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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / drug effects*
  • Allantoin
  • Animals
  • Caenorhabditis elegans / metabolism
  • Caenorhabditis elegans Proteins / metabolism
  • Drosophila melanogaster / drug effects
  • Drug Synergism
  • Ficusin
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Gene Regulatory Networks / drug effects
  • Insulin-Like Growth Factor I / metabolism
  • Lipid Metabolism
  • Lipids
  • Longevity / drug effects*
  • Longevity / genetics
  • Metformin
  • Rifampin
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Sirolimus
  • Sterol Regulatory Element Binding Protein 1 / metabolism
  • Transcriptome
  • Transforming Growth Factor beta / metabolism


  • 5-(4-phenylbutoxy)psoralen
  • Caenorhabditis elegans Proteins
  • Lipids
  • Sterol Regulatory Element Binding Protein 1
  • Transforming Growth Factor beta
  • Allantoin
  • Insulin-Like Growth Factor I
  • Metformin
  • Ficusin
  • Rifampin
  • Sirolimus