Fisetin as a senotherapeutic
Photo by  Hal Gatewood  on  Unsplash

Photo by Hal Gatewood on Unsplash

To the growing list of senolytics—compounds that can kill senescent cells—we can add yet another: fisetin, a natural compound present in strawberries and many other fruits and vegetables. A recent study has shown that this relatively simple molecule exerts senolytic activity in both mouse and human cells, and can significantly extend the lifespan of laboratory mice.

Senescent cells, which accumulate in the body as we get older and promote age-related deterioration, represent something of a biological paradox. Their genomes are full of DNA lesions, a situation that usually triggers apoptosis (cell death). (A cell with a lot of damaged DNA is at risk of oncogenic mutation, so if a cell can’t repair its DNA, the decent thing for it to do is kill itself so that it doesn’t turn into a tumor.) However, senescent cells stubbornly refuse to die, instead persisting with their damage-riddled genomes and doing nasty things to their neighboring cells, degrading the tissues in which they reside.

We now know that senescent cells survive their own damaged genomes by activating anti-apoptotic pathways. This implies that if we could block these pro-survival mechanisms, we could convince senescent cells to die after all. Indeed, several studies have identified compounds that can inhibit anti-apoptotic proteins and kill senescent cells.

A prominent example is a flavonoid polyphenol compound called quercetin, one of the earliest senolytics to be reported, which can eliminate senescent cells and extend some metrics of healthspan. However, quercetin did not affect all types of senescent cells, and was most effective in conjunction with dasatinib, an anticancer drug with significant side effects. In other words, there is still room in the medicine cabinet for compounds that are more efficacious, have a broader (or at least non-overlapping) cell type specificity, and don’t need to be administered alongside other drugs with associated toxicity.

Hence, a multi-lab team set about testing other members of the flavonoid family for senolytic activity. They screened around a dozen compounds, yielding two hits: fisetin (found in fruits and vegetables) and curcumin, a well-studied component of turmeric. In the paper we’re discussing today, they followed up only on fisetin.

Luminescence assay showing that fisetin eliminates senescent cells (from Figure 3 of Yousefzadeh et al.)

Luminescence assay showing that fisetin eliminates senescent cells (from Figure 3 of Yousefzadeh et al.)

The screen itself was conducted in mouse cells, so the authors confirmed the findings in human fibroblasts. However, the doses involved were very high, in the 10 µM range, raising questions about whether fisetin could be pharmaceutically useful in intact animals.

The ensuing in vivo tests, performed in laboratory mice, yielded impressive results: dietary supplementation with fisetin decreased the expression of a key senescence marker by around 50%. Importantly, the reduction in senescent cells persisted for a month after the mice were returned to a normal (non-supplemented) diet, strongly indicating that fisetin had eliminated senescent cells, or permanently reverted them to a non-senescent state, rather than temporarily altering their behavior. This “hit and run” mode of action means that the drug could be administered acutely, rather than chronically, and still yield its benefits.

The in vivo effect was functionally significant: Fisetin diminished the so-called SASP (“senescence-associated secretory phenotype”), a program of inflammatory gene expression that is largely responsible for the promotion of aging by senescent cells. Moreover, the compound decreased the senescent cell burden in rapidly aging mutant mice as well as genetically normal mice, as well as in explanted human tissue. As with quercetin, fisetin exhibited some cell-type specificity, exerting the greatest benefits in adipose tissue and kidney and the weakest effect on certain immune cell lineages (macrophages and dendritic cells).

Possibly by inhibiting the SASP, the fisetin diet increased median and maximum lifespan by approximately 10%. Critically, the lifespan extension was observed in mice who were already very old when they began the treatment—85 weeks, roughly equivalent to the human age of 75 years.

On the strength of these findings, multiple clinical trials of fisetin as a treatment for age-related frailty are already underway (in the pre-recruitment or recruitment stages).

Moreover, as I pointed out in the context of similar findings regarding the antibiotic azithromycin, it is unlikely that botanical evolution has optimized fisetin as a senotherapeutic—i.e., the chances are good that small tweaks to the molecule could increase its senolytic activity, broaden its cell type specificity, or introduce other improvements.

No need to run to the chemistry lab and start derivatizing fisetin, however, as the authors are way ahead of you. The authors note in their conclusion:

Interestingly, preliminary medicinal chemistry on fisetin has identified analogues with enhanced senotherapeutic activity, suggesting that even more effective flavonoids can be developed for extending healthspan with minor alterations in the structure of fisetin.

Whatever they come up with, I hope it’s strawberry-flavored.