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Preface

This risk-benefit analysis is part of Forever Healthy's "Rejuvenation Now" initiative that seeks to continuously identify potential rejuvenation therapies and systematically evaluate their risks, benefits, and associated therapeutic protocols to create transparency.

Section 1: Overview 

Motivation

Senolytics are agents that selectively induce apoptosis of senescent cells. Fisetin is a flavonoid polyphenol found in many types of fruits and vegetables (Arai et al., 2000) 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 RBA focuses on the risks and benefits of using fisetin as a senolytic rather than its more common use as a supplement.

Key Questions 

This RBA seeks to answer the following questions:

• Which health and/or longevity benefits result from the use of fisetin as a senolytic? 

• Which risks are involved in the use of fisetin as a senolytic (general and method-specific)?

• What are the potential risk mitigation strategies?

• Which method or combination of methods of using fisetin as a senolytic are most effective?

• Which of the available methods are safe for use?

• What is the best therapeutic protocol available at the moment?  

Impatient readers may choose to skip directly to Section 6 for the conclusion and tips on practical application. 

Section 2: Methods

Analytic model

The RBA has been prepared based on the principles outlined in A Comprehensive Approach to Benefit-Risk Assessment in Drug Development ( Sarac et al., 2012 ). 

Literature search

A literature search was conducted on Pubmed and the Cochrane Library using the search terms shown in Table 1 . Titles and abstracts of the resulting studies were screened and relevant articles downloaded in full text. The references of the full-text articles were manually searched in order to identify additional trials that may have been missed by the search terms.

Because of the small number of papers available on the topic, we also searched for studies in which fisetin was found to influence any of the 6 known Senescent Cell Anti-Apoptotic Pathways (SCAPs). 

Table 1: Literature Search 

Recommended Reading

The following sites offer information on fisetin as a senolytic at a consumer level and are useful as an introduction to the topic:

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  • Animal Data Shows Fisetin To Be A Surprisingly Effective Senolytic - fightaging.org

  • Fisetin May Be A Low Hanging Fruit For Aging - leafscience.org 

  • Fisetin: A Powerful Senolytic That Extends Health And Lifespan - alivebynature.com 

Abbreviation list

Section 3: Existing evidence

Summary of ongoing clinical trials 

There are currently 3, phase 2 clinical trials underway (clinicaltrials.gov) 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. 

Summary of results from preclinical trials  (animals & in vitro)

Only 2 papers directly related to the use of fisetin as a senolytic were identified, neither of which were conducted in humans (Yousefzadeh et la., 2018; Zhu et al., 2017). The other 5 studies included in the table relate to pharmacokinetics, risk, and lifespan extension. 

Table 2: Preclinical trials

Section 4: Risk-Benefit Analysis

Decision Model

Risk and benefit criteria

The decision profile is made of up risk and benefit criteria extracted from the outcomes of the above-mentioned papers. The benefit criteria are organized by category and include the type, magnitude, and duration of the benefit as well as its perceived importance to the patient. The risk criteria are organized by category, type, severity, frequency, detectability, and mitigation. All are assigned numerical values: 

1 = low

2 = moderate

3 = high

The numerical values for both risk and benefit criteria are then summarized serving as the justification for the weighting in the following column.

Weight

The criteria are weighted on a value scale to enable comparison (based on the relative importance of a difference). Risk and benefit criteria are assigned to either low (1-1.66), medium (1.67-2.33), or high (2.34-3) weighted categories.

Weighting is independent of data sets and the final weights are based on consensus with justification based on the preceding columns of the table.

Score

Each category is assessed according to the performance of fisetin therapy against the comparator (physiological aging) whereby a numerical value is assigned for each criterion -1 (inferior), 0 (equivalent or non-inferior) and +1 (superior) to the comparator.

Uncertainty

Uncertainty is determined according to the amount and quality of the evidence, whether it came from human or animal studies and whether methodological flaws, conflicting studies, or conflicts of interest (funding) by the authors are present. Human evidence is initially assigned a score of "1", evidence from rodent studies, "2", and in vitro or lower animal studies, "3". The uncertainty score is then adjusted by upgrading or downgrading using the above-mentioned criteria. 

Weighted score

The weights and scores are multiplied to produce weighted scores that enable direct comparison (-3 → +3) and then adjusted using the uncertainty score. Weighted scores may be upgraded where the uncertainty of the evidence is low or downgraded where the uncertainty of the evidence is high. 

Benefit assessment 

Table 4: Benefit assessment