The DOI matches its Crossref record; 67 of the 71 references it cites were found in a registry or an index; 4 of the 40 sources its claims cite were checked for support.
Cardiac glycosides are broad-spectrum senolytics
Open accessAbstract
Senescence is a cellular stress response that results in the stable arrest of old, damaged or preneoplastic cells. Oncogene-induced senescence is tumor suppressive but can also exacerbate tumorigenesis through the secretion of pro-inflammatory factors from senescent cells. Drugs that selectively kill senescent cells, termed senolytics, have proved beneficial in animal models of many age-associated diseases. Here, we show that the cardiac glycoside, ouabain, is a senolytic agent with broad activity. Senescent cells are sensitized to ouabain-induced apoptosis, a process mediated in part by induction of the pro-apoptotic Bcl2-family protein NOXA. We show that cardiac glycosides synergize with anti-cancer drugs to kill tumor cells and eliminate senescent cells that accumulate after irradiation or in old mice. Ouabain also eliminates senescent preneoplastic cells. Our findings suggest that cardiac glycosides may be effective anti-cancer drugs by acting through multiple mechanism. Given the broad range of senescent cells targeted by cardiac glycosides their use against age-related diseases warrants further exploration.
Overview
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Written from the paper’s full text.
TL;DR
Cardiac glycosides, especially ouabain, act as broad-spectrum senolytics that preferentially kill senescent cells across oncogene-, therapy-, replicative-, and irradiation-induced models. The effect involves apoptosis partly through NOXA and Na⁺/K⁺-ATPase inhibition, and ouabain also reduces senescent cells and inflammation in old mice and preneoplastic lesions.
Key findings
- Screening the 1,280-compound LOPAC library in IMR90 ER:RAS oncogene-induced senescence and etoposide-induced senescence identified ouabain and CGP-74514A as compounds that selectively killed both senescent models; ouabain also killed cells senesced by doxorubicin, palbociclib, or replicative exhaustion and eliminated p16INK4a-positive primary bronchial epithelial cells.
- Ouabain’s EC50 was about 50-fold lower in senescent than normal cells; digoxin and digitoxin were also senolytic, with digitoxin active near plasma concentrations reported in cardiac patients (20–33 nM). Bufalin and aglycone forms also showed activity, arguing the glycoside chain is not required.
- Senescent-cell killing occurred via apoptosis: cleaved caspase 3 and caspase 3/7 activity increased, and pan-caspase inhibition blocked death, whereas ferroptosis, pyroptosis, or necroptosis inhibitors did not. Mechanistically, ouabain effects were linked to Na⁺/K⁺-ATPase inhibition, K⁺ loss, and partial dependence on NOXA, with JNK, GSK3-β, and p38 signaling involved.
- In vivo, ouabain reduced Nras-positive senescent hepatocytes in immunosuppressed mice, eliminated β-catenin-positive preneoplastic pituitary cells ex vivo, reduced lung senescent cells and Il1a/Il6 after 6 Gy irradiation, and in 24-month-old female mice lowered p16INK4a in liver, heart, and kidney, reduced liver SA-β-Gal, and reversed some age-associated blood, motor, and immune-infiltration changes; plasma ouabain was 1.24 ± 0.48 ng/ml 24 h after a treatment round.
Methods
- Unbiased drug screens used IMR90 ER:RAS cells for oncogene-induced senescence and etoposide-treated IMR90 cells for therapy-induced senescence, with the LOPAC 1,280 library and viability readouts by automated microscopy; additional senescence models included doxorubicin, palbociclib, replicative exhaustion, irradiation, and multiple cancer cell lines.
- Mechanistic work used RNA-seq, GSEA, xCell, qRT-PCR, immunoblot, siRNA/shRNA knockdown, intracellular ion probes, caspase activity assays, and inhibitors of apoptosis and signaling pathways.
- Mouse studies included C57BL/6J mice given 6 Gy total-body irradiation, C.B17 scid/beige mice with transposon-mediated NRASG12V expression, ex vivo cultured embryonic pituitaries from a β-catenin model, and 98–103-week-old female C57BL/6J mice treated intermittently with 1 mg/kg ouabain intraperitoneally for 13 weeks, with physical tests, blood chemistry, ELISA, IHC, and RNA-seq.
Limitations
- The paper states that it remains unclear whether Na⁺/K⁺-ATPase inhibition fully explains the senolytic effects of cardiac glycosides, how much of the benefit in old mice is specifically due to senolysis versus other effects, and whether these compounds have senolytic activity in humans.
- The authors note that cardiac glycosides are pleiotropic, so alternative or complementary explanations—including direct killing of specific immune infiltrates—cannot be excluded; mouse resistance to ouabain due to Atp1a1 differences also complicates translation.
- Evident from the text: several age-related endpoints were non-significant trends (for example grip strength, p21Cip1, and LINE1 ORF1), some bystander doxorubicin data are described as not shown, old mice were not littermates, and the study is preclinical with small mouse cohorts.
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Claims the paper makes
64 Own result · 26 Not checked yet · 26 Own interpretation · 5 Own method · 2 Supported · 1 Partly supported · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Therapy-induced senescence determines the response to chemo- and radiotherapy 40”
§ Cardiac glycosides are broad-spectrum senolytics > Discussion
What the sources say
- Partly supportedcites [40] Schmitt, C. A. et al. A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy. Cell 109, 335–346 (2002). sourceExperimental — accuracy not yet measured
The Abstract and Discussion report that senescence contributes to chemotherapy response and improves post-therapy prognosis in mice with lymphomas treated with cyclophosphamide. Our copy also mentions radiation as a possible trigger of senescence, but does not establish that senescence determines the response to radiotherapy. The claim therefore extends beyond the treatment and model tested. (LLM, conf=0.88)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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- Partly supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Treatment of IMR90 cells with etoposide caused senescence (Extended data Fig 2a)”
§ Cardiac glycosides are broad-spectrum senolytics > Results > A drug screen identifies ouabain as a broad-spectrum senolytic
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“eliminate senescent cells that accumulate after irradiation or in old mice.”
- Also stated in: § Dual benefit of ouabain on therapy-induced senescence · plain
“Treatment with ouabain resulted in a reduced presence of senescent cells”
- Also stated in: § Ouabain treatment resets immune infiltration in old mice · plain
“reduced p16INK4a levels when comparing ouabain-treated old mice with their age-matched counterparts”
§ Cardiac glycosides are broad-spectrum senolytics > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Dual benefit of ouabain on therapy-induced senescence · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“co-staining with antibodies recognizing cleaved caspase 3 showed that ouabain selectively induced apoptosis of β-catenin + senescent cells (Fig 4h).”
§ Cardiac glycosides are broad-spectrum senolytics > Results > Ouabain eliminates preneoplastic senescent cells
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Treatment with inhibitors of JNK, GSK3-ß or p38 signalling, confirmed the involvement of these pathways on the induction of NOXA (Fig 3j) and apoptosis in senescent cells treated with CGs (Fig 3k).”
§ Cardiac glycosides are broad-spectrum senolytics > Results > Mechanism explaining the senolytic properties of cardiac glycosides
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Ouabain treatment not only preferentially killed cells undergoing senescence triggered by oncogenic RAS (Fig 1d), or etoposide (Fig 1i), but also those exposed to doxorubicin (Fig 2a), the CDK4/6 inhibitor palbociclib (Fig 2b) or undergoing replicative senescence (Fig 2c).”
§ Cardiac glycosides are broad-spectrum senolytics > Results > Cardiac glycosides induce apoptosis of senescent cells
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Curcumin, a general inhibitor of P-type pumps 31, also displayed senolytic activity”
§ Cardiac glycosides are broad-spectrum senolytics > Results > Mechanism explaining the senolytic properties of cardiac glycosides
What the sources say
- Not checked yetcites [31] Dao, T. T. et al. Demethoxycurcumin is A potent inhibitor of P-Type ATPases from diverse kingdoms of life. PLoS ONE 11, e0163260 (2016). source
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Mice treated with CGs displayed reduced numbers of Nras-positive senescent hepatocytes due to increased apoptosis”
§ Cardiac glycosides are broad-spectrum senolytics > Results > Ouabain eliminates preneoplastic senescent cells
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Senescent cells displayed increased intracellular concentrations of all these cations.”
§ Cardiac glycosides are broad-spectrum senolytics > Results > Mechanism explaining the senolytic properties of cardiac glycosides
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We noted that both ouabain and digoxin induced a subset of pro-apoptotic Bcl2 family proteins (Fig 3g).”
§ Cardiac glycosides are broad-spectrum senolytics > Results > Mechanism explaining the senolytic properties of cardiac glycosides
plaindirect- Asserted: passes — The authors put it forward as true.
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- Probably not a substantial claim. 24
- It may state two separate claims as one. 35
Every source the paper cites for this claim was checked and supports it.
In the paper
“It has been proposed that a two-step combination of senescence-inducing anti-cancer agents followed by senolytics could be an improved strategy to treat cancer 43.”
§ Cardiac glycosides are broad-spectrum senolytics > Results > Dual benefit of ouabain on therapy-induced senescence
What the sources say
- Supportedcites [43] Wang, L. & Bernards, R. Taking advantage of drug resistance, a new approach in the war on cancer. Front. Med. 12, 490–495 (2018). source
The section “A one-two punch model for cancer therapy” explicitly proposes inducing senescence in cancer cells with a first drug, then using a senolytic to eradicate them. Its stated advantage is sequential rather than simultaneous treatment, matching the citing sentence’s proposed two-step strategy; the paper presents this as a proposal, not an established clinical outcome. (LLM, conf=0.94)
hedgedconditional- Asserted: fails — The authors may not put it forward as true.
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Probably not a substantial claim. The authors may not put it forward as true. The paper’s conclusions may not depend on it.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Therapy-induced senescence plays an important role in determining the outcome of anti-cancer treatment 40, whilst also being responsible for some of its side effects 41.”
§ Cardiac glycosides are broad-spectrum senolytics > Results > Dual benefit of ouabain on therapy-induced senescence
What the sources say
- Supportedcites [40] Schmitt, C. A. et al. A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy. Cell 109, 335–346 (2002). source
Citation 40 is attached to the treatment-outcome clause, not the separate side-effects clause cited to 41. The Abstract reports better post-chemotherapy prognosis in mice bearing tumors capable of drug-induced senescence, and the Discussion states that senescence contributed to treatment outcome. (LLM, conf=0.93)
- Supportedcites [41] Demaria, M. et al. Cellular senescence promotes adverse effects of chemotherapy and cancer relapse. Cancer Discov. 7, 165–176 (2016). source
The citation to this paper is attached to the side-effects clause, not the preceding claim about treatment outcomes. The Discussion reports a direct role for therapy-induced senescent cells in several chemotherapy side effects in mice, while describing the human fatigue finding as a correlation. (LLM, conf=0.93)
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“While senescent MEFs were not killed by high doses of ouabain, ouabain behaved as a senolytic in BNL CL.2 murine liver cells”
§ Cardiac glycosides are broad-spectrum senolytics > Results > Ouabain eliminates preneoplastic senescent cells
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Bufalin also displayed senolytic properties (Fig 2g) as did ouabagenin, the aglycone of ouabain”
§ Cardiac glycosides are broad-spectrum senolytics > Results > Cardiac glycosides induce apoptosis of senescent cells
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“confirmed, as previously shown 38, that preneoplastic clusters of β-catenin positive cells were senescent: they were arrested (ki67 -) and enriched for markers of senescent such as p21CIP1 or Glb1”
§ Cardiac glycosides are broad-spectrum senolytics > Results > Ouabain eliminates preneoplastic senescent cells
What the sources say
- Not checked yetcites [38] Gonzalez-Meljem, J. M. et al. Stem cell senescence drives age-attenuated induction of pituitary tumours in mouse models of paediatric craniopharyngioma. Nat. Commun. 8, 1819 (2017). source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Treatment with CGs resulted in cleaved caspase 3 and induced caspase 3/7 activity in senescent cells”
§ Cardiac glycosides are broad-spectrum senolytics > Results > Cardiac glycosides induce apoptosis of senescent cells
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Treatment with ABT-737 or ouabain specifically eliminated the β-catenin-positive senescent cells (Fig 4g and Extended data Fig 6a-b) without affecting other cell types in the pituitary”
§ Cardiac glycosides are broad-spectrum senolytics > Results > Ouabain eliminates preneoplastic senescent cells
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We also observed an ouabain-dependent activation of JNK, GSK3-ß and p38 in senescent cells (Fig 3h).”
§ Cardiac glycosides are broad-spectrum senolytics > Results > Mechanism explaining the senolytic properties of cardiac glycosides
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“supplementation with KCl prevented ouabain-induced (but not ABT-263-induced) death of senescent cells (Fig 3e).”
§ Cardiac glycosides are broad-spectrum senolytics > Results > Mechanism explaining the senolytic properties of cardiac glycosides
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Here, we show that the cardiac glycoside, ouabain, is a senolytic agent with broad activity.”
- Also stated in: § Cardiac glycosides induce apoptosis of senescent cells · boosted
“Taken together these results further demonstrate that ouabain behaves as a broad-spectrum senolytic agent.”
§ Cardiac glycosides are broad-spectrum senolytics > Abstract
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Also stated in: § Cardiac glycosides induce apoptosis of senescent cells · boosted
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Overexpression of rATP1A1 prevented the senolytic effects of ouabain, but not those of ABT-263 (Fig 3f).”
§ Cardiac glycosides are broad-spectrum senolytics > Results > Mechanism explaining the senolytic properties of cardiac glycosides
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the killing of senescent cells by CGs was prevented by pan-caspase inhibitors but not by inhibitors of ferroptosis, pyroptosis or necroptosis”
§ Cardiac glycosides are broad-spectrum senolytics > Results > Cardiac glycosides induce apoptosis of senescent cells
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“While CG-resistant Atp1a1 is downregulated in the liver of old mice, the expression of CG-sensitive Atp1a3 increases (Supplementary Fig 6).”
§ Cardiac glycosides are broad-spectrum senolytics > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“levels of ouabain in blood dropped to undetectable levels at the end of the ‘holiday’ period.”
§ Cardiac glycosides are broad-spectrum senolytics > Results > Ouabain treatment resets immune infiltration in old mice
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“A subset of the identified compounds behave as broad-spectrum senolytics while others are just selective against a specific type of senescent cells.”
§ Cardiac glycosides are broad-spectrum senolytics > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“ABT-263 treatment that caused a drop of platelets in blood and decreased platelet infiltration in livers of mice”
§ Cardiac glycosides are broad-spectrum senolytics > Results > Ouabain treatment resets immune infiltration in old mice
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Treatment with ouabain resulted in a reduced presence of senescent cells and lower expression of cytokines such as Il1a or Il6 (Fig 5f-h).”
§ Cardiac glycosides are broad-spectrum senolytics > Results > Dual benefit of ouabain on therapy-induced senescence
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This regime was well tolerated in mice, with levels of ouabain in plasma reaching 1.24+/-0.48 ng/ml 24h after a round of treatment”
§ Cardiac glycosides are broad-spectrum senolytics > Results > Ouabain treatment resets immune infiltration in old mice
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“blood phosphate levels were lower in old mice and this decrease was significantly reversed upon ouabain treatment”
§ Cardiac glycosides are broad-spectrum senolytics > Results > Ouabain treatment resets immune infiltration in old mice
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Using GSEA analysis, we observed the upregulation of gene signatures associated with senescence, inflammation and aging in old mice, a trend that significantly reversed upon ouabain treatment”
§ Cardiac glycosides are broad-spectrum senolytics > Results > Ouabain treatment resets immune infiltration in old mice
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Using xCell, we observed that the immune infiltration in the liver changed in old mice. Interestingly, many of these changes were significantly reversed in ouabain-treated old mice”
§ Cardiac glycosides are broad-spectrum senolytics > Results > Ouabain treatment resets immune infiltration in old mice
plaindirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“suggesting that the senolytic properties of CGs could be related to the inhibition of their canonical target, Na+, K+-ATPase, although we cannot formally exclude that CGs induce senolysis via other cellular mechanisms.”
§ Cardiac glycosides are broad-spectrum senolytics > Results > Mechanism explaining the senolytic properties of cardiac glycosides
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Senescent cells are present in pre-neoplastic and fibrotic lesions, they accumulate in old tissues and are associated with an increasing list of pathologies 8.”
§ Cardiac glycosides are broad-spectrum senolytics > Introduction
What the sources say
- Not checked yetcites [8] McHugh, D. & Gil, J. Senescence and aging: Causes, consequences, and therapeutic avenues. J. Cell Biol. 217, 65–77 (2018). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may state two separate claims as one.
In the paper
“Currently Bcl2 family inhibitors are the most widely used senolytics, having been shown effective at killing a range of senescent cells in vivo”
§ Cardiac glycosides are broad-spectrum senolytics > Introduction
What the sources say
- Not checked yetcites [23] Ovadya, Y. & Krizhanovsky, V. Strategies targeting cellular senescence. J. Clin. Invest. 128, 1247–1254 (2018). source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Irradiation, chemotherapy and some targeted anti-cancer drugs, including aurora kinase inhibitors, all induce senescence 40,42.”
§ Cardiac glycosides are broad-spectrum senolytics > Results > Dual benefit of ouabain on therapy-induced senescence
What the sources say
- Not checked yetcites [40] Schmitt, C. A. et al. A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy. Cell 109, 335–346 (2002). source
- Not checked yetcites [42] Wang, L. et al. High-throughput functional genetic and compound screens identify targets for senescence induction in cancer. Cell Rep. 21, 773–783 (2017). source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Oncogene-induced senescence protects against tumor initiation 34–37.”
§ Cardiac glycosides are broad-spectrum senolytics > Results > Ouabain eliminates preneoplastic senescent cells
What the sources say
- Not checked yetcites [34] Collado, M. et al. Tumour biology: senescence in premalignant tumours. Nature 436, 642 (2005). source
- Not checked yetcites [35] Michaloglou, C. et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436, 720–724 (2005). source
- Not checked yetcites [36] Braig, M. et al. Oncogene-induced senescence as an initial barrier in lymphoma development. Nature 436, 660–665 (2005). source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
In the paper
“These preneoplastic senescent cells are the subject of active immune surveillance and failure of this process results in increased tumor risk 5.”
§ Cardiac glycosides are broad-spectrum senolytics > Results > Ouabain eliminates preneoplastic senescent cells
What the sources say
- Not checked yetcites [5] Kang, T. W. et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479, 547–551 (2011). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“clearing senescent cells from progeroid or naturally aging mice improves healthspan 10, increases lifespan 12 and benefits an array of pathologies”
§ Cardiac glycosides are broad-spectrum senolytics > Introduction
What the sources say
- Not checked yetcites [10] Baker, D. J. et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236 (2011). source
- Not checked yetcites [12] Baker, D. J. et al. Naturally occurringp16(Ink4a)-positive cells shorten healthy lifespan. Nature 530, 184–189 (2016). source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“For in vivo studies, mice were randomly assigned to treatment groups.”
§ Cardiac glycosides are broad-spectrum senolytics > Methods > Statistical analysis
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“whilst also contributing to their side effects 41.”
§ Cardiac glycosides are broad-spectrum senolytics > Discussion
What the sources say
- Not checked yetcites [41] Demaria, M. et al. Cellular senescence promotes adverse effects of chemotherapy and cancer relapse. Cancer Discov. 7, 165–176 (2016). source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Moreover, the broad specificity of CGs as senolytics, and the causal role of senescence in age-related disease suggest that CGs might have benefits that extend beyond their anti-cancer properties.”
§ Cardiac glycosides are broad-spectrum senolytics > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Senescence has a causal role in age-related disease.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Although our data suggest that the senolytic effects of CGs are due to on-target inhibition of the Na+/K+-ATPase, it needs to be clarified whether this inhibition (fully) explains the senolytic properties of CGs.”
§ Cardiac glycosides are broad-spectrum senolytics > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
In the paper
“Given that chemotherapy, radiotherapy and some targeted anti-cancer drugs rely on senescence induction, a follow-up senolytic treatment has been proposed as a way to improve cancer therapy 42.”
§ Cardiac glycosides are broad-spectrum senolytics > Discussion
What the sources say
- Not checked yetcites [42] Wang, L. et al. High-throughput functional genetic and compound screens identify targets for senescence induction in cancer. Cell Rep. 21, 773–783 (2017). source
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, their senolytic action may require intermittent rather than continuous usage, and depending on the indication, administration could be local rather than systemic.”
§ Cardiac glycosides are broad-spectrum senolytics > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
In the paper
“The accumulation of senescent cells in ageing organisms contributes to many diseases, including cancer 46.”
§ Cardiac glycosides are broad-spectrum senolytics > Results > Ouabain treatment resets immune infiltration in old mice
What the sources say
- Not checked yetcites [46] Childs, B. G., Durik, M., Baker, D. J. & van Deursen, J. M. Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nat. Med. 21, 1424–1435 (2015). source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“OIS is a powerful tumor suppressor mechanism 34–37.”
§ Cardiac glycosides are broad-spectrum senolytics > Discussion
What the sources say
- Not checked yetcites [34] Collado, M. et al. Tumour biology: senescence in premalignant tumours. Nature 436, 642 (2005). source
- Not checked yetcites [35] Michaloglou, C. et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436, 720–724 (2005). source
- Not checked yetcites [36] Braig, M. et al. Oncogene-induced senescence as an initial barrier in lymphoma development. Nature 436, 660–665 (2005). source
- Not checked yetcites [37] Chen, Z. et al. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436, 725–730 (2005). source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Senescent cells are associated with cancer, accumulate with age and are present in many pathologies 9.”
§ Cardiac glycosides are broad-spectrum senolytics > Discussion
What the sources say
- Not checked yetcites [9] Munoz-Espin, D. & Serrano, M. Cellular senescence: from physiology to pathology. Nat. Rev. Mol. Cell Biol. 15, 482–496 (2014). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“The results presented here are consistent with those of the Collado group, that also identified CGs as senolytic in the context of bleomycin-induced senescence of cancer cells (crossreference).”
§ Cardiac glycosides are broad-spectrum senolytics > Discussion
What the sources say
- Not checked yetcites crossreference
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In particular, the fact that CGs will eliminate incipient preneoplastic cells, should reduce the rate of cancer initiation and could suggest a prophylactic use to diminish cancer incidence.”
§ Cardiac glycosides are broad-spectrum senolytics > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The above results suggest that CGs can be combined with anti-cancer therapies to both enhance the elimination of cancer cells and avoid the accumulation of bystander senescent cells responsible of some of the side effects of these treatments.”
§ Cardiac glycosides are broad-spectrum senolytics > Results > Dual benefit of ouabain on therapy-induced senescence
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Given that digoxin has a long history of use in the clinic and its side effects can be monitored and managed 56”
§ Cardiac glycosides are broad-spectrum senolytics > Discussion
What the sources say
- Not checked yetcites [56] Li, B. et al. Ouabain ameliorates bleomycin induced pulmonary fibrosis by inhibiting proliferation and promoting apoptosis of lung fibroblasts. Am. J. Transl. Res. 10, 2967–2974 (2018).
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Genetic and pharmacological strategies have demonstrated the benefits of eliminating senescent cells in the context of aging and disease 10,12,51.”
§ Cardiac glycosides are broad-spectrum senolytics > Discussion
What the sources say
- Not checked yetcites [10] Baker, D. J. et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236 (2011). source
- Not checked yetcites [12] Baker, D. J. et al. Naturally occurringp16(Ink4a)-positive cells shorten healthy lifespan. Nature 530, 184–189 (2016). source
- Not checked yetcites [51] Childs, B. G. et al. Senescent cells: an emerging target for diseases of ageing. Nat. Rev. Drug Discov. 16, 718–735 (2017). source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In conclusion, the above results suggest that ouabain can be used as a senolytic beyond cancer and that besides eliminating senescent cells, ouabain reduced the levels of local inflammation and immune infiltration”
§ Cardiac glycosides are broad-spectrum senolytics > Results > Ouabain treatment resets immune infiltration in old mice
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Both sexes were used throughout the study.”
§ Cardiac glycosides are broad-spectrum senolytics > Methods > Mouse models and drug treatments
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This result suggests that ouabain is not just a senolytic compound but it also has a synthetic lethal interaction with RAS, which potentially makes it a cancer therapy with a useful dual mechanism of action.”
§ Cardiac glycosides are broad-spectrum senolytics > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The canonical activity of CGs is to inhibit the Na+, K+-ATPase 25 but other activities have been suggested to explain their pleiotropic effects 26.”
§ Cardiac glycosides are broad-spectrum senolytics > Discussion
What the sources say
- Not checked yetcites [25] Therien, A. G. & Blostein, R. Mechanisms of sodium pump regulation. Am. J. Physiol. Cell Physiol. 279, C541–C566 (2000). source
- Not checked yetcites [26] Prassas, I. & Diamandis, E. P. Novel therapeutic applications of cardiac glycosides. Nat. Rev. Drug Discov. 7, 926–935 (2008). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The broad-spectrum senolytic action of CGs suggest that they might target a common vulnerability induced by senescence.”
§ Cardiac glycosides are broad-spectrum senolytics > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“Mice have been described more resistant than human to the canonical effects of CGs due to differences in the Atp1a1 protein 32.”
§ Cardiac glycosides are broad-spectrum senolytics > Discussion
What the sources say
- Not checked yetcites [32] Price, E. M. & Lingrel, J. B. Structure-function relationships in the Na,K-ATPase alpha subunit: site-directed mutagenesis of glutamine-111 to arginine and asparagine-122 to aspartic acid generates a ouabain-resistant enzyme. Biochemistry 27, 8400–8408 (1988). source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All replicates in this study represent different mice.”
§ Cardiac glycosides are broad-spectrum senolytics > Methods > Statistical analysis
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The mice used for all experiments were randomly assigned to control or treatment groups.”
- Also stated in: § Mouse models and drug treatments · plain
“The mice were randomly assigned to control or treatment group.”
§ Cardiac glycosides are broad-spectrum senolytics > Methods > Mouse models and drug treatments
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Also stated in: § Mouse models and drug treatments · plain
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These differences in specificity open up possibilities for the choice of senolytic depending on their intended clinical use.”
§ Cardiac glycosides are broad-spectrum senolytics > Discussion
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our data suggest that broad-spectrum senolytics such as CGs, will also eliminate other subsets of senescent cells such as preneoplastic cells, bystander senescent cells induced by anti-cancer therapy and age-associated senescent cells which contribute to chronic inflammation.”
§ Cardiac glycosides are broad-spectrum senolytics > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“This protocol is preferred because lower scores are often due to the mouse failing to grip the bar effectively, rather than reflecting muscular strength.”
§ Cardiac glycosides are broad-spectrum senolytics > Methods > Physical tests
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
How senolytics affect cancer initiation, progression, and treatment is poorly defined or understudied.
“Despite the many roles that senescence plays in cancer initiation, progression and treatment, how senolytics can affect these processes is poorly defined.”
“Despite the multiple roles that senescence holds during cancer initiation, progression and treatment, how senolytics impact on these processes is understudied.”
The paper relies on this without support.
There is a need to identify further compounds with senolytic properties because of side-effects of known senolytics.
“Due to the important side-effects associated to known senolytic compounds, there is a need to identify further compounds with senolytic properties.”
The paper relies on this without support.
Senescence occurs at different stages of cancer evolution and treatment.
“Senescence occurs at different stages of cancer evolution and treatment.”
The paper relies on this without support.
Chemotherapy, radiotherapy and some targeted anti-cancer drugs rely on senescence induction.
“Given that chemotherapy, radiotherapy and some targeted anti-cancer drugs rely on senescence induction”
The paper relies on this without support.
Cardiac glycosides have been used in the clinic for a long time.
“CGs have been used in the clinic for a long time.”
The paper relies on this without support.
Digoxin and digitoxin are used for heart failure and atrial arrhythmia.
“Digoxin and digitoxin are used for the treatment of heart failure and atrial arrhythmia.”
The paper relies on this without support.
Senescence has a causal role in age-related disease.
“the causal role of senescence in age-related disease”
The paper relies on this without support.
A factor limiting the use of cardiac glycosides has been their potential for side effects.
“a factor limiting their use has been the potential for side effects.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Cardiac glycosides, including the widely prescribed digoxin, were able to selectively kill TIS cancer cells in culture and invivo 208,209 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [209]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“We also find that lung fibroblasts and prostate stromal cells, commonly used as models for senolytic drug development, are classified as SID5 by SenCID (Figure S3H) in two independent datasets85”
From Single-cell senescence identification reveals senescence heterogeneity, trajectory, and modulators (2024) · cites this paper as [85]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Cardiac glycosides, such as ouabain and digoxin, inhibit Na⁺/K⁺-ATPase and may capitalize on altered membrane potential or reduced stress tolerance that is more pronounced in SnCs than in non-SnCs48,49.”
From Emerging strategies in senotherapeutics: from broad-spectrum senolysis to precision reprogramming (2026) · cites this paper as [48]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Some of these compounds, e.g. ouabain13, have wide-spectrum senolytic action, whereas others such as BIX-01294, limit their effect to specific conditions13.”
From Discovery of senolytics using machine learning (2023) · cites this paper as [13]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The drop in cell number compared to untreated controls is indicated by the nuclei count and reflects cell death13,15.”
From Discovery of senolytics using machine learning (2023) · cites this paper as [13]
Experimental — accuracy not yet measured
The cited source says what the claim attributes to it.
In the citing paper
“Recently, the cardiac glycoside ouabain demonstrated senolytic activity, at least in part, through the induction of NOXA, a proapoptotic BCL-2 family protein203,204.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [203]
The cited source says what the claim attributes to it.
In the citing paper
“Other senolytic compounds, including cardiac glycosides, are widely used clinically and cooperate with prosenescence therapies to kill cancer cells (Guerrero et al. 2019).”
From Senescence and the SASP: many therapeutic avenues (2020) · cites this paper as Guerrero et al. 2019
The cited source says what the claim attributes to it.
In the citing paper
“Despite encouraging results, to date there are few known compounds with proven senolytic action11–19,23–28”
From Discovery of senolytics using machine learning (2023) · cites this paper as [13]
The cited source says what the claim attributes to it.
In the citing paper
“Senolytics have shown substantial promise in ameliorating symptoms of many conditions in mice11–20”
From Discovery of senolytics using machine learning (2023) · cites this paper as [13]
The cited source says what the claim attributes to it.
In the citing paper
“We assembled a list of 58 previously identified senolytics mined from 15 sources11–19,23–28 (Fig. 1b).”
From Discovery of senolytics using machine learning (2023) · cites this paper as [13]
The cited source says what the claim attributes to it.
In the citing paper
“Senolytic cardiac glycosides activate a transcriptional programme resulting in the induction of several pro-apoptotic Bcl-2 family proteins13.”
From Discovery of senolytics using machine learning (2023) · cites this paper as [13]
In the citing paper
“similar results have been obtained by another group performing independently cell-based screenings and using other unrelated chemical libraries”
From Identification and characterization of Cardiac Glycosides as senolytic compounds (2019) · cites this paper as [50]
In the citing paper
“such broad-spectrum senolytics, which target different types of senescent cells that coexist in the tumor microenvironment, could have benefits that go beyond potentiating prosenescence therapies (Guerrero et al. 2019).”
From Senescence and the SASP: many therapeutic avenues (2020) · cites this paper as Guerrero et al. 2019
In the citing paper
“The senolytic effect of cardiac glycosides has been previously linked to its canonical target, the Na+/K+ ATPase pump13.”
From Discovery of senolytics using machine learning (2023) · cites this paper as [13]
In the citing paper
“Specifically, ouabain induces the expression of the BH3-only pro-apoptotic protein NOXA, which mediates its senolytic effect.”
From Discovery of senolytics using machine learning (2023) · cites this paper as [13]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Cardiac glycosides are broad-spectrum senolytics > Extended Data
“Representative images of immunofluorescence staining of GFP and cleaved caspase-3 and quantification of intensity levels in 1/2 independent experiments (n = 200 cells).”
§ Cardiac glycosides are broad-spectrum senolytics > Extended Data
“Data represent mean ± s.d; n represents number of mice.”
Citations
Cites
Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2
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The senescence-associated secretory phenotype: the dark side of tumor suppression
Coppé, J.-P., Desprez, P.-Y., Krtolica, A., & Campisi, J. (2010) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-121808-102144 · Cited by 5,206
xCell: digitally portraying the tissue cellular heterogeneity landscape
Aran, D., Hu, Z., & Butte, A. J. (2017) · Genome Biology · doi:10.1186/s13059-017-1349-1 · Cited by 4,397
Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders
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Naturally occurring p16Ink4a-positive cells shorten healthy lifespan
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Cited by
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“…screens have pinpointed compounds as varied as heat-shock protein inhibitors (Fuhrmann-Stroissnigg et al. 2017), cardiac glycosides GENES & DEVELOPMENT 1569 (Guerrero et al. 2019; Triana-Martínez et al. 2019), and p53–MDM2 interaction inhibitors (Jeon et al. 2017) as harboring senolytic activity.”
BackgroundInfluentialSelf-citationCellular senescence and senolytics: the path to the clinic
Chaib, S., Tchkonia, T., & Kirkland, J. L. (2022) · Nature Medicine · doi:10.1038/s41591-022-01923-y · Cited by 1,134
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Therapy-Induced Senescence: Opportunities to Improve Anticancer Therapy
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Self-citationThe flavonoid procyanidin C1 has senotherapeutic activity and increases lifespan in mice
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Targeting senescent cells in translational medicine
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“Recently, cardiac glycosides (CGs) have been identified as a family of compounds with potent senolytic activity (Guerrero et al, 2019; Triana-Martı́nez et al, 2019).”
BackgroundGonzález‐Gualda, E., Pàez‐Ribes, M., Lozano‐Torres, B., Macias, D., Wilson, J. R., González‐López, C., Ou, H., Mirón‐Barroso, S., Zhang, Z., Lérida‐Viso, A., et al. (2020) · Aging Cell · doi:10.1111/acel.13142 · Cited by 303
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BackgroundTherapy-Induced Senescence: An “Old” Friend Becomes the Enemy
Saleh, T., Bloukh, S., Carpenter, V. J., Alwohoush, E., Bakeer, J., Darwish, S., Azab, B., & Gewirtz, D. A. (2020) · Cancers · doi:10.3390/cancers12040822 · Cited by 295
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A Senescence-Centric View of Aging: Implications for Longevity and Disease
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Cellular senescence and SASP in tumor progression and therapeutic opportunities
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“To date, various senolytic drugs have been developed, including first-generation senolytics like dasatinib and quercetin (D + Q) [160], BCL-2 family inhibitors (such as ABT-263 and ABT-737) [163], and cardiac glycosides like ouabain and digitoxin [170].”
BackgroundCellular senescence at the crossroads of inflammation and Alzheimer's disease
Guerrero, A., De Strooper, B., & Arancibia-Cárcamo, I. L. (2021) · Trends in Neurosciences · doi:10.1016/j.tins.2021.06.007 · Cited by 236
Self-citationA BET family protein degrader provokes senolysis by targeting NHEJ and autophagy in senescent cells
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Senescent Cells: Emerging Targets for Human Aging and Age-Related Diseases
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“The cardiac glycoside (CG) ouabain can work as a novel senolytic agent with broad activity, while senescent cells are subject to ouabain-induced apoptosis, a process mediated partially by induction of the proapoptotic NOXA, a Bcl-2 family member [100].”
BackgroundCellular senescence in cancer: from mechanisms to detection
Ou, H., Hoffmann, R. J., González‐López, C., Doherty, G. J., Korkola, J. E., & Muñoz‐Espín, D. (2020) · Molecular Oncology · doi:10.1002/1878-0261.12807 · Cited by 208
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Cellular Senescence: Molecular Targets, Biomarkers, and Senolytic Drugs
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Senescence as a therapeutic target in cancer and age-related diseases
McHugh, D., Durán, I., & Gil, J. (2025) · Nature Reviews Drug Discovery · doi:10.1038/s41573-024-01074-4 · Cited by 197
“Another class of senolytic drugs that target the aberrant ionic homeostasis of SnCs are cardiac glycosides (CGs) such as ouabain or digoxin 119,120 .”
InfluentialSelf-citationGalactose‐modified duocarmycin prodrugs as senolytics
Guerrero, A., Guiho, R., Herranz, N., Uren, A., Withers, D. J., Martínez‐Barbera, J. P., Tietze, L. F., & Gil, J. (2020) · Aging Cell · doi:10.1111/acel.13133 · Cited by 172
Self-citationSimilarities and interplay between senescent cells and macrophages
Behmoaras, J., & Gil, J. (2021) · Journal of Cell Biology · doi:10.1083/jcb.202010162 · Cited by 158
Self-citationWhy Senescent Cells Are Resistant to Apoptosis: An Insight for Senolytic Development
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Cellular Senescence: From Mechanisms to Current Biomarkers and Senotherapies
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Senescence as a therapeutically relevant response to CDK4/6 inhibitors
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Self-citationSingle-cell senescence identification reveals senescence heterogeneity, trajectory, and modulators
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Lysosomal control of senescence and inflammation through cholesterol partitioning
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Discovery of senolytics using machine learning
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“Moreover, this effect is combined to a downregulation of the expression of senescence-associated cytokines in the second model and an improvement of mice physical condition in the third model, respectively 37 .”
BackgroundCellular senescence in malignant cells promotes tumor progression in mouse and patient Glioblastoma
Salam, R., Saliou, A., Bielle, F., Bertrand, M., Antoniewski, C., Carpentier, C., Alentorn, A., Capelle, L., Sanson, M., Huillard, E., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-36124-9 · Cited by 132
Targeting Aging Pathways in Chronic Obstructive Pulmonary Disease
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Targeting Senescent Cells for a Healthier Aging: Challenges and Opportunities
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Recent advances in the discovery of senolytics
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Lipids as Regulators of Cellular Senescence
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“Additionally, directed removal of senescent cells or associated SASP improves health considerably, at least in animal models (Zhu et al., 2015; Jeon et al., 2017; Bussian et al., 2018; Guerrero et al., 2019; Zhang et al., 2019).”
BackgroundSenolytics for Cancer Therapy: Is All that Glitters Really Gold?
Carpenter, V. J., Saleh, T., & Gewirtz, D. A. (2021) · Cancers · doi:10.3390/cancers13040723 · Cited by 124
Cellular senescence and cardiovascular diseases: moving to the “heart” of the problem
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Senescent Cells: A Therapeutic Target in Cardiovascular Diseases
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“Senolytics such as navitoclax [162,279], anti-GPNMB vaccination [222], digoxin [217,218,280], BPTES [220], and 17-DMAG (alvespimycin) [281], reduce atherosclerotic plaque formation and inflammation in atherosclerotic model mice.”
BackgroundDiversity of the Senescence Phenotype of Cancer Cells Treated with Chemotherapeutic Agents
Bojko, A., Czarnecka‐Herok, J., Charzyńska, A., Dąbrowski, M., & Sikora, E. (2019) · Cells · doi:10.3390/cells8121501 · Cited by 112
“Human colon HCT116 (CCL-247) cancer cell line was kindly provided by Dr. Bert Vogelstein (Johns Hopkins University, Baltimore, MD, USA).”
BackgroundInfluentialReshaping of the tumor microenvironment by cellular senescence: An opportunity for senotherapies
D’Ambrosio, M., & Gil, J. (2023) · Developmental Cell · doi:10.1016/j.devcel.2023.05.010 · Cited by 111
Self-citationTargeting senescence as an anticancer therapy
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Self-citationTargeting senescent cells for a healthier longevity: the roadmap for an era of global aging
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“In drug screens using models of oncogene-induced senescence in normal cells vs. therapy-induced senescent cells, cardiac glycosides (CGs) were identified as a class of senolytics [67, 68].”
Senescent tumor cells: an overlooked adversary in the battle against cancer
Park, S. S., Choi, Y. W., Kim, J., Kim, H. S., & Park, T. J. (2021) · Experimental & Molecular Medicine · doi:10.1038/s12276-021-00717-5 · Cited by 100
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“Many drug classes, ranging from fibrates to cardiac glycosides, have been reported to have senolytic properties in animal models [103].”
BackgroundBeyond Tumor Suppression: Senescence in Cancer Stemness and Tumor Dormancy
Triana-Martínez, F., Loza, M. I., & Domínguez, E. (2020) · Cells · doi:10.3390/cells9020346 · Cited by 102
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The redox-senescence axis and its therapeutic targeting
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Detection of senescence using machine learning algorithms based on nuclear features
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InfluentialSelf-citationCellular Senescence: Mechanisms and Therapeutic Potential
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Current senolytics: Mode of action, efficacy and limitations, and their future
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Cell senescence in neuropathology: A focus on neurodegeneration and tumours
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“Subsequently, senolytics including heat shock protein (HSP)-90 inhibitors 6 , cardiac glycosides 7,17 and bromodomain and extra-terminal domain (BET) family protein inhibitors 8 have been discovered through high-throughput screens and detailed mechanistic studies.”
BackgroundTargeting senescent cells to attenuate cardiovascular disease progression
Song, P., Zhao, Q., & Zou, M. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101072 · Cited by 81
Strategies for senolytic drug discovery
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“The senolytic activity of cardiac steroids was identified by two separate studies that used high-throughput screening to detect active compounds from commercial drug libraries (Guerrero et al., 2019; Triana-Martinez et al., 2019 ).”
BackgroundCellular senescence in the aging brain: A promising target for neurodegenerative diseases
Sahu, M. R., Rani, L., Subba, R., & Mondal, A. C. (2022) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2022.111675 · Cited by 75
Targeting Cell Senescence and Senolytics: Novel Interventions for Age-Related Endocrine Dysfunction
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Targeting senescent cells improves functional recovery after spinal cord injury
Paramos-de-Carvalho, D., Martins, I., Cristóvão, A. M., Dias, A. F., Neves-Silva, D., Pereira, T., Chapela, D., Farinho, A., Jacinto, A., & Saúde, L. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109334 · Cited by 74
Targeting tumor cell senescence and polyploidy as potential therapeutic strategies
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Senescent cells as promising targets to tackle age-related diseases
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Therapeutic Potential of Senolytics in Cardiovascular Disease
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“[78] identified that cardiac glycosides (CG) are broad-spectrum senolytics.”
BackgroundRole of Senescence and Aging in SARS-CoV-2 Infection and COVID-19 Disease
Lynch, S. M., Guo, G., Gibson, D. S., Bjourson, A. J., & Singh, T. (2021) · Cells · doi:10.3390/cells10123367 · Cited by 70
“Cardiac glycosides, such as digoxin, which is currently used to treat irregular heartbeat in atrial fibrillation, have also been reported to have broad senolytic activity [14,15].”
BackgroundHuang, W., He, Y., Jiang, R., Deng, Z., & Long, F. (2022) · ACS Catalysis · doi:10.1021/acscatal.1c05729 · Cited by 68
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The Jekyll and Hyde of Cellular Senescence in Cancer
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Therapeutic targeting of senescent cells in the CNS
Riessland, M., Ximerakis, M., Jarjour, A. A., Zhang, B., & Orr, M. E. (2024) · Nature Reviews Drug Discovery · doi:10.1038/s41573-024-01033-z · Cited by 77
“Another cardiac glycoside, ouabain, was shown to selectively eliminate cells undergoing oncogene-induced senescence in a mouse model of liver cancer 105 .”
Cell Senescence, Multiple Organelle Dysfunction and Atherosclerosis
Machado-Oliveira, G., Ramos, C., Marques, A. R. A., & Vieira, O. V. (2020) · Cells · doi:10.3390/cells9102146 · Cited by 70
cFLIP suppression and DR5 activation sensitize senescent cancer cells to senolysis
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Senolytic targets and new strategies for clearing senescent cells
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Cellular Senescence and Senotherapies in the Kidney: Current Evidence and Future Directions
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COPI vesicle formation and N-myristoylation are targetable vulnerabilities of senescent cells
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“…been identified, including dasatinib and quercetin (referred to as D + Q) 9 , Bcl2 family inhibitors such as ABT-263 and ABT-737 10–12 , a modified FOXO4-p53 interfering peptide 13 , HSP90 inhibitors 14 , cardiac glycosides 15,16 and β-galactosidase-activated nanoparticles and pro-drugs 17–19 .”
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Senescence under appraisal: hopes and challenges revisited
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“Likewise, ouabain and digoxin, two members of the cardiac glycoside family of organic compounds, can induce apoptosis in senescent cluster cells [175].”
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“However,senolyticactivityhasproven tovarywidely inef fi cacy betweendifferentsenescentcontextsand thelistof senolytics continues to grow, including cardiac glycosides, and perhaps the most widely used BCL-2 inhibitors such as Navitoclax 84 – 86 .”
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Metadata
- Authors
- Guerrero, A., Herranz, N., Sun, B., Wagner, V., Gallage, S., Guiho, R., Wolter, K., Pombo, J., Irvine, E. E., Innes, A. J., Birch, J., Glegola, J., Manshaei, S., Heide, D., Dharmalingam, G., Harbig, J., Olona, A., Behmoaras, J., Dauch, D., Uren, A. G., Zender, L., Vernia, S., Martínez-Barbera, J. P., Heikenwalder, M., Withers, D. J., & Gil, J.
- Affiliations
- MRC London Institute of Medical Sciences (GB)
- German Cancer Research Center (DE)
- University College London (GB)
- Universitätsklinikum Tübingen (DE)
- Hammersmith Hospital (GB)
- Corresponding author
- Gil, Jesús
- ORCID
- Guerrero, Ana
- Herranz, Nicolás
- Sun, Bin
- Wagner, Verena
- Gallage, Suchira
- Guiho, Romain
- Wolter, Katharina
- Irvine, Elaine E.
- Innes, Andrew J.
- Birch, Jodie
- Manshaei, Saba
- Heide, Danijela
- Harbig, Jule
- Behmoaras, Jacques
- Uren, Anthony G.
- Zender, Lars
- Vernia, Santiago
- Martínez-Barbera, Juan Pedro
- Withers, Dominic J.
- Gil, Jesús
- Venue
- Nature Metabolism
- Published
- 2019-10-21
- Volume
- 1
- Issue
- 11
- Pages
- 1074-1088
- ISSN
- 2522-5812 (ISSN-L)
- PMC
- PMC6887543
- OpenAlex
- W2980638238
- Cited by
- 359
- References
- 71
- Citations by year
- 2026: 36 · 2025: 60 · 2024: 58 · 2023: 49 · 2022: 52 · 2021: 52 · 2020: 48 · 2019: 4
- FWCI
- 26.75
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion)
- Funders
- RCUK | Medical Research Council (MC-A652-5PZ00)
- RCUK | MRC | Medical Research Foundation (MC-A652-5PZ00)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- cardiac glycosides, ouabain, senolytics, cellular senescence, oncogene-induced senescence, Noxa, apoptosis, radiation-induced senescence, age-related diseases
- MeSH terms
- Animals, Antineoplastic Agents, Cardiac Glycosides, Humans, Ouabain, Quercetin, Cellular Senescence, Apoptosis, Mice, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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