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Today, we want to bring your attention to a recent mouse study on fisetin, a commonly available supplement that has proven effective at destroying senescent cells.

What are senescent cells?

As we age, increasing amounts of our cells enter into a state known as senescence. Normally, these cells destroy themselves by a self-destruct process known as apoptosis and are disposed of by the immune system. Unfortunately, as we age, the immune system declines, and increasing numbers of senescent cells escape apoptosis and accumulate in the body.

Senescent cell accumulation is one of the main processes of aging, and it can be considered a core reason that we age and suffer form age-related diseases.

These senescent cells do not divide or support the tissues of which they are a part; instead, they emit a range of harmful pro-inflammatory signals. Their presence causes many problems, including impairing tissue repair and increasing chronic inflammation, and is linked with the progression of osteoarthritis [1-2], atherosclerosis [3], cancer [4], and other age-related diseases.

Even worse, the harmful signals created by senescent cells can also encourage other nearby cells to enter the same senescent state; this is often called the bystander effect.

It has suggested that finding ways to clear these problem cells might be a way to prevent or delay age-related diseases, and, indeed, positive results have been shown in mouse studies [5-7]. Therapies that remove senescent cells are commonly known as senolytics or senotherapeutics.

Fisetin shows promise as a senolytic

Fisetin is a plant polyphenol from the flavonoid group that is encountered in many plant species. It is found in various fruits and vegetables, most notably strawberries, but is also present in apples, onions, and cucumbers.

It comes from the same family of compounds as another senolytic compound, quercetin; however, while quercetin only appears to work as a senolytic when used in combination with dasatinib, it appears that fisetin works on its own.

Until recently, there was only cell data for fisetin, but a new study in mice has shown some impressive results against senescent cells [8].

Abstract

Senescence is a tumor suppressor mechanism activated in stressed cells to prevent replication of damaged DNA. Senescent cells have been demonstrated to play a causal role in driving aging and age-related diseases using genetic and pharmacologic approaches. We previously demonstrated that the combination of dasatinib and the flavonoid quercetin is a potent senolytic improving numerous age-related conditions including frailty, osteoporosis and cardiovascular disease. The goal of this study was to identify flavonoids with more potent senolytic activity.

A panel of flavonoid polyphenols was screened for senolytic activity using senescent murine and human fibroblasts, driven by oxidative and genotoxic stress, respectively. The top senotherapeutic flavonoid was tested in mice modeling a progeroid syndrome carrying a p16INK4a-luciferase reporter and aged wild-type mice to determine the effects of fisetin on senescence markers, age-related histopathology, disease markers, health span and lifespan. Human adipose tissue explants were used to determine if results translated.

Of the 10 flavonoids tested, fisetin was the most potent senolytic. Acute or intermittent treatment of progeroid and old mice with fisetin reduced senescence markers in multiple tissues, consistent with a hit-and-run senolytic mechanism. Fisetin reduced senescence in a subset of cells in murine and human adipose tissue, demonstrating cell-type specificity. Administration of fisetin to wild-type mice late in life restored tissue homeostasis, reduced age-related pathology, and extended median and maximum lifespan.

The natural product fisetin has senotherapeutic activity in mice and in human tissues. Late life intervention was sufficient to yield a potent health benefit. These characteristics suggest the feasibility to translation to human clinical studies.

These researchers report fairly impressive results from fisetin, as its effectiveness is close to that of dasatinib, a cancer drug considered top of the current senolytic drugs. According to these results, fisetin is able to destroy 25-50% of senescent cells, depending on the tissue/organ type on which it is tested.

During the study, the researchers gave the mice 100 mg/kg daily over the course of five days. This dosage was very high, although, given the generally low bioavailability of flavonoids, it is not unusual.

Conclusion

The search for effective senolytic agents is currently at fever pitch, and with companies such as UNITY Biotechnology entering human trials with potentially even more powerful therapies to remove senescent cells, it is a truly exciting time to be alive.

Senolytics represent the first true rejuvenation biotechnology that directly addresses a particular aging process, and we are now very close to seeing if the results seen in other species will translate. While we should, of course, remain grounded, given the history of the poor translation of results from mice to men, we can also be somewhat optimistic given that these therapies do target aging processes common to both species.

Literature

[1] Jeon, O. H., Kim, C., Laberge, R. M., Demaria, M., Rathod, S., Vasserot, A. P., … & Baker, D. J. (2017). Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nature medicine, 23(6), 775-781.

[2] Xu, M., Bradley, E. W., Weivoda, M. M., Hwang, S. M., Pirtskhalava, T., Decklever, T., … & Lowe, V. (2016). Transplanted Senescent Cells Induce an Osteoarthritis-Like Condition in Mice. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, glw154.

[3] Childs, B. G., Baker, D. J., Wijshake, T., Conover, C. A., Campisi, J., & van Deursen, J. M. (2016). Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science, 354(6311), 472-477.

[4] Coppé, J.-P., Desprez, P.-Y., Krtolica, A., & Campisi, J. (2010). The Senescence-Associated Secretory Phenotype: The Dark Side of Tumor Suppression. Annual Review of Pathology, 5, 99–118

[5] Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., Van De Sluis, B., … & van Deursen, J. M. (2011). Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature, 479(7372), 232-236.

[6] Zhu, Y., Tchkonia, T., Pirtskhalava, T., Gower, A. C., Ding, H., Giorgadze, N., … & O’Hara, S. P. (2015). The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging cell, 14(4), 644-658.

[7] Roos, C. M., Zhang, B., Palmer, A. K., Ogrodnik, M. B., Pirtskhalava, T., Thalji, N. M., … & Zhu, Y. (2016). Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging cell.

[8] Yousefzadeh, M. J., Zhu, Y., McGowan, S. J., Angelini, L., Fuhrmann-Stroissnigg, H., Xu, M., … & McGuckian, C. (2018). Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine36, 18-28.

About the author

Steve Hill

Steve serves on the LEAF Board of Directors and is the Editor in Chief, coordinating the daily news articles and social media content of the organization. He is an active journalist in the aging research and biotechnology field and has to date written over 500 articles on the topic as well as attending various medical industry conferences. In 2019 he was listed in the top 100 journalists covering biomedicine and longevity research in the industry report – Top-100 Journalists covering advanced biomedicine and longevity created by the Aging Analytics Agency. His work has been featured in H+ magazine, Psychology Today, Singularity Weblog, Standpoint Magazine, and, Keep me Prime, and New Economy Magazine. Steve has a background in project management and administration which has helped him to build a united team for effective fundraising and content creation, while his additional knowledge of biology and statistical data analysis allows him to carefully assess and coordinate the scientific groups involved in the project. In 2015 he led the Major Mouse Testing Program (MMTP) for the International Longevity Alliance and in 2016 helped the team of the SENS Research Foundation to reach their goal for the OncoSENS campaign for cancer research.
  1. October 7, 2018

    I can’t find any data on the bioavailability of Fisetin in humans after consumption of Fisetin containing supplements. Without it there is no basis for taking a Fisetin supplement. Do you know of any such data involving Fisetin supplements?

    • October 7, 2018

      Eric, aside from the human cell data in this study and anecdotal stories from some people there is no human data. For that reason we do not recommend anyone starts taking it unless they intend to conduct a proper controlled experiment and have the appropriate scientific background and experience to do so.

  2. October 15, 2018

    “the researchers gave the mice 100 mg/kg daily over the course of five days”. If I try the same 5 day course, what’s the potential downside (other than it not effectively clearing out senescence cells). Are there potential serious side effects?

    • October 23, 2018

      I tried something close to their numbers translated to my size…per other sites that would be 500mg/60kg subject – I’m 90kg so I took 700mg. The effect seems to be that my immune system dips. My mucousal membrane seems to swell a bit, almost to discomfort…but that has been it for me. I’ve backed down to just one day every 2 weeks and will move to one day a month (I’ve got a lifetime to pull down the senescent load). I also take quercetin 150mg with the fisetin. Hope it works for us all :-)

  3. October 27, 2018

    I’ve been taking 600mg Fisetin in 25ml olive oil for the past 3 days. I also added 1600mg Quercetin +500mg Bromelain for the hell of it. The fat and bromelain are thought to increase absorption. and quercetin has been shown to increase the effect of dasatinib.So far no adverse side effects, feel fine. Nothing else to report, I’m in my 30s so perhaps to young to see any major effects. I’ll continue for another 2 days and then try again in 6 months. Perhaps with higher dose.

  4. January 3, 2019

    There is evidence to suggest that oral bioavailability of Fisetin is roughly 44%. Not sure if I can link in comments, but there is a clinical trial that states this (M Dzakwan et al 2017 IOP Conf. Ser.: Mater. Sci. Eng. 259 012016) . Curious if anyone can confirm that I need to multiply my oral mg/kg dose by .441 to calculate the required dose. I am trying to achieve a specific concentration through oral administration. Is this possible?

  5. July 15, 2019

    One issue with senolytics is: increasing necessity of the compound. Let’s say you have removed 10% SENS cells of your body, including your immune cells. Someone has to ensure that remaining 90% of cells would replicate safely and fill up the void. Doing so rate of senescence itself will go up and you need more exogenous senolytics.

    • mm
      July 15, 2019

      If this was true then the mice would die sooner rather than later in studies testing senolytics, but they do not, they tend to live either longer lifespans or enjoy longer healthspans but die at a similar time as they normally would. The results do not support this accelerated senescence hypothesis.

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