What do you do about cells that refuse to die?
That was the question researchers at the Mayo Clinic asked themselves in the mid-2010s. Senescent cells — cells that have stopped functioning but that the body can't get rid of — had been identified as one of the fundamental drivers of biological aging. The problem was mapped. Now they needed to find a way to do something about it.
The first breakthrough came in 2015, when Mayo Clinic's research team showed they could extend lifespan and improve health in mice by selectively eliminating senescent cells. They used a combination of the drug dasatinib and the flavonoid quercetin — the very first senolytic pair. The concept of "senolytics" was born: compounds that can selectively target senescent cells without harming healthy ones.
But quercetin was just the beginning.
Fisetin: the most potent natural senolytic
In 2018, the same research group published a study in EBioMedicine testing ten naturally occurring flavonoids side by side. The question was simple: is there something better?
The answer was fisetin. A flavonoid found in strawberries, apples and onions — but in concentrations so low you'd need to eat roughly 130 strawberries to reach 250 mg. In the study, fisetin outperformed every other compound tested, including resveratrol, curcumin and quercetin. In aged mice, fisetin reduced markers of cellular senescence across multiple tissues, restored tissue homeostasis and extended both median and maximum lifespan.
Most remarkably, the treatment worked despite being initiated late in life.
Intermittent dosing: why two days is enough
One of the most important insights from the research isn't about which substance works, but about how it should be administered.
Senolytic compounds don't work like conventional supplements. They don't need to be taken daily. Instead, research shows they're most effective as short, concentrated interventions followed by rest. Researchers call it a hit-and-run mechanism: a brief exposure that temporarily disables senescent cells' survival networks and triggers programmed cell death. Then the body's own systems take over.
It's a fundamental departure from how we normally think about supplements. Senescent cells don't need constant pressure — they need a signal strong enough to breach their defenses. Two days is enough. Then a month of rest before the next cycle.
This intermittent protocol has become the standard across clinical senolytic research.
Fisetin vs synthetic senolytics
For a long time, the big question was: can a natural flavonoid truly compare with more advanced approaches?
In a 2025 study published in Aging Cell, researchers at the University of Colorado Boulder addressed that question directly. They compared intermittent fisetin treatment with two of the most sophisticated methods available: genetic removal of senescent cells (a laboratory technique not possible in humans) and the synthetic drug ABT-263, also known as Navitoclax.
The results were striking. Fisetin improved physical function and grip strength in aged mice to the same extent as both alternatives. No statistically significant difference. A natural flavonoid — matching the most advanced tools research has to offer.
The researchers also observed that fisetin treatment counteracted age-related changes in skeletal muscle gene expression, including reduced levels of senescence-related genes.
Piperlongumine: a senolytic compound from long pepper
Fisetin isn't the only natural compound with senolytic potential. In 2016, researchers published a study in the journal Aging identifying piperlongumine — a substance found naturally in long pepper (Piper longum) — as an entirely new type of senolytic compound.
Piperlongumine was shown to selectively induce cell death in senescent cells by triggering apoptosis, without affecting healthy cells to the same degree. In combination with other senolytic substances, it demonstrated synergistic effects.
Fisetin clinical trials: where the research stands in 2025
Interest in senolytics has exploded. Clinical trials are underway at the Mayo Clinic, Johns Hopkins, Harvard and several other institutions. Fisetin is being tested in studies covering everything from frailty and bone tissue to post-COVID and vascular function.
Most studies remain preclinical — conducted in cell cultures and animal models. But clinical trials are growing in number, and the early data is promising. A study at Mayo Clinic's Long COVID clinic showed that 64% of patients who received fisetin reported significant improvements in symptoms including fatigue, muscle pain and orthostatic hypotension.
The field is young. But the direction is clear. And it points toward the same thing: short, intensive interventions with natural senolytic compounds — with fisetin at the centre.
Read about why senescent cells accumulate →
Sources: Zhu et al., "New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors," EBioMedicine, 2018. Murray et al., "Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging," Aging Cell, 2025. Xu et al., "Senolytics improve physical function and increase lifespan in old age," Nature Medicine, 2018. Wang et al., "Discovery of piperlongumine as a potential novel lead for the development of senolytic agents," Aging, 2016. Hurt et al., "Longitudinal Progression of Patients with Long COVID Treated in a Post-COVID Clinic," Journal of Primary Care & Community Health, 2024.
