression, not just the depression associated with lupus. A recent study showed that having a neuropsychiatric disorder like major depressive disorder can predict higher levels of inflammation and deficits in executive function, a sign of dementia later in life. This lends to the idea that inflammation not only contributes to depression but also contributes to aging. 

Overall, if senescent cells are at least partially to blame for the inflammation associated with aging and depression, then senolytics like fisetin can potentially treat both. By killing senescent cells responsible for secreting pro-inflammatory molecules, senolytic compounds may mitigate inflammation and reduce depression and age-related diseases.

Source

Saito Y, Miyajima M, Yamamoto S, Sato T, Miura N, Fujimiya M, Chikenji TS. Accumulation of Senescent Neural Cells in Murine Lupus With Depression-Like Behavior. Front Immunol. 2021 Nov 3;12:692321. doi: 10.3389/fimmu.2021.692321. PMID: 34804003; PMCID: PMC8597709.

 

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