Fisetin Found in Strawberries Clears Senescent Cells in Mice

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. EBioMedicine, 36, 18-28.