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

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-b 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. Agilent RNA 6000 Nano reagents Agilent Technologies 5067-1511 Deposited Data Raw and Processed RNA-Seq data This paper GEO: GSE108263 Raw and Processed Lipidomics data This Paper MetaboLights: MTBLS648 Experimental Models: Organisms/Strains C. elegans: Strain Bristol wild-type N2 Caenorhabditis Genetics Center N2 C. elegans: Strain daf-2(e1370)III Caenorhabditis Genetics Center CB1370 C. elegans: Strain daf-16(mu86) I Caenorhabditis Genetics Center CF1038 C. elegans: Strain daf-7(e1372) III Caenorhabditis Genetics Center CB1372 C. elegans: Strain eat-2 (ad1116) II Caenorhabditis Genetics Center DA1116 C. elegans: Strain sbp-1 (ep79) III Caenorhabditis Genetics Center CE541 D. melanogaster: Male Bloomington Drosophila Stock Center Oregon-R Oligonucleotides Primer: sbp-1 Forward: gca cgt tct gac atg tgg aa This paper N/A Primer: sbp-1 Reverse: ccg cca aac cca gat tgt ct This paper N/A

WormCat: an online tool for annotation and visualization of Caenorhabditis elegans genome-scale data

“…We have identified differential enrichment 706 in lipid metabolism genes and collagens from intestine and hypodermis, defined a 2018). They found that one triple drug combination (Rifa/Psora/Allan) activated 723 lipogenic metabolism through the transcription factor SBP-1/SREBP-1 and determined 724 that the drug-induced longevity was dependent on SBP-1 function (Admasu et al 2018). 725…”

“…The authors also made the striking observation that a distinct triple drug combination 726 (Rifa/Rapa/Psora) reduced lifespan, even though each single drug or drug pairs 727 increased longevity (Admasu et al 2018). To determine if any gene expression 728 categories might explain this effect, we used WormCat to analyze category enrichment 729 for the up and downregulated genes for each single drug, pairwise or triple drug 730 combination (Fig 6A, Figs S9, S10; Tables S11, S12).…”

“…Our results suggest 853 that many genes in this family could have important functions in spermatogenesis and 854 that the appearance of MSPs and TTKs in a dataset could also serve as a marker for 855 maleness. Finally, we used WormCat to analyze a dataset consisting of RNA-seq from 856 C. elegans treated with multiple lifespan changing drugs alone or in combination, plus 857 one mutation animal strain that extends lifespan (Admasu et al 2018). The 858 classification and graphical output allowed us to identify upregulation of sterol 859 metabolism genes in a triple-drug combination that was not present in the single or 860 double drug treatments.…”

A Waddington Epigenetic Landscape for the C. elegans embryo

“…, 11, 25 7, 10, 28, 38 22 T10E9.8 --D 1592. 6 5,11,12 7,28,5,[11][12][13]23,35 7 Y23H5B. 4, 5, 11-13, 19, 23, 35-37 7, 38 Y48G8AL.15 -Nucleoside diphosphate kinase D 1081.5 4, 5, 12, 19, 22, 25, 29, 51 7, 28 Y49F6B.5 sdz-32…”

Moonshots for aging

“…One proof-of-concept, aging-limiting cocktail is the Yamanaka pluripotency factors (24) that was tested with good results in a mouse model of the premature aging condition, progeria (25). Manipulating both insulin-like growth factor (IGF) and sterol-responsive element binding protein (SREBP) also produced strong synergistic healthspan-extending effects (26). Several other combinations have likewise been validated in model organisms (27,28).…”