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Doubling healthy lifespan using drug synergy

Tesfahun Dessale, Krishna Chaithanya Batchu, Diogo Barardo, Ng Li Fang, Vanessa Yuk Man Lam, Linfan Xiao, Markus R. Wenk, Nicholas S. Tolwinski, Jan Gruber
doi: https://doi.org/10.1101/153205
Tesfahun Dessale
1Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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Krishna Chaithanya Batchu
2Science Divisions, Yale-NUS College, Singapore
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Diogo Barardo
2Science Divisions, Yale-NUS College, Singapore
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Ng Li Fang
2Science Divisions, Yale-NUS College, Singapore
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Vanessa Yuk Man Lam
2Science Divisions, Yale-NUS College, Singapore
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Linfan Xiao
2Science Divisions, Yale-NUS College, Singapore
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Markus R. Wenk
1Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
3Singapore Lipidomics Incubator, Life Sciences Institute, National University of Singapore, Singapore
4Department of Biological Sciences, National University of Singapore, Singapore
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Nicholas S. Tolwinski
2Science Divisions, Yale-NUS College, Singapore
4Department of Biological Sciences, National University of Singapore, Singapore
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Jan Gruber
1Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
2Science Divisions, Yale-NUS College, Singapore
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Summary

Pharmacological interventions that target human ageing would extend individual healthspan and result in dramatic economic benefits to rapidly ageing societies worldwide. For such interventions to be contemplated they need to comprise drugs that are efficacious when given to adults and for which extensive human safety data are available. Here we show that dramatic lifespan extension can be achieved in C.elegans by targeting multiple, evolutionarily conserved ageing pathways using drugs that are already in human use. By targeting multiple synergistic ageing pathways, we are able to slow ageing rate, double lifespan and improves healthspan while minimize developmental and fitness trade-offs. Moreover, we established that there is no synergistic benefit in a daf-2 or daf-7 background, implying the involvement of the TGFβ and IGF pathways in this synergy. Employing lipidomics and transcriptomics analysis we found lipid metabolism to be affected resulting in increased monounsaturated fatty acids (MUFA) and decrease membrane peroxidation index. Our best drug combination showed a conserved lifespan extension in fruit flies. To the best of our knowledge, this is the largest lifespan effect ever reported for any adult-onset drug treatment in C. elegans. This drug-repurposing approach, using drugs already approved for humans to target multiple conserved aging pathways simultaneously, could lead to interventions that prevent age-related diseases and overall frailty in a rapidly ageing population.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted August 01, 2017.
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Doubling healthy lifespan using drug synergy
Tesfahun Dessale, Krishna Chaithanya Batchu, Diogo Barardo, Ng Li Fang, Vanessa Yuk Man Lam, Linfan Xiao, Markus R. Wenk, Nicholas S. Tolwinski, Jan Gruber
bioRxiv 153205; doi: https://doi.org/10.1101/153205
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Doubling healthy lifespan using drug synergy
Tesfahun Dessale, Krishna Chaithanya Batchu, Diogo Barardo, Ng Li Fang, Vanessa Yuk Man Lam, Linfan Xiao, Markus R. Wenk, Nicholas S. Tolwinski, Jan Gruber
bioRxiv 153205; doi: https://doi.org/10.1101/153205

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