Discovery of senolytics using machine learning

Certain senolytics that work well for one cell type are highly toxic against other non-senescent cell types.

“certain senolytics that work well for one cell-type are highly toxic against other non-senescent cell-types19,24.”

• cites [19] Zhu, Y. et al. New agents that target senescent cells: the flavone, fisetin, and the BCL-X inhibitors, A1331852 and A1155463. Aging 9, 955–963 (2017). sourcePartly supported

  The Results report that fisetin is senolytic in HUVECs but not in the other cell types tested, supporting cell-type-specific effectiveness. The Discussion says nonsenescent cells may be affected at higher concentrations, with apoptosis only at still higher concentrations. It does not show that a senolytic is highly toxic to another nonsenescent cell type at a concentration where it works as a senolytic. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [24] Li, W., He, Y., Zhang, R., Zheng, G. & Zhou, D. The curcumin analog EF24 is a novel senolytic agent. Aging 11, 771–782 (2019). sourceSupported

Removal of senescent cells has been linked to adverse effects due to blockage of their beneficial roles in processes such as wound healing and liver function.

“removal of senescent cells has also been linked to some adverse effects due to blockage of their beneficial roles in processes such as wound healing and liver function21,22.”

• cites [21] Demaria, M. et al. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev. Cell 31, 722–733 (2014). sourcePartly supported

  The Results section (‘Elimination of Senescent Cells Delays Cutaneous Wound Healing’; page unavailable) reports that removing senescent cells delayed wound closure in mice. The paper also discusses senescent cells limiting fibrosis after liver injury, but it does not report an effect of their removal on liver function. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [22] Grosse, L. et al. Defined p16 senescent cell types are indispensable for mouse healthspan. Cell Metab. 32, 87–99.e6 (2020). sourceSupported

To date there are few known compounds with proven senolytic action.

“Despite encouraging results, to date there are few known compounds with proven senolytic action11–19,23–28”

• cites [11] Fuhrmann-Stroissnigg, H. et al. Identification of HSP90 inhibitors as a novel class of senolytics. Nat. Commun. 8, 422 (2017). sourceSupported
• cites [12] Guerrero, A. et al. Galactose-modified duocarmycin prodrugs as senolytics. Aging Cell. 19, e13133 (2020). sourceSupported
• cites [13] Guerrero, A. et al. Cardiac glycosides are broad-spectrum senolytics. Nat. Metab. 1, 1074–1088 (2019). sourceSupported
• cites [14] Senolytic compounds. Patent no. 20200121620, (2018).Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [15] Triana-Martínez, F. et al. Identification and characterization of Cardiac Glycosides as senolytic compounds. Nat. Commun. 10, 4731 (2019). sourceSupported
• cites [16] Yosef, R. et al. Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL. Nat. Commun. 7, 11190 (2016). sourceSupported
• cites [17] Yousefzadeh, M. J. et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine 36, 18–28 (2018). sourceSupported
• cites [18] Zhu, Y. et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. 14, 644–658 (2015). sourceSupported
• cites [19] Zhu, Y. et al. New agents that target senescent cells: the flavone, fisetin, and the BCL-X inhibitors, A1331852 and A1155463. Aging 9, 955–963 (2017). sourceSupported
• cites [23] Lafontaine, J. et al. Senolytic targeting of Bcl-2 anti-apoptotic family increases cell death in irradiated sarcoma cells. Cancers https://doi.org/10.3390/cancers13030386 (2021). sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

The training data comprised 58 previously identified senolytics mined from 15 sources.

“We assembled a list of 58 previously identified senolytics mined from 15 sources11–19,23–28 (Fig. 1b).”

• cites [11] Fuhrmann-Stroissnigg, H. et al. Identification of HSP90 inhibitors as a novel class of senolytics. Nat. Commun. 8, 422 (2017). sourceSupported
• cites [12] Guerrero, A. et al. Galactose-modified duocarmycin prodrugs as senolytics. Aging Cell. 19, e13133 (2020). sourceSupported
• cites [13] Guerrero, A. et al. Cardiac glycosides are broad-spectrum senolytics. Nat. Metab. 1, 1074–1088 (2019). sourceSupported
• cites [14] Senolytic compounds. Patent no. 20200121620, (2018).Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [15] Triana-Martínez, F. et al. Identification and characterization of Cardiac Glycosides as senolytic compounds. Nat. Commun. 10, 4731 (2019). sourceSupported
• cites [16] Yosef, R. et al. Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL. Nat. Commun. 7, 11190 (2016). sourceSupported
• cites [17] Yousefzadeh, M. J. et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine 36, 18–28 (2018). sourceSupported
• cites [18] Zhu, Y. et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. 14, 644–658 (2015). sourceSupported
• cites [19] Zhu, Y. et al. New agents that target senescent cells: the flavone, fisetin, and the BCL-X inhibitors, A1331852 and A1155463. Aging 9, 955–963 (2017). sourceSupported
• cites [23] Lafontaine, J. et al. Senolytic targeting of Bcl-2 anti-apoptotic family increases cell death in irradiated sarcoma cells. Cancers https://doi.org/10.3390/cancers13030386 (2021). sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

The hit confirmation rate for the 21 tested candidate compounds was 14.28%.

“We then tested the 21 candidate compounds and found three with clear senolytic action: periplocin and oleandrin, two cardiac glycosides which have not been previously identified as senolytics, and ginkgetin, a natural non-toxic biflavone; this amounts to a hit confirmation rate of 14.28% (Fig. 3c, d and Supplementary Fig. 4c).”

Principal component analysis shows that more than 100 dimensions are needed to accurately explain the variability in the data, with 111 features for 99% of explained variance.

“a principal component analysis shows that more than 100 dimensions are needed to accurately explain the variability in the data (111 features for 99% of explained variance, Supplementary Fig. 1b).”

Treatment of senescent IMR90 ER:RAS cells with periplocin, oleandrin, or ginkgetin reduced nuclei counts compared with proliferating non-senescent IMR90 controls, with an effect comparable to the positive control.

“Treatment of senescent IMR90 ER:RAS cells with the three compounds showed reduced nuclei counts when compared with proliferating, non-senescent IMR90 controls with an effect comparable to the positive control (Fig. 3c, d and Supplementary Fig. 5a).”

An optimal senolytic effect was reached with addition of 46.4 nM ouabain (IC50 control = 231 nM; IC50 senescence = 28 nM) to 4-OHT-induced IMR90 ER:RAS cells.

“An optimal senolytic effect was reached with addition of 46.4 nM ouabain (IC50 control = 231 nM; IC50 senescence = 28 nM) to 4-OHT-induced IMR90 ER:RAS cells.”

The selected panel of positives includes compounds that target the senescent phenotype in a variety of cell types.

“The selected panel of positives includes compounds that target the senescent phenotype in a variety of cell types (Fig. 1b).”

The experimental screen suggested that oleandrin had enhanced senolytic activity compared to the known cardiac glycoside ouabain, particularly in the low nanomolar range.

“Our experimental screen suggested that oleandrin had enhanced senolytic activity as compared to the known cardiac glycoside ouabain, particularly in the low nanomolar range (Fig. 3c).”

At 10 nM, ouabain and periplocin showed no cytotoxic activity in IMR90-ER:STOP proliferating control cells or in IMR90-ER:RAS cells undergoing OIS.

“While ouabain and periplocin showed no cytotoxic activity in IMR90-ER:STOP proliferating control cells nor in IMR90-ER:RAS cells undergoing OIS, oleandrin showed a significant drop in cellular content in OIS cell cultures at 10 nM”

The positive compounds were mined from highly heterogeneous sources that utilised different cell lines, screening assays, and methods for induction of the senescent phenotype.

“The positive compounds were mined from highly heterogeneous sources that utilised different cell lines, screening assays, and methods for induction of the senescent phenotype (Fig. 1b).”

The authors mined a panel of 58 senolytics reported in the literature.

“we mined a panel of 58 senolytics reported in the literature”

Treatment of oncogene-induced and replicative senescent cells with 10 nM oleandrin induced an evident increase in caspase-3/7 activity compared to control cells and cells treated with oleandrin and periplocin.

“Importantly, treatment of oncogene-induced and replicative senescent cells with 10 nM oleandrin induced an evident increase in caspase-3/7 activity when compared to control cells, as well as cells treated with oleandrin and periplocin”

Senescent cells displayed increased intracellular K+.

“We confirmed that senescent cells displayed increased intracellular K+.”

Louvain clustering of the Tanimoto distance graph found plateaus at k = 5 and k = 6 clusters.

“we found an almost linear increase in the number of clusters, and two plateaus at k = 5 and k = 6 clusters (Fig. 1e)”

The three newly found senolytic compounds have potency comparable to known senolytics.

“The compounds have potency comparable to known senolytics”

• Also stated in: § Introduction · plain

  “with potencies and dose-responses comparable to known senolytics”

In senescent A549 cells, the three compounds had lower IC50 values than in normal cells.

“The dose-response curves showed a lowered IC50 for the three compounds in senescent cells as compared to normal cells (Supplementary Fig. 6d).”

Silhouette coefficients averaged across all compounds were consistently low.

“we found consistently low values for the silhouette coefficient averaged across all compounds”

• cites [58] Hastie, T., Friedman, J. & Tibshirani, R. The Elements of Statistical Learning. Springer Series in Statistics. https://doi.org/10.1007/978-0-387-21606-5 (2001). sourceNot checked — no full text of the source

Only oleandrin at 10 nM significantly reduced K+ intracellular concentration during OIS and replicative senescence in IMR90 cells.

“However, only oleandrin at 10 nM significantly reduced K+ intracellular concentration during OIS and replicative senescence in IMR90 cells (Fig. 5a, b and Supplementary Fig. 9h, i)”

Both SVM and RF models displayed poor performance.

“We found that both SVM and RF models displayed poor performance (Fig. 2b)”

The three compounds had lower IC50 values for nuclei counts from senescent cells than from normal cells.

“The dose-response curves showed a lower IC50 for the three compounds in nuclei counts from senescent cells as compared to nuclei from normal cells (Fig. 3d).”

Alternative models, including logistic regressors, a Naïve Bayes classifier, and SMOTE data augmentation, displayed worse performance than the SVM and RF models.

“We also evaluated a number of alternative models of varied complexity, including logistic regressors, a Naïve Bayes classifier, as well as data augmentation methods for imbalanced classification (SMOTE63); these additional models displayed worse performance than the SVM and RF models (Supplementary Table 2).”

• cites [63] Chawla, N. V., Bowyer, K. W., Hall, L. O. & Kegelmeyer, W. P. SMOTE: synthetic minority over-sampling technique. J. Artif. Intell. Res. https://doi.org/10.1613/jair.953 (2002). sourceNot checked yet

At 10 nM, oleandrin showed a significant drop in cellular content in OIS cell cultures.

“While ouabain and periplocin showed no cytotoxic activity in IMR90-ER:STOP proliferating control cells nor in IMR90-ER:RAS cells undergoing OIS, oleandrin showed a significant drop in cellular content in OIS cell cultures at 10 nM”

The basic flavone scaffold present in ginkgetin is also present in inactive compounds herbacetin and morin.

“Similarly, the basic flavone scaffold present in ginkgetin (Supplementary Fig. 8b, coloured blue) is also present in inactive compounds, herbacetin and morin.”

The training data have a heavy imbalance between the number of positives and negatives.

“This is further exacerbated by the heavy imbalance between the number of positives and negatives included in the training data.”

The same three compounds validated in oncogene-induced senescent cells (periplocin, oleandrin, ginkgetin) also displayed strong senolytic action in senescent A549 cells.

“we found that the same three compounds validated in oncogene-induced senescent cells (periplocin, oleandrin, ginkgetin) also displayed strong senolytic action in senescent A549 cells.”

Feature selection identified a reduced set of 165 normalised features.

“we identified a reduced set of 165 normalised features (Supplementary Fig. 1a).”

The selected compounds are extreme outliers, with prediction scores at least 8 standard deviations away from the bulk of compounds screened.

“The selected compounds are extreme outliers, with prediction scores at least 8 standard deviations away from the bulk of compounds screened (Fig. 2e).”

More than half of the 58 training senolytics were maximally distant from the newly discovered senolytics in Tanimoto descriptor space.

“More than half of the training compounds were found to be maximally distant from our newly discovered senolytics”

None of the cardiac glycosides ouabain, periplocin, and oleandrin induced unwanted changes in proliferation at 10 nM in proliferating IMR90 cells.

“observing that none of the cardiac glycosides induced unwanted changes in proliferation at 10 nM concentration (Supplementary Fig. 9g).”

Low adjusted Rand index scores, with mean ARI < 0.05 for 100 runs, indicate that compounds do not cluster according to the source from which they were obtained.

“We found low ARI scores (Fig. 1e) across all cluster resolutions described by the γ parameter; moreover, the ARI scores showed pronounced troughs at the plateaus detected with the Louvain method (mean ARI < 0.05 for 100 runs of the clustering method), which we regarded as sufficient evidence that compounds do not cluster according to the source from which they were obtained.”

• cites [61] Gates, A. J. & Ahn, Y.-Y. The impact of random models on clustering similarity. bioRxiv https://doi.org/10.1101/196840 (2017). sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

k-means clustering of the positives revealed an almost linear decrease in the k-means score with respect to the number of clusters.

“We first clustered the positives with the k-means algorithm58 and the cosine distance between feature vectors; this analysis revealed an almost linear decrease in the k-means score with respect to the number of clusters (Fig. 1c).”

• cites [58] Hastie, T., Friedman, J. & Tibshirani, R. The Elements of Statistical Learning. Springer Series in Statistics. https://doi.org/10.1007/978-0-387-21606-5 (2001). sourceNot checked — no full text of the source

The XGBoost model substantially outperformed a deep learning model based on message-passing neural networks.

“We also benchmarked the XGBoost model against a deep learning model based on message-passing neural networks that have shown excellent performance across a range of molecular property prediction tasks39, but these were substantially outperformed by the XGBoost model (Supplementary Fig. 2).”

• cites [39] Stokes, J. M. et al. A deep learning approach to antibiotic discovery. Cell 181, 475–483 (2020). sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

The authors combined the 58 literature senolytics with another panel of 19 senolytics reported in a commercial patent.

“We combined these positives with another panel of 19 senolytics reported in a commercial patent14.”

• cites [14] Senolytic compounds. Patent no. 20200121620, (2018).Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Testing 21 candidate compounds identified three with clear senolytic action: periplocin, oleandrin, and ginkgetin.

“We then tested the 21 candidate compounds and found three with clear senolytic action: periplocin and oleandrin, two cardiac glycosides which have not been previously identified as senolytics, and ginkgetin, a natural non-toxic biflavone; this amounts to a hit confirmation rate of 14.28% (Fig. 3c, d and Supplementary Fig. 4c).”

Oleandrin does not affect the proliferative capacity and viability of normal cells at that nanomolar concentration.

“Moreover, we saw that oleandrin does not affect the proliferative capacity and viability of normal cells at that nanomolar concentration, indicating promising senolytic potential.”

The method reduced the number of compounds for experimental screening by more than 200-fold.

“our method led to large gains in efficiency by reducing the number of compounds for experimental screening by more than 200-fold.”

Only oleandrin induced a significant increase in NOXA mRNA expression at 10 nM.

“We observed that only oleandrin induced a significant increase in NOXA mRNA expression at a low concentration of 10 nM (Fig. 5c, d)”

The library of negative compounds contained 2465 compounds from LOPAC-1280 and Prestwick FDA-approved-1280.

“The library of negative compounds contains 2465 compounds from the LOPAC-1280 (Library of Pharmacologically Active Compounds; Merck, Darmstadt, Germany) and Prestwick FDA-approved-1280 (Prestwick Chemical, Illkirch, France).”

Classic physicochemical descriptors calculated from SMILES strings were sufficient to train useful models.

“In our approach, we found that classic physicochemical descriptors57 calculated from SMILES strings were sufficient to train useful models.”

• cites [57] RDKit: Open-source cheminformatics. https://www.rdkit.org.Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

The models generally displayed poor performance as quantified by common classification metrics, producing large numbers of false positives and false negatives in cross-validation.

“Moreover, our models generally displayed poor performance as quantified by common classification metrics, producing large numbers of false positives and false negatives in cross-validation.”

Treatment with oleandrin for three days resulted in reduced expression of proinflammatory cytokines IL1α, IL1β and IL8 mRNA in surviving cells in OIS and replicative senescence.

“Furthermore, treatment with oleandrin for three days resulted in reduced expression of proinflammatory cytokines IL1α, IL1β and IL8 mRNA in the surviving cells in OIS (Supplementary Fig. 9l) and replicative senescence (Supplementary Fig. 9m).”

The machine learning models were trained on just 58 chemical structures with proven senolytic action.

“Second, our machine learning models were trained on just 58 chemical structures with proven senolytic action, which is much smaller data than typically considered in the field”

After three days of treatment with 10 nM oleandrin, mRNA expression of senescence markers p16 and p21 was reduced in surviving cells in both OIS and replicative senescence cell cultures.

“Moreover, after three days of treatment with 10 nM oleandrin, the mRNA expression of the senescence markers p16 and p21 was found to be reduced in the surviving cells in both OIS (Supplementary Fig. 9j) and replicative senescence (Supplementary Fig. 9k) cell cultures.”

The training data had a strong imbalance between the number of senolytic and non-senolytic compounds, which introduced additional challenges for model training.

“These design choices produced a strong imbalance between the number of senolytic and non-senolytic compounds, which introduced additional challenges for model training.”

The performance metrics computed on the 30% held-out compounds are over-optimistic because feature selection and model selection accessed the full dataset.

“Therefore, the performance metrics computed on a set of 30% held-out compounds are over-optimistic, since model selection benefitted from accessing those testing samples during feature selection and cross-validation on the full data.”

The steroid hormone core structure alone present in periplocin, oleandrin, and ouabain is insufficient for senolytic activity, when compared with inactive compounds taurocholic acid and gamma-oryzanol.

“The steroid hormone core structure alone (Supplementary Fig. 8a, coloured red) present in periplocin, oleandrin and ouabain is insufficient for senolytic activity, when compared to inactive compounds taurocholic acid and gamma-oryzanol.”

Oleandrin has a more substantial senolytic effect than ouabain in replicative senescence and therapy-induced senescence in epithelial cancer cells.

“This indicates that oleandrin has a more substantial senolytic effect than ouabain in replicative senescence and therapy-induced senescence in epithelial cancer cells (Fig. 4c and Supplementary Fig. 9b, d, e).”

Oleandrin inhibits its canonical target at lower concentrations than ouabain in senescent cells.

“indicating that oleandrin inhibits its canonical target at lower concentrations than ouabain in senescent cells.”

Oleandrin has enhanced and highly specific senolytic activity at a lower drug concentration.

“which is indicative of an enhanced and highly specific senolytic activity at a lower drug concentration (Fig. 4a, b).”

The heterogeneity of the positive compounds bears the risk of introducing bias in the models and limiting their predictive power if specific chemical families are overrepresented in the training data.

“This bears the risk of introducing bias in our models and limit their predictive power if specific chemical families are overrepresented in the training data.”

Artificial intelligence can take maximum advantage of small and heterogeneous drug screening data.

“demonstrates that artificial intelligence can take maximum advantage of small and heterogeneous drug screening data”

Senolytic cardiac glycosides activate a transcriptional programme resulting in the induction of several pro-apoptotic Bcl-2 family proteins.

“Senolytic cardiac glycosides activate a transcriptional programme resulting in the induction of several pro-apoptotic Bcl-2 family proteins13.”

• cites [13] Guerrero, A. et al. Cardiac glycosides are broad-spectrum senolytics. Nat. Metab. 1, 1074–1088 (2019). sourceNot checked yet

Only two compounds have shown efficacy in clinical trials: dasatinib and quercetin in combination therapy.

“only two compounds have shown efficacy in clinical trials (dasatinib and quercetin in combination therapy29).”

• cites [29] Hickson, L. J. et al. Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. EBioMedicine 47, 446–456 (2019). sourceNot checked yet

The authors' approach led to several hundred-fold reduction in drug screening costs.

“Our approach led to several hundred-fold reduction in drug screening costs”

Oleandrin displays improved senolytic performance over benchmark senolytic cardiac glycosides.

“AI-identified compound oleandrin displays improved senolytic performance over benchmark senolytic cardiac glycosides”

The Tanimoto distance results provide some validation that the machine learning approach can effectively identify diverse compounds for specific biological effects such as senolysis.

“which provides some validation that our machine learning approach can effectively identify diverse compounds for specific biological effects such as senolysis.”

The glycoside linkages and furanone moiety are likely contributing to target binding and potency of periplocin, oleandrin, and ouabain beyond physicochemical properties.

“Hence the glycoside linkages (Supplementary Fig. 8a, coloured blue) and furanone moiety (Supplementary Fig. 8a, purple) are likely contributing to target binding and potency, beyond physicochemical properties (e.g. solubility or cell permeability).”

The low silhouette coefficients suggest little similarity among the senolytic compounds chosen for training.

“which further suggests little similarity among the senolytic compounds chosen for training.”

Oleandrin induces apoptosis in senescent cells at lower concentrations than ouabain.

“confirming that oleandrin induces apoptosis in senescent cells at lower concentrations than ouabain (Fig. 4d and Supplementary Fig. 9f).”

Senolytics have shown substantial promise in ameliorating symptoms of many conditions in mice.

“Senolytics have shown substantial promise in ameliorating symptoms of many conditions in mice11–20”

• cites [11] Fuhrmann-Stroissnigg, H. et al. Identification of HSP90 inhibitors as a novel class of senolytics. Nat. Commun. 8, 422 (2017). sourceNot checked yet
• cites [12] Guerrero, A. et al. Galactose-modified duocarmycin prodrugs as senolytics. Aging Cell. 19, e13133 (2020). sourceNot checked yet
• cites [13] Guerrero, A. et al. Cardiac glycosides are broad-spectrum senolytics. Nat. Metab. 1, 1074–1088 (2019). sourceNot checked yet
• cites [14] Senolytic compounds. Patent no. 20200121620, (2018).Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [15] Triana-Martínez, F. et al. Identification and characterization of Cardiac Glycosides as senolytic compounds. Nat. Commun. 10, 4731 (2019). sourceNot checked yet
• cites [16] Yosef, R. et al. Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL. Nat. Commun. 7, 11190 (2016). sourceNot checked yet
• cites [17] Yousefzadeh, M. J. et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine 36, 18–28 (2018). sourceNot checked yet
• cites [18] Zhu, Y. et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. 14, 644–658 (2015). sourceNot checked yet
• cites [19] Zhu, Y. et al. New agents that target senescent cells: the flavone, fisetin, and the BCL-X inhibitors, A1331852 and A1155463. Aging 9, 955–963 (2017). sourceNot checked yet
• cites [20] Chang, J. et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat. Med. 22, 78–83 (2016). sourceNot checked yet

Seemingly poor models can be employed effectively with adequate checks and balances on the structure of the data, plus careful interpretation of misclassification errors.

“Our results thus show that seemingly poor models can be employed effectively with adequate checks and balances on the structure of the data, plus a careful interpretation of misclassification errors.”

The robustness of results can be assessed with randomised repeats of model training and screening.

“Although cutoff selection is highly problem-dependent, the robustness of results can be assessed with randomised repeats of model training and screening (Supplementary Fig. 10).”

Oleandrin has a potent effect over benchmark cardiac glycosides.

“confirming the potent effect of oleandrin over benchmark cardiac glycosides.”

Artificial intelligence and machine learning can help discover new and better-performing active compounds for a given pharmacological group.

“Our work thus demonstrates that artificial intelligence and machine learning can help discover new and better-performing active compounds for a given pharmacological group.”

The success of the approach demonstrates that machine learning can take maximum advantage of literature data, even when such data is heterogeneous and of much smaller scale than typically expected.

“The success of our approach demonstrates that machine learning can take maximum advantage of literature data, even when such data is heterogeneous and of much smaller scale than typically expected71.”

• cites [71] Bender, A. & Cortés-Ciriano, I. Artificial intelligence in drug discovery: what is realistic, what are illusions? Part 1: Ways to make an impact, and why we are not there yet. Drug Discovn Today. https://doi.org/10.1016/j.drudis.2020.12.009 (2021). sourceNot checked yet

• AssumptionRests on an assumption: Senolysis is a rare molecular property and the number of senolytics reported in the literature so far is limited.

The three compounds have a potency comparable or higher to senolytics previously described in the literature.

“We showed that these compounds have a potency comparable or higher to senolytics previously described in the literature”

The approach identified oleandrin, a cardiac glycoside with stronger potency than the benchmark senolytic cardiac glycoside ouabain.

“Importantly, our approach identified oleandrin, a cardiac glycoside with stronger potency than the benchmark senolytic cardiac glycoside ouabain.”

Cardiac glycosides employed in heart conditions have severe limitations due to toxicity.

“A caveat, however, is that cardiac glycosides that have been employed in heart conditions have severe limitations due to toxicity76”

• cites [76] Zhai, J., Dong, X., Yan, F., Guo, H. & Yang, J. Oleandrin: a systematic review of its natural sources, structural properties, detection methods, pharmacokinetics and toxicology. Front. Pharmacol. 13, 822726 (2022). sourceNot checked yet

  Checked before — its earlier verdict is held back until a new check runs.

Careful data assembly, curation, and quality control were key for success.

“We found that careful data assembly, curation, and quality control were key for success.”

The machine learning strategy revealed three compounds (ginkgetin, oleandrin, and periplocin) that selectively eliminate cells displaying oncogene- and therapy-induced senescence.

“Our strategy revealed three compounds (ginkgetin, oleandrin and periplocin) that selectively eliminate cells displaying oncogene- and therapy-induced senescence.”

The screening library was designed to balance similarity with the training data against exploration of novel chemical spaces.

“We carefully designed the screening library to balance similarity with the training data against exploration of novel chemical spaces (Fig. 2f).”