Effects ofCaenorhabditis elegans sgk‐1mutations on lifespan, stress resistance, andDAF‐16/FoxOregulation

Abstract

The AGC family serine–threonine kinases Akt and Sgk are similar in primary amino acid sequence and in vitro substrate specificity, and both kinases are thought to directly phosphorylate and inhibit FoxO transcription factors. In the nematode Caenorhabditis elegans, it is well established that AKT-1 controls dauer arrest and lifespan by regulating the subcellular localization of the FoxO transcription factor DAF-16. SGK-1 is thought to act similarly to AKT-1 in lifespan control by phosphorylating and inhibiting the nuclear translocation of DAF-16/FoxO. Using sgk-1 null and gain-of-function mutants, we now provide multiple lines of evidence indicating that AKT-1 and SGK-1 influence C. elegans lifespan, stress resistance, and DAF-16/FoxO activity in fundamentally different ways. Whereas AKT-1 shortens lifespan, SGK-1 promotes longevity in a DAF-16-/FoxO-dependent manner. In contrast to AKT-1, which reduces resistance to multiple stresses, SGK-1 promotes resistance to oxidative stress and ultraviolet radiation but inhibits thermotolerance. Analysis of several DAF-16/FoxO target genes that are repressed by AKT-1 reveals that SGK-1 represses a subset of these genes while having little influence on the expression of others. Accordingly, unlike AKT-1, which promotes the cytoplasmic sequestration of DAF-16/FoxO, SGK-1 does not influence DAF-16/FoxO subcellular localization. Thus, in spite of their similar in vitro substrate specificities, Akt and Sgk influence longevity, stress resistance, and FoxO activity through distinct mechanisms in vivo. Our findings highlight the need for a re-evaluation of current paradigms of FoxO regulation by Sgk.

Movement decline across lifespan of Caenorhabditis elegans mutants in the insulin/insulin‐like signaling pathway

“…All mutants had previously been reported to extend lifespan (Friedman & Johnson, 1988; Hertweck, Gobel, & Baumeister, 2004; Kenyon et al., 1993; McElwee, Bubb, & Thomas, 2003; Murphy, Lee, & Kenyon, 2007; Paradis, Ailion, Toker, Thomas, & Ruvkun, 1999; Tullet et al., 2008; Zhang et al., 2008). However, the sgk‐1 mutant has been observed to have variable lifespan (Chen, Guo, Dumas, Ashrafi, & Hu, 2013; Mizunuma, Neumann‐Haefelin, Moroz, Li, & Blackwell, 2014; Xiao et al., 2013). We used the log‐rank test to analyze survival.…”

“…Disruption of this process would be expected to extend lifespan, and indeed RNAi for sgk‐1 has been reported to extend lifespan (Hertweck et al., 2004). In other reports, the sgk‐1 mutant is short‐lived (Chen et al., 2013; Xiao et al., 2013). Mizunuma et al.…”

“…RNAi for the SGK‐1 protein has been reported to extend lifespan (Hertweck et al., 2004), but other studies report shortened lifespan for sgk‐1 mutants (Chen et al., 2013; Xiao et al., 2013). The SGK‐1 protein complexes with AKT‐1/AKT‐2 to phosphorylate DAF‐16/FOXO ; therefore, disruption of this process would be expected to extend lifespan.…”

A microRNA program in the C. elegans hypodermis couples to intestinal mTORC2/PQM-1 signaling to modulate fat transport

“…Active insulin signaling results in AKT-dependent phosphorylation of DAF-16, restricting its localization to the cytoplasm; conversely, low levels of insulin-like ligands or inactivation of daf-2 causes dephosphorylation of DAF-16/FoxO, driving it into the nucleus to modify the expression of its target genes (Lin et al 2001). Although controversial, SGK-1 may function in part through DAF-16 to modulate C. elegans development, stress resistance, and life span (Hertweck et al 2004;Chen et al 2013). To assess whether DAF-16, which represses vitellogenesis in the daf-2 mutant (DePina et al 2011), also functions downstream from SGK-1 to negatively regulate vitellogenin production, we crossed the daf-16-null mutation into the Pvit-3::GFP; sgk-1 mutant background.…”

Macromolecular Degradation Systems and Cardiovascular Aging

“…24 Moreover, the loss-offunction assays for multiple types of substrates downstream of mTOR leads to an extended lifespan in worms, suggesting that it plays a crucial role in cellular senescence. 25 Furthermore, there are several reports that these signaling pathways are involved in longevity in Drosophila and mice. 26 …”