DAF-21/Hsp90 is required for C. elegans longevity by ensuring DAF-16/FOXO isoform A function

Abstract

The FOXO transcription factor family is a conserved regulator of longevity and the downstream target of insulin/insulin-like signaling. In Caenorhabditis elegans, the FOXO ortholog DAF-16A and D/F isoforms extend lifespan in daf-2 insulin-like receptor mutants. Here we identify the DAF-21/Hsp90 chaperone as a longevity regulator. We find that reducing DAF-21 capacity by daf-21(RNAi) initiated either at the beginning or at the end of larval development shortens wild-type lifespan. daf-21 knockdown employed from the beginning of larval development also decreases longevity of daf-2 mutant and daf-2 silenced nematodes. daf-16 loss-of-function mitigates the lifespan shortening effect of daf-21 silencing. We demonstrate that DAF-21 specifically promotes daf-2 and heat-shock induced nuclear translocation of DAF-16A as well as the induction of DAF-16A-specific mRNAs, without affecting DAF-16D/F localization and transcriptional function. DAF-21 is dispensable for the stability and nuclear import of DAF-16A, excluding a chaperone-client interaction and suggesting that DAF-21 regulates DAF-16A activation upstream of its cellular traffic. Finally, we show a selective requirement for DAF-21 to extend lifespan of DAF-16A, but not DAF-16D/F, transgenic daf-2 mutant strains. Our findings indicate a spatiotemporal determination of multiple DAF-21 roles in fertility, development and longevity and reveal an isoform-specific regulation of DAF-16 activity.

Using the drug-protein interactome to identify anti-ageing compounds for humans

“…To determine whether the effects of tanespimycin on lifespan require hsp-90 , we also exposed worms to tanespimycin treatment in the presence of hsp-90(RNAi) . Consistent with previous reports, hsp-90(RNAi) significantly shortened C. elegans lifespan [43]. Furthermore, in the absence of HSP-90, tanespimycin treatment no longer increased lifespan compared to vehicle controls.…”

DnaJ chaperones contribute to canalization

“…This evidence suggests that these DnaJ genes are involved in canalization as part of a genetic network having multiple interacting clients, as Waddington had originally described canalization (Loison, ), rather than being involved in the seam cell development pathway. Our finding that the decrease in lifespan following the RNAi knockdown of some DnaJs, such as DNAJC3/ dnj‐7 , DNAJB11/ dnj‐20 , and DNAJC2/ dnj‐11 , is particularly intriguing, since an increase in expression of heat shock proteins such as HSF‐1 (Morley & Morimoto, ), daf‐21 /Hsp90 (Somogyvári, Gecse, & Sőti, ), hsp70 (Tatar, Khazaeli, & Curtsinger, ), and hsp‐16.2 (Rea, Wu, Cypser, Vaupel, & Johnson, ), has been shown to increase lifespan. In these DnaJs, expression decrease might decanalize the phenotype whilst the population might increase lifespan and propagate.…”

Transcriptomics-based screening identifies pharmacological inhibition of Hsp90 as a means to defer aging

“…Further, we treated C. elegans with RNAi against daf-21 , the gene encoding Hsp90 in this organism. RNAi against daf-21 already during larval stages impairs growth and has been reported to even shorten lifespan (Somogyvári et al, 2018). Nevertheless, when we knocked down this gene only from young adulthood, animals lived longer (Fig 3G, Table S10) – which is fully consistent with our Hsp90 inhibitor data.…”