Fisetin: Antioxidant and Senolytic

Aging brings with it a myriad of health issues including an increased risk of diabetes, heart disease, cancer, and neurodegenerative diseases. A supplement that can mitigate the root cause of some of these age-related conditions is a very alluring idea. But does the research back it up?

This article delves into the recent research on a natural compound called fisetin that may prove to be a key anti-aging component. Or...it could be just one more way to keep mice healthy. We'll probe the evidence for using fisetin as a longevity compound and explore the research on supplemental fisetin's health benefits. We will also explore the timing and dosages of fisetin used in clinical trials. Finally, you will be able to draw your own conclusions as to whether there is sufficient evidence for using fisetin at this time.

Read through the research and decide for yourself whether fisetin is worth trying or is something to keep an eye on for the future.

Fisetin

Fisetin is a natural flavonol found in several types of fruits and vegetables. It is being studied for a variety of health benefits including preventing complications from diabetes to heart disease, and as a longevity compound. Fisetin has shown in several recent studies to clear out senescent cells holding a lot of promise for healthy aging.

Cellular senescence:

At the end of a cell's life, a cell becomes senescent, giving off signals that it needs to be removed by the immune system. The chemical signals that it gives off are pro-inflammatory cytokines, so it becomes a source of low-level inflammation. Senescent cells sometimes are called 'zombie cells'. They aren't quite dead, but no longer function as a cell.

The process of cellular senescence is a natural part of the cell cycle, and important in both wound healing and in stopping cells from becoming cancerous. You want a damaged cell (or cancerous) to stop the cell cycle, hang out a flag, and say it is time to be killed off and recycled.

Cellular senescence is triggered by a number of circumstances including[ref]:

  • Telomeres being too short for replication (learn more about telomeres here)
  • Injuries, burns, UV exposure, etc
  • Too much oxidative stress in the cell
  • Mitochondrial dysfunction
  • Toxicity due to misfolded proteins

Senescent cells increase with age:

Younger people with a good immune system have no problem clearing out senescent cells. The process of cell-cycle arrest and clearing out cellular insults works well, just as it is supposed to.

The number of senescent cells increases with age. Older people often have a problem clearing out all of the senescent cells, and this relates directly to some of the diseases associated with aging.

I mentioned above that cells hang out a flag when they become senescent. The senescent cells' 'flag' waves when they need to be killed off and recycled. The wave is a chemical signal of inflammatory cytokines. Local inflammation can occur, and neighboring cells also become senescent when the senescent cells aren't cleared quickly. The secretion of inflammatory cytokines by senescent cells is known as 'senescence-associated secretory phenotype' (SASP).[ref]  Stopping this low-grade inflammation is one goal in longevity science.

Clearing out senescent cells has shown to prevent the onset of age-related diseases in animal studies. This increases healthspan (number of years of healthy living), as well as increasing lifespan (in animals).[ref]

The animal studies on this are pretty cool, and they clearly show that a buildup of senescent cells is one major aspect of the diseases of aging. Human studies on longevity are harder to fund and take a much longer time (of course).

Targeting senescent cells, likewise, seems to be an effective way to combat some of the problems of aging.[ref]

Two pathways exist by which increased senescent cells could lead to the chronic diseases of aging:

  • First, stem cells becoming senescent can lead to a decreased ability for stem cells to renew tissue.
  • Second, an increased number of senescent cells can cause chronic inflammation.[ref]

Why don't senescent cells die? In addition to the SASP signals calling for the cell to stop dividing and be destroyed through apoptosis, senescent cells also upregulate something called the senescent-cell anti-apoptotic pathway (SCAP). This pathway prevents apoptosis or the clearing out of cells.

Clearing out senescent cells with senolytics:

Senolytics are compounds that target and clear out senescent cells. They do this by targeting the SCAP pathway. Senolytics are a relatively new concept, with the first studies on them published in 2015. This concept of being able to clear out senescent cells in aging has prompted a lot of interest, and a bunch of studies have been published on senolytics in the past few years.[ref]

Initial work with senolytics focused on the similarities between cancer cells that don't divide and senescent cells. This led researchers to experiment with a chemotherapy drug called dasatinib. Further research showed that dasatinib plus quercetin, a natural compound found in fruits and vegetables, was even more effective at clearing senescent cells and increasing healthspan (animal studies).[ref][ref]

Fisetin has shown to act as a senolytic in several promising new studies.

Studies on fisetin as a senolytic:

 


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