Cardiac glycosides
Cardiac glycosides as senolytics (ouabain, digoxin, digitoxin, proscillaridin A)
Written by Aaron CuhaReviewed Sep 2026
Also known as: Ouabain, Digoxin, Digitoxin, Proscillaridin A, Cardioglycosides
Two 2019 papers reported that cardiac glycosides kill senescent cells in culture and in mice. Digoxin separately has one of the largest outcome trials in cardiology, 6,800 patients, which measured heart failure and not senescence. These are two different bodies of evidence and they do not transfer to each other.
Overview
Cardiac glycosides inhibit the sodium-potassium ATPase pump. Two independent groups reported in 2019 that this makes them senolytic: senescent cells sit slightly depolarised with a higher internal hydrogen ion concentration, so pump inhibition tips them into apoptosis at concentrations that spare normal cells. The Nature Metabolism paper named ouabain as a broad-spectrum senolytic acting partly through induction of the pro-apoptotic protein NOXA, and cleared senescent cells from irradiated and old mice. The Nature Communications paper showed the same class effect in human cells in culture and eradicated xenografted tumours in mice with a senescence-inducing plus senolytic combination. A 2021 paper found the opposite in another setting, reporting that apoptosis resistance in senescent cells is an intrinsic barrier to cardiac glycoside senolysis, so the finding is not uniform.
The human record for digoxin is large and it is about the heart. The Digitalis Investigation Group trial randomised 6,800 patients with heart failure and an ejection fraction of 0.45 or less to digoxin or placebo for an average of 37 months. Mortality was unaffected: 1,181 deaths on digoxin and 1,194 on placebo, risk ratio 0.99. Hospitalisation for worsening heart failure fell from 34.7 percent to 26.8 percent, risk ratio 0.72. That trial is the reason digoxin is still prescribed. It measured nothing about senescence and it is not evidence that digoxin clears senescent cells in people.
One trial connects the two. NCT06240403, at the University of Leeds, is a randomised, quadruple-masked phase 2 of digoxin 0.125 mg daily versus placebo for three months in 100 people with heart failure and type 2 diabetes, with a laboratory primary endpoint: senescence-associated beta-galactosidase expression in cultured adipose microvascular endothelial cells. It was verified in September 2026 as NOT YET RECRUITING. No senolytic has improved a clinical outcome in a randomised trial in humans, and the first randomised human test of a cardiac glycoside as a senolytic has not begun enrolling and is not measuring a clinical outcome.
Mechanism of action
Established in human cells in culture and in mice: inhibition of the sodium-potassium ATPase depolarises the membrane and acidifies the cell. Senescent cells are already partially depolarised, which is the proposed basis of selectivity, and ouabain additionally induces the pro-apoptotic protein NOXA. Work in BRAF-V600E senescent cells indicates the senolysis requires the signalling arm of pump binding, not just ion transport blockade. In humans, the established pharmacology of digoxin is inotropic and neurohormonal, at plasma concentrations chosen for the heart, not for senolysis.
Human evidence
Two separate things, which must not be merged. Digoxin has decades of human data including a 6,800-patient randomised outcome trial, all of it about heart failure. The senolytic human record is one registered phase 2 with a laboratory endpoint that has not started enrolling.
- Digitalis Investigation Group trial, 6,800 patients randomised, average 37 months: no effect on mortality (risk ratio 0.99), fewer hospitalisations for worsening heart failure (26.8 versus 34.7 percent, risk ratio 0.72). United States government and industry supported. It measured no senescence endpoint.
- NCT06240403, University of Leeds, phase 2, 100 planned, digoxin versus placebo for three months in heart failure with type 2 diabetes. Primary endpoint is senescence-associated beta-galactosidase in cultured adipose endothelial cells. Status NOT YET RECRUITING as of September 2026.
- No published human study has measured senescent cell burden after cardiac glycoside dosing.
What this does not tell you: The heart failure evidence cannot tell you anything about senescence, and the senolytic laboratory work cannot tell you what digoxin does to senescent cells in a living person. Even if the Leeds trial reports a positive biomarker result, a change in a laboratory marker is not a clinical outcome. Cardiac glycosides have a narrow therapeutic index and established arrhythmia risk, which nothing in the senolytic literature alters.
Reading the research record
This entry exists because two evidence bases with the same drug name get quoted as though they were one. Digoxin has a large, old, high-quality human trial record, and it was assembled to answer whether digoxin keeps people with heart failure alive and out of hospital. The answer was: no change in mortality, fewer heart failure hospitalisations. That record does not transfer to the senolytic claim by proximity.
The senolytic claim rests on two 2019 papers in human cell culture and mice, one of which carries an erratum, and is contradicted in part by a 2021 paper reporting intrinsic apoptosis resistance in senescent cells. The first randomised human test of the senolytic idea, NCT06240403, has a biomarker primary endpoint and had not begun enrolling as of September 2026. Any mention of these drugs carries the narrow therapeutic index and arrhythmia risk, which is why self-experimentation with digoxin for ageing is a materially different proposition from self-experimentation with a supplement.
The evidence, charted
Fig. 1 · evidence composition
2of 6 citations (33%) are in people
Counted from the citation list on this page. The Human count is the same number shown in the badge at the top. Both understate any literature larger than the sources we cite.
Fig. 2 · evidence over time
Evidence spans 4 distinct years, 1997 to 2026, counted from the citation list on this page.
Fig. 3 · legal status at a glance
US
Approved
UK
Approved
AU
Approved
CA
Approved
Approved in all four jurisdictions shown. A jurisdiction's classification is a regulatory fact, not a verdict on the science; see Legal status below for the full text and any notes.
Key studies & citations
- Human1997
The effect of digoxin on mortality and morbidity in patients with heart failure
6,800 patients with heart failure and ejection fraction 0.45 or less randomised to digoxin or placebo, average follow-up 37 months. Mortality unchanged: 1,181 deaths (34.8 percent) versus 1,194 (35.1 percent), risk ratio 0.99, 95 percent confidence interval 0.91 to 1.07. Hospitalisation for worsening heart failure fell from 34.7 to 26.8 percent, risk ratio 0.72. This is cardiology evidence and says nothing about senescence.
New England Journal of Medicine - Human2026
Digoxin and Senolysis in Heart Failure and Diabetes Mellitus
University of Leeds, phase 2, randomised, quadruple-masked, estimated enrolment 100, digoxin 0.125 mg daily versus placebo for three months. Primary outcome is senescence-associated beta-galactosidase expression in cultured adipose microvascular endothelial cells, a laboratory marker. Status NOT YET RECRUITING, verified live September 2026.
ClinicalTrials.gov - In vitro2019
Cardiac glycosides are broad-spectrum senolytics
Human cells in culture plus mice. Ouabain sensitised senescent cells to apoptosis, mediated in part by induction of the pro-apoptotic BCL-2 family protein NOXA, and eliminated senescent cells accumulating after irradiation and in old mice, including senescent preneoplastic cells.
Nature Metabolism - In vitro2019
Identification and characterization of Cardiac Glycosides as senolytic compounds
Human cells in culture plus mouse xenografts. Membrane depolarisation and intracellular acidification were proposed as the selectivity mechanism. A senescence-inducing plus senolytic combination eradicated xenografted tumours in mice and eliminated senescence-induced lung fibrosis. The paper carries an erratum published in 2020.
Nature Communications - In vitro2021
Ouabain and chloroquine trigger senolysis of BRAF-V600E-induced senescent cells by targeting autophagy
Cell culture. Senolysis by ouabain required signal transduction through the sodium-potassium ATPase, not ion transport blockade alone: a pump inhibitor that blocked transport without triggering signalling was not senolytic.
Aging Cell - In vitro2021
Apoptosis resistance of senescent cells is an intrinsic barrier for senolysis induced by cardiac glycosides
Cell culture, and it points the other way. Senescent cells in this work were intrinsically resistant to apoptosis in a manner that limited cardiac glycoside senolysis. Published alongside the 2019 findings, it is part of why this class is not a settled senolytic.
Cellular and Molecular Life Sciences
Frequently asked questions
Does digoxin clear senescent cells in people?
Nobody knows. No published human study has measured senescent cell burden after dosing a cardiac glycoside. One randomised phase 2 at the University of Leeds plans to measure it in adipose endothelial cells, and as of September 2026 it had not started recruiting.
Does the big digoxin heart failure trial support taking it for ageing?
No. The Digitalis Investigation Group trial randomised 6,800 people and measured death and hospitalisation in heart failure. Mortality was unchanged. It measured no senescence endpoint and enrolled no healthy participants.
Which cardiac glycoside is the senolytic in the papers?
Ouabain is the compound named in the Nature Metabolism work, with digoxin, digitoxin and proscillaridin A described as sharing the class effect. Ouabain is not a marketed medicine in the United States.
Is the senolytic finding disputed?
Partly. A 2021 paper in Cellular and Molecular Life Sciences reported that intrinsic apoptosis resistance in senescent cells is a barrier to cardiac glycoside senolysis, which points against the 2019 results. Both are in cell culture and both are on this page.