• Fisetin targets biologically aged cells in mice and human tissues.
  • Administration of fisetin to mice late in life reduced age-related disease characteristics and extended median and maximum lifespan.

When cells are stressed and need to prevent the replication of damaged DNA, which could lead to cancer, they engage in a process called senescence — an arrest in cell growth and replication. But senescence is a double-edged sword, as senescent cells play a causal role in driving aging and age-related diseases. So, the search has been on for naturally occurring compounds that eliminate senescent cells to promote healthy aging and longevity.

Yousefzadeh and colleagues from the Scripps Research Institute and the University of Minnesota published a study in EBioMedicine showing that the natural product fisetin can therapeutically kill senescent cells in mice and human tissues. Late-life intervention with this natural, yellow plant pigment found in fruits and vegetables, such as strawberries, apples, persimmons, onions, and cucumbers, was sufficient to yield a potent health benefit in mice.

“Our results suggest that supplementation or even intermittent treatment with this safe, natural product could improve healthy aging, even in elderly individuals,” stated the authors in the article.

Senolytics kill off senescent cells

Addressing cell senescence is fundamental to reducing the severity or delaying the onset of age-associated diseases. Although senescent cells are rare in young people, they increase with age in multiple tissues. Drugs able to selectively kill senescent cells termed senolytics or senotherapeutics have been identified that improve many aspects of aging in mouse models of accelerated and natural aging.

For example, the combination of the chemotherapeutic dasatinib and the natural plant pigment quercetin improves many aspects of aging in mouse models of accelerated and natural aging. Similarly, Navitoclax decreases the abundance of some but not all human and mouse senescent cell types in cell cultures.

Although these cancer therapeutics could be repurposed as senolytics, they can cause considerable toxicity including an immune cell deficiency called neutropenia and substantially reduced levels of blood components that trigger clotting called platelets. So, safer and improved senotherapeutic drugs and combinatorial approaches are needed to eliminate senescent cells safely from multiple organs or even within a single tissue. For these reasons, Yousefzadeh and colleagues set out to identify natural compounds with more potent senolytic activity.

Fisetin is a senotherapeutic in mice and human explants

In this study, the researchers screened a panel of plant metabolites called flavonoids for therapeutic senolytic activity. Out of the 10 flavonoids screened in mouse and human cells, fisetin was most effective at reducing senescent markers. Since fisetin is a natural compound found in various fruits (strawberries, apples, mangoes, persimmons, kiwis, and grapes) and vegetables (tomatoes, onions, and cucumbers) that humans readily consume, it has a good chance of applying to actual human beings. Importantly, no adverse effects of fisetin have been reported, even when given at high doses.

Yousefzadeh and colleagues treated 2-year-old mice with fisetin (100 mg/kg) for 5 consecutive days orally, which they then analyzed for senescent cells. They chose to look for senescent cells in fat tissue since it typically has a clear upregulation of senescence markers, has a significant increase in the fraction of senescent cells, and injection of senescent fat cell precursors called pre-adipocytes is sufficient to induce frailty in young mice. What they found was that the short-term treatment with fisetin significantly reduced the fraction of senescent markers and cells in mouse fat.

To determine if fisetin also reduces senescence in human fat tissue, Yousefzadeh and colleagues treated adipose explants removed during surgery with fisetin in lab dishes. The tissue explants were treated for 2 days with fisetin, washed, and cultured for an additional day before measuring senescence. Fisetin treatment caused a significant reduction in the percent of senescent cells as well as the gene activity of senescent markers. These data support the translational potential of fisetin to reduce senescent cell burden.

(Yousefzadeh et al. 2018 | EBioMedicine) Acute fisetin treatment reduces senescent cell burden in aged healthy mice and human explants. These plots show the effects of fisetin on the senescent burden in aged healthy mice (left) and human (right) explants. Two-year-old mice were given fisetin (100 mg/kg) or vehicle for 5 days by oral gavage and analyzed for senescent cells (SA-β-gal+) three days later. Human adipose tissue explants were treated with fisetin (20 μM) for two days and then analyzed for senescent cells one day later. In both plots, there is a significant reduction in senescent cells with fisetin treatment. 

To determine if fisetin-mediated clearance of senescent cells impacts the health or lifespan of mice, mice were continuously fed a diet containing fisetin (500 mg/kg) beginning at 85 weeks of age, roughly equivalent to age 75 years in humans. Importantly, chronic administration of fisetin to mice late in life improved tissue maintenance, suppressed age-related disease characteristics, and extended median and maximum lifespan. 

(Yousefzadeh et al. 2018 | EBioMedicine) Late-life intervention with fisetin in healthy, aged mice extends lifespan. The left plot shows the survival of both male and female mice that were treated with 500 mg/kg fisetin or fed a control diet with no drug at 85-weeks of age (>20 months). The right plot shows the median lifespan of the same cohort of mice, with each dot representing an individual animal. These plots show that fisetin significantly increased the lifespan of aged mice.

Can fisetin be used to treat age-related diseases in humans?

Taken together, these data establish that the natural product fisetin has senotherapeutic activity in mice and human tissues and that reducing the senescent cell burden in mice with fisetin even late in life is sufficient to have a significant health impact. “These results suggest that we can extend the period of health, termed healthspan, even towards the end of life,” said Dr. Paul D. Robbins, a senior author on the study and currently the leader of the Biology of Aging Medical Discovery Team at the University of Minnesota. “But there are still many questions to address, including the right dosage, for example.”

What’s key is the safety profile of fisetin is known in humans. This means that fisetin can be tested for its ability to reduce senescent cell burden and alleviate dysfunction in elderly subjects through clinical trials.