The Rejuvenation Now Risk-Benefit Analysis of Fisetin as a Senolytic Therapy

The Forever Healthy Foundation's Rejuvenation Now program is engaged in the production of detailed analyses of risk and reward for presently available treatments that may act to slow or reverse aging. I think this is helpful, as a great deal of information exists, but is very scattered, and there is far too much uninformed hype out there. Putting all of the facts together in one place, coupled to a sober assessment of what those facts mean, is a good use of resources. This is particularly true given that senolytic therapies presently exist, and, to the degree to which these treatments successfully clear senescent cells with minimal side-effects, should be expected to produce sizable benefits to health for all old people who use them. Those old people just need to be told, so that they can make an informed choice about their own health.

One of the potential senolytic therapies of interest is a cheap and readily available supplement, fisetin. This is interesting because animal data shows it to be about as good as the dasatinib plus quercetin combination. One might ask how a supplement can be readily available for years, and yet no-one noticed that if you take the whole bottle at once, it significantly reverses inflammatory age-related conditions. Perhaps that is in fact the case, but as the analysis from the Forever Healthy Foundation notes, we just don't know. Human trials are ongoing, and we might expect initial publications from the research groups involved over the next year. This will clarify whether or not fisetin happens to be unusually effective in mice only.

In a sense, either outcome would be surprising. The important parts of the biochemistry of senescent cells, when it comes to the operation of senolytic drugs, are essentially the same between mice and humans. The dasatinib and quercetin combination has been shown to work in humans much as it does in mice when it comes to destroying these cells. Yet fisetin has been readily available and widely used as a supplement for a while, without the sort of attendant murmuring one might expect given the sizable benefits it should produce if it is as senolytic in humans as it is in mice. We shall see what the story is when the clinical trial data for fisetin emerges. Meanwhile, many more self-experimenters are using fisetin than are using the far more proven dasatinib and quercetin combination, given that fisetin is much more easily obtained.

Fisetin Senolytic Therapy Risk-Benefit Analysis

Senolytics are agents that selectively induce apoptosis of senescent cells. Fisetin is a flavonoid polyphenol found in many types of fruits and vegetables that is believed to act as a senolytic in addition to its numerous other known benefits. Although natural senolytics are less potent, compared to the targeted senolytics, they have lower toxicity and are thus, likely to be more readily translatable to clinical medicine. This risk-benefit analysis focuses on the risks and benefits of using fisetin as a senolytic rather than its more common use as a supplement.

There are currently three phase 2 clinical trials underway and the first data is expected to be reported in about a year. The data from the phase 1 trials has not been published. All trials are being conducted by the same investigators at the Mayo clinic using the same treatment protocol. Only two papers directly related to the use of fisetin as a senolytic were identified, neither of which were conducted in humans. The other 5 studies included in the table relate to pharmacokinetics, risk, and lifespan extension.

To the best of our knowledge, there haven't been any studies published on the pharmacokinetics of fisetin in humans. Only one animal study on fisetin has reported any form of toxicity from fisetin use and the authors concluded that the elevations in ALT/AST levels (indications of liver toxicity) were in large part due to the vehicle used to administer the fisetin (DMSO). However, the fisetin + vehicle group showed significantly higher elevations than the vehicle alone group indicating that high doses of fisetin may additionally burden the liver because of its poor bioavailability. At a lower dose (112 mg/kg), fisetin didn't significantly increase apoptosis or lead to liver toxicity. Intermittent dosing and use of a form of fisetin with increased bioavailability are likely to mitigate the risk of liver toxicity.

Fisetin has been shown to decrease senescent cell biomarkers as well as the numbers of senescent cells in a variety of tissues, including ex vivo, human adipose tissue as well as in vivo, in mice. The primary risk mitigation strategy is to wait to commence therapy until clinical trial data has been published that describes the possible benefits and adverse effects. At the current time, the only form and dose that has been tested in phase 1 clinical trials is the so-called "Mayo Protocol". The Mayo Protocol consists of taking 20 mg/kg of oral fisetin on two consecutive days and repeating the same dose, one month later.