Monthly senolytic pulse

Where the pulse scheme comes from

The idea behind the pulse: senescent cells are not to be suppressed permanently but removed in short bursts. Rarely and high instead of daily and low.

The scheme comes from the AFFIRM study at the Mayo Clinic: 40 frail women aged 70 and over, fisetin on 2 consecutive days in 2 consecutive months, against placebo, primary endpoint 6-minute walking distance and gait speed after 1 month. Exactly the right study.

It began on February 6, 2018. The registry entry gives November 1, 2026 as the estimated completion; the status is enrolling by invitation. That is 8.5 years for 40 participants without a single reported value. Small studies with frail older people are slow, and the pandemic fell in the middle. The facts remain: the most frequently cited human study on fisetin has been running for over 8 years without a result. The scheme is thus well founded, but unproven.

Fisetin: a very good first study

That fisetin is on the shelf at all is due to a 2018 paper in EBioMedicine. A group had screened plant compounds in the test tube for which ones kill senescent cells. Fisetin was the best hit.

Then it went into old wild-type mice aged over 20 months, that is, late in life and not lifelong. Compared with control feed, fisetin extended average and maximum lifespan, senescence markers fell in several tissues, and human adipose tissue in the test tube showed the same effect. Late administration, lifespan gain, matching mechanism: you can hardly ask more of a first study.

What the independent testing program found

The Interventions Testing Program is the only place where mouse data are truly replicated: 3 independent sites, genetically heterogeneous mice, publication regardless of outcome. In 2023 it was fisetin’s turn, 600 ppm in the feed from 20 months, in two schemes: continuous or 3 days every 2 weeks.

The result: no significant lifespan extension, in either sex, with either of the two schemes. The second finding weighs more heavily. The program checked whether fisetin does at all what it is known for, and found no reduction in senescence markers: not in the liver, not in the kidney, not in the brain. The authors were therefore unable to answer the actual question at all.

There are real differences from the first study: a different mouse strain, a different dose, a different preparation, different sites, and the authors explicitly restrict their conclusions to the doses and routes of administration used here. The claim is therefore not refuted. But it is unreliable, and for someone buying capsules, that amounts to the same thing.

The gap between study and capsule

The Mayo study tests 20 milligrams of fisetin per kilogram of body weight, so 1,600 milligrams a day for a person weighing 80 kilograms. Commercially available capsules typically contain 100 to 500 milligrams; depending on the product, 3 to 16 capsules would be needed on a pulse day.

This is not a dosage recommendation but a classification: most users take a fraction of what is actually being tested. The pulse on the shelf and the pulse in the protocol are not the same thing.

Quercetin and apigenin do not belong in this protocol

Quercetin appears in combination products as if it were part of the pulse. In the human studies on senolytics, however, it was always included together with dasatinib, never alone. The combination does not exist for convenience: different senescent cell types depend on different survival pathways, and the two substances cover different ones. Selling quercetin on its own makes as much sense as buying one blade of a pair of scissors.

Then there is absorption. A pharmacological review sums it up: oral absorption ranged from 0 to over 50 percent of the dose, half-lives from 0.7 to 2.4 hours, and the data were insufficient to attribute the observed effects to quercetin.

Apigenin is usually lumped in with them but does something different: it is considered senomorphic, not senolytic. Senolytic means the old cells die; senomorphic means they remain and release fewer inflammatory substances. That may be better tolerated, but it is a different goal. There are mouse studies on it and no known human data with clinical endpoints.

What the studies show

EBioMedicine 2018, screening and mouse study

Cell culture screening of plant compounds, fisetin as the best hit. In old wild-type mice aged over 20 months, fisetin extended average and maximum lifespan, with fewer senescence markers in several tissues.

Interventions Testing Program 2023

3 independent sites, genetically heterogeneous mice, 600 ppm fisetin in the feed from 20 months, two schemes. No significant lifespan extension, in either sex and with either scheme, and no reduction in senescence markers in the liver, kidney and brain.

AFFIRM, Mayo Clinic

40 women aged 70 and over with frailty, fisetin on 2 consecutive days in 2 consecutive months against placebo, primary endpoint 6-minute walking distance after 1 month. Start February 6, 2018, completion given in the registry November 1, 2026, status enrolling by invitation. No reported result.

Review on the absorption of quercetin

Across the studies, oral absorption ranged from 0 to over 50 percent of the dose; half-lives were between 0.7 and 2.4 hours. The data were insufficient to clarify whether quercetin can be held responsible for the observed effects.

Where the data are missing

For the pulse scheme, there is no reported endpoint in humans. The only study testing it against placebo has been running for over 8 years and has published neither efficacy nor tolerability. Everything circulating as evidence comes from mice or from open-label pilot studies with the prescription combination in patients.

More serious is that the mechanism is shaky too. In the standardized replication program, it could not even be shown that fisetin removes senescent cells. This means that not only the evidence of benefit is missing, but also the intermediate step on which the product promises rely.

How to do it

The widespread protocol comes from the Mayo study AFFIRM and provides for fisetin alone, on 2 consecutive days in 2 consecutive months, tested at 20 milligrams per kilogram of body weight, so 1,600 milligrams a day at 80 kilograms. Converted to commercially available capsules of 100 to 500 milligrams, you would arrive at 3 to 16 capsules on a pulse day, depending on the product. Quercetin does not belong in this scheme but in the separate combination with the prescription drug dasatinib, and apigenin, with its senomorphic rather than senolytic action, is a different class of action without known human data with clinical endpoints; there is no evidence for the often-mentioned intake in the morning with fat.

This is a description and not a recommendation, because there is no evidence of efficacy for this scheme. AFFIRM has been testing it against placebo since February 6, 2018 and has reported nothing to this day, neither on effect nor on tolerability; the registry lists November 1, 2026 as the estimated completion. In the independent Interventions Testing Program in 2023, fisetin did not extend lifespan, in either sex or with either of the two schemes, and the senescence markers fell neither in the liver nor the kidney nor the brain. This means that not only the evidence of benefit is missing, but also the intermediate step underneath.

Safety

There are no robust safety data for high-dose pulses, because the only placebo-controlled study on this has reported nothing. In food amounts, all three substances are unproblematic. For quercetin, an interaction with blood thinners and some antibiotics is known: anyone who takes medication regularly should clarify high doses with a physician beforehand. The larger price is not paid in euros anyway: anyone who considers their own cell renewal taken care of with a capsule may end up training one session less.

Sources

• Yousefzadeh MJ et al., fisetin screening and mouse study, EBioMedicine 2018
• Harrison DE et al., Interventions Testing Program, fisetin analysis, GeroScience (online December 2023)
• AFFIRM study, Mayo Clinic, registry entry since February 6, 2018
• Pharmacological review on the absorption of quercetin