Fisetin - an effective senolytic

Originally published in the blog; moved here.
For those unfamiliar with the topic, accumulation of senescent (old, damaged, no longer replicating) cells in our tissues and organs is one of the reasons why our organs lose their functionality and why we age. Not only those old cells malfunction, they also secret pro-inflammatory signals (Jian-Lin Res, 2009) and produce toxic substances into the extra-cellular environment, thus leading to many age-related diseases. Moreover, they translate the senescent phenotype to the neighboring cells suggesting to them to assume the same senescent expression.  

When we are young, our immune system promptly eliminates the senescent cells. As we grow older, this house-cleaning process slows down.  
Elimination of the senescent cells, along (ideally) with periodic activation of telomerase (telomere lengthening enzyme/process), is one of very promising anti-aging strategies. I will cover that approach in detail in one of later posts. 

A senolytic is a compound or a drug or a supplement that selectively kills senescent cells leaving healthy young cells unaffected. 
Fisetin is a flavonoid, a polyphenol found in small concentrations in fruits and vegetables such as strawberry, apple, persimmon, grape, onion, and cucumber. See the fisetin content in food at the end of the post.
Fisetin is close in structure to quercetin, but not as well studied. ​

Besides its senolytic properties, Fisetin has also been long known to be an anti-oxidant and to have anti-inflammatory and anti-cancer properties (Maher P, 2015). In addition, Fisetin is not only neuroprotective like other flavonoids, which stems from their anti-oxidant properties, but it is also neurotrophic (causes growth of new brain cells) (Sagara, 2004).
Studies on mice and human tissues have also identified that fisetin acts as a senolytic.
A recent study (Yousefzadeh M, 2018) looked at 11 promising senolytic compounds, including curcumin and quercitin, and found fisetin to be the most effective. 
 
The main findings and conclusions from the study were:
  • Fisetin targets and destroys senescent cells both in mice and, ex vivo, in human fat tissue;
  • Even with late in life intervention, mice fed with Fisetin lived 10-15% longer than control mice. That is a 50% increase in the remaining life after treatment with fisetin;
  • Long-term administration of Fisetin led to higher glutathione levels (our natural powerful anti-oxidant);
  • Fisetin decreased pro-inflammatory signaling.

Dosage

What we know - 
  • To date, there are no completed studies (clinical trials) of fisetin on humans. The above study was done on mice and on human fat tissue placed in a petri dish;
  • ​This publication (Anroop B, 2016), provides animal to human dose conversion ratios; and human to mice is 1-to-12 (mice dose [in "per kg of body weight"] divided by  12 should be considered for humans). We can use this conversion ratio to convert the dose in the mice study;
  • In the above Fisetin study (Yousefzadeh M, 2018), normal/wild-type (vs. genetically engineered to have a pre-disposition to disease and health issues) mice were given orally intermittently (6 to 8 weeks of age, then 12 to 14 weeks of age) - 100 mg/kg of body weight. That was the dose found to be effective as a senolytic for the mice. That will be approximately 8.2 mg/kg of body weight in humans (100 mg/12). Translating that to a 60-kg/132 lb. human, that will be ~ 500 mg of Fisetin a day, or ~ 600 mg of Fisetin a day for a 75 kg/165 lb person, for extended periods of time;
  • The above study also tested Fisetin on human fat tissue in a petri dish; the tissue was exposed to fesitin for 48 hours; the conclusion is that fisetin works on human tissue (not only on mice); what is unclear is what the oral dose would be to achieve the same tissue concentration and the senolytic effect; 
  • Mayo Clinic is currently conducting a human trial of Fisetin: 20/mg/kg/day, orally for 2 consecutive days, for 2 consecutive months (2 cycles of two days with a month break) to see if it can reduce frailty and inflammation in elderly women. The 40 study participants are 70 to 90 years old. The dose translates to 1.2 g/d for a 60-kg/132 lb  person or 1.5 g/d for a 75 kg/165 lb person. 

Toxicity. How much is safe?
​
  • Currently, none of the studies with Fisetin revealed any toxicity of the compound at any level. The maximum level of Fisetin tested in another mice study (Currais, 2014) was 2000 mg/kg of body weight orally, for 2 consecutive days (acute toxicity test). No signs of toxicity were observed with the Fisetin administration at that level.
  • If we translate that into human dose: 14 g/d for a 60 kg/132lb person or 18 g/d for a 75 kg/165 lb person. Please keep in mind that those 14 and 18 g/d are a mathematical calculation - this dose has NOT been tested on humans. 
 
Other relevant studies and information:
  • the average dietary intake of naturally occurring fisetin in fruit and vegetable is 0.1 - 1 mg/day;
  • strawberries have the highest natural levels of fisetin. A clinical trial (Chen T, 2012) of 60 g/day of freeze-dried strawberries (approximately 9 - 10 mg of Fisetin a day; that is over 100 times less than the dose in the Mayo Clinic trial) showed a reversal of pre-cancerous lesions in humans and an improvement in several other health markers. Limitations: 1. it's unclear to what extent that anti-tumor effect stems from fisetin alone vs. also from other compounds in strawberries; 2. the anti-tumor dose and senylitic dose may be different. Having said that, consuming lots of strawberries may be an option for those who prefer to not take supplements;
  • Fisetin is not a patented compound and is available from many nutraceutical companies as a supplement. 

What we have no information about
  • Degree of the dose dependency of fisetin and the optimal dose. In other words, will fisetin be as effective or how much less effective in smaller doses? Or will it have even more senolytic (anti-aging) effect in larger doses? 
  • The optimal dosage for the senolytic effect.

Fisetin as a Senolytic. Summary

  • Fisetin has been shown to be a very effective senolytic compound for mice, and may possibly be a very effective senolytic for humans;
  • The dosage currently used in a clinical trial is 20 mg/kg of body weight for two consecutive days, then a month break and a second round. If you decide to try Fisetin, I would limit the dosage at the level used in that study;
  • The orally administered dose that was found effective in mice as a senolytic will likely translate to 8.3 mg/kg of body weight in humans for prolonged periods of time;
  • Lots of strawberries in a diet will provide a little bit of Fisetin for those who prefer food sources to supplements (a pound of fresh strawberries contains about 70 mg of Fisetin).  

Additional References and Literature. Will be expanded 

https://www.ebiomedicine.com/article/S2352-3964(18)30373-6/pdf

Phase 2 human trial on Fisetin - https://clinicaltrials.gov/ct2/show/NCT03430037

​https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3689181

https://www.ncbi.nlm.nih.gov/pubmed/15312169/