The idea of a ‘fountain of youth’ has been a tantalizing thought throughout human history. While it might have always seemed to be a futile dream, our understanding of the biology of aging is at a point now where we are able to effectively extend the lifespans of model organisms; from simple yeast cells to complex mammals.
Our team works to identify small molecules that can serve as therapeutic compounds in aging. Our approach generally involves doing in silico (computational) drug screens using machine learning or other algorithms, based on ‘omics’ or other large complex datasets. We search for compounds that activate longevity pathways or reverse detrimental aging changes. Once we get candidate lists of compounds, we validate these in model organisms such as worms or mice for their aging-therapeutic potential and discern the mechanism of action of the compounds.
Our work has led us to explore multiple routes to promote healthy aging through small molecules, including (A) compounds that activate the longevity transcription factor FOXO3 to increase cell-protective signaling cascades [1,2], (B) certain anti-retrovirals that activate the mito-cytosolic stress transcription factor ATF4 , (C) epigenetic modifier drugs known as histone deacetylase (HDAC) inhibitors , (D) doxazosin, an alpha blocker associated with improved movement patterns with age in humans , and (E) inhibitors of HSP90 that activate the unfolded protein response via the transcription factor HSF1 and promote proteostasis . We also have other small molecules that are in secret development :-). And all of these compounds require further research before applying to humans as an intervention to promote healthy aging [7,8].
For a great presentation on a drug we discovered that extends healthspan and lifespan–the anti-retroviral zidovudine–I’d invite you to listen to Rebecca McIntyre, a PhD student (graduated oct 2022) give a talk at the ARDD 2022 conference in Copenhagen:
Curious to know more about biomedical longevity interventions? Some of these blogs may be of interest to you:
- Should I take rapamycin to slow my aging?
- Should I take nicotinamide riboside to slow my aging?
- Should I take metformin for aging?
- Why we should develop medicines that target aging itself
References (* indicates equal contribution and # indicates correspondence). For an extended reference list see the about page.
- 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.
- 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.
- 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.
- McIntyre RL, Daniels EG, Molenaars M, Houtkooper RH, JanssensGE#. From molecular promise to preclinical results: HDAC inhibitors in the race for healthy aging drugs.EMBO Mol Med. 2019 Sep;11(9):e9854. doi: 10.15252/emmm.201809854.
- McIntyre RL, Rahman M, Vanapalli SA , Houtkooper RH, Janssens GE#. Biological Age Prediction From Wearable Device Movement Data Identifies Nutritional and Pharmacological Interventions for Healthy Aging. Front. Aging, 2021July. doi.org/10.3389/fragi.2021.708680
- Janssens GE*, Lin X*, Millan-Arino L*, Seinstra RI, Stroustrup N, Nollen EAA, Riedel CR. Transcriptomics-Based Screening Identifies Pharmacological Inhibition of Hsp90 as a Means to Defer Aging.Cell Rep. 2019Apr 9;27(2):467-480.e6. doi: 10.1016/j.celrep.2019.03.044.
- Janssens GE#, Houtkooper RH. Identification of longevity compounds with minimized probabilities of side effects.Biogerontology. 2020Jun 19. doi: 10.1007/s10522-020-09887-7.
- Liu YJ, McIntyre RL, Janssens GE#.Considerations regarding public use of longevity interventions. Frontiers in Aging2022. 3:2022, DOI 10.3389/fragi.2022.903049