Completed
Researchers at the Laboratory Genetic Metabolic Disease are looking at drug development in a different way. By evaluating transcriptional changes in any disease state, they are able to computationally screen tens of thousands of compounds that have a high probability of interacting, preventing, or eliciting the same effect. Their computational pipelines are greatly accelerating the drug discovery process.

Transcriptome-based drug screening is emerging as a powerful tool to identify compounds to intervene in many different diseases. Here researchers from the AMC have developed approaches which were validated for their ability to identify compounds that slow aging. The team hypothesized that, by mimicking the transcriptional signature of the highly conserved longevity intervention of FOXO3 (daf-16 in worms) overexpression, they could identify and repurpose compounds with similar downstream effects to increase longevity. Their in silico screen, utilizing the LINCS transcriptome database of genetic and compound interventions, identified several FDA-approved compounds that activate FOXO downstream targets in mammalian cells.

These included the neuromuscular blocker atracurium, which also robustly extended both lifespan and healthspan in C. elegans. This longevity was dependent on both daf-16 (orthologous to FOXO) signaling and inhibition of the neuromuscular acetylcholine receptor. Other neuromuscular blockers tubocurarine and pancuronium caused similar healthspan benefits. Further validating their approach, the researchers demonstrated nuclear localization of DAF-16 upon atracurium treatment, and, using RNAseq transcriptomics, identified activation of DAF-16 downstream effectors. Together, these data demonstrate the capacity to mimic genetic lifespan interventions with drugs, and in doing so, reveal that the neuromuscular acetylcholine receptor regulates the highly conserved FOXO/DAF-16 longevity pathway. In general, this approach may be valuable to other disease areas.

Conclusion

The work indeed identified the FOXO activator Atracurium and was published as described on the AMC website (ref1). We followed this up with a review on FOXO3 activators (ref2). The drug screen we performed was then expanded, and we discovered that the NRTI Zidovudine extends lifespan in worms via ATF-4 (ref3), which we also followed up with a review on NRTIs and lifespan extension (ref4). We continued the transcriptional drug screening and identified that the HDAC1/2 inhibitor reverses aspects of aging in mice in multiple organs (ref5). HDAC inhibitors are a drug class we previously reviewed for their influence on healthy aging (ref6). Finally, expanding again on the transcriptional drug screening, we found that Low Dose Naltrexone extends lifespan via SKN-1/NRF in worms (ref7). On the bottom of this page you can find the relevant publications of the team, related to their drug screening work.

Amsterdam UMC researchers involved in this project

Rashmi Kamble
Michael Petr
Morten Scheibye-Knudsen

Publications

1.McIntyre RL, Denis SW, Kamble R, Molenaars M, Petr M, Schomakers BV, Rahman M, Gupta S, Toth ML, Vanapalli SA, Jongejan A, Scheibye-Knudsen M, Houtkooper RH, Janssens GE#. Inhibition of the neuromuscular acetylcholine receptor with atracurium activates FOXO/DAF-16-induced longevity.Aging Cell. 2021 Aug;20(8):e13381. doi: 10.1111/acel.13381. Epub 2021 Jul 6.

2.McIntyre RL, Liu YJ, Hu M, Morris BJ, Willcox BJ, Donlon TA, Houtkooper RH, Janssens GE#.Pharmaceutical and nutraceutical activation of FOXO3 for healthy longevity.Ageing Res Rev.2022 Jun;78:101621. doi: 10.1016/j.arr.2022.101621. Epub 2022 Apr 11. PMID: 35421606.

3.McIntyre RL, Molenaars M, Schomakers BV, Gao AW, Kamble R, Jongejan A, van Weeghel M, van Kuilenburg ABP, Possemato R, Houtkooper RH, Janssens GE#. Anti-retroviral treatment with zidovudine alters pyrimidine metabolism, reduces translation, and extends healthy longevity via ATF-4.Cell Rep. 2023 Jan 31;42(1):111928. doi: 10.1016/j.celrep.2022.111928. Epub 2022 Dec 30. PMID: 36640360.

4.Brochard T, McIntyre RL, Houtkooper RH, Seluanov A, Gorbunova V, Janssens GE#.Repurposing nucleoside reverse transcriptase inhibitors (NRTIs) to slow aging. Ageing Res Rev. 2023 Dec;92:102132. doi: 10.1016/j.arr.2023.102132. Epub 2023 Nov 19. PMID: 37984625.

5.Tammaro A, Daniels EG, Hu IM, ‘t Hart KC, Reid K, Juni RP, Butter LM, Vasam G, Kamble R, Jongejan A, Aviv RI, Roelofs JJTH, Aronica E, Boon RA, Menzies KJ, Houtkooper RH, Janssens GE#. HDAC1/2 inhibitor therapy improves multiple organ systems in aged mice.iScience. 2023 Dec 12;27(1):108681. doi: 10.1016/j.isci.2023.108681. PMID: 38269100; PMCID: PMC10805681.

6.McIntyre RL, Daniels EG, Molenaars M,HoutkooperRH, JanssensGE#. From molecular promise to preclinical results: HDAC inhibitors in the race for healthy aging drugs.EMBO Mol Med. 2019Sep;11(9):e9854. doi: 10.15252/emmm.201809854.

7.Li W, McIntyre RL, Schomakers BV, Kamble R, Luesink AHG, van Weeghel M, Houtkooper RH, Gao AW#, Janssens GE#.Low-dose naltrexone extends healthspan and lifespan in C.elegansvia SKN-1 activation.iScience. 2024 May 8;27(6):109949. doi: 10.1016/j.isci.2024.109949. PMID: 38799567; PMCID: PMC11126937.