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Dev Cell. 2018 Oct 8;47(1):67-79.e5. doi: 10.1016/j.devcel.2018.09.001. Epub 2018 Sep 27.

Drug Synergy Slows Aging and Improves Healthspan through IGF and SREBP Lipid Signaling.

Author information

1
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117608, Singapore; Department of Biochemistry, College of Medicine and Health Science, University of Gondar, Gondar, P.O. Box 196, Ethiopia.
2
Science Divisions, Yale, NUS College, Singapore 138527, Singapore.
3
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117608, Singapore; Singapore Lipidomics Incubator, Life Sciences Institute, National University of Singapore, Singapore 117456, Singapore.
4
Science Divisions, Yale, NUS College, Singapore 138527, Singapore; Department of Biological Sciences, National University of Singapore, Singapore, Singapore.
5
Science Divisions, Yale, NUS College, Singapore 138527, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117608, Singapore. Electronic address: jangruber467@gmail.com.

Abstract

There is growing interest in pharmacological interventions directly targeting the aging process. Pharmacological interventions against aging should be efficacious when started in adults and, ideally, repurpose existing drugs. We show that dramatic lifespan extension can be achieved by targeting multiple, evolutionarily conserved aging pathways and mechanisms using drug combinations. Using this approach in C. elegans, we were able to slow aging and significantly extend healthy lifespan. To identify the mechanism of these drug synergies, we applied transcriptomics and lipidomics analysis. We found that drug interactions involved the TGF-β pathway and recruited genes related with IGF signaling. daf-2, daf-7, and sbp-1 interact upstream of changes in lipid metabolism, resulting in increased monounsaturated fatty acid content and this is required for healthy lifespan extension. These data suggest that combinations of drugs targeting distinct subsets of the aging gene regulatory network can be leveraged to cause synergistic lifespan benefits.

KEYWORDS:

C. elegans; D. melanogaster; IGF; aging; drug synergy; lifespan; lipidomics; mTOR; monounsaturated fatty acids; transcriptomics

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