Direct Inhibition of the Longevity-Promoting Factor SKN-1 by Insulin-like Signaling in C. elegans

Section on Developmental and Stem Cell Biology, Joslin Diabetes Center
Cell (Impact Factor: 33.12). 04/2008; 132(6):1025-38. DOI: 10.1016/j.cell.2008.01.030
Source: PubMed

ABSTRACT Insulin/IGF-1-like signaling (IIS) is central to growth and metabolism and has a conserved role in aging. In C. elegans, reductions in IIS increase stress resistance and longevity, effects that require the IIS-inhibited FOXO protein DAF-16. The C. elegans transcription factor SKN-1 also defends against oxidative stress by mobilizing the conserved phase 2 detoxification response. Here we show that IIS not only opposes DAF-16 but also directly inhibits SKN-1 in parallel. The IIS kinases AKT-1, -2, and SGK-1 phosphorylate SKN-1, and reduced IIS leads to constitutive SKN-1 nuclear accumulation in the intestine and SKN-1 target gene activation. SKN-1 contributes to the increased stress tolerance and longevity resulting from reduced IIS and delays aging when expressed transgenically. Furthermore, SKN-1 that is constitutively active increases life span independently of DAF-16. Our findings indicate that the transcription network regulated by SKN-1 promotes longevity and is an important direct target of IIS.

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Available from: T Keith Blackwell, Dec 10, 2014
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    • "Interestingly, the mammalian orthologue of the stress-response transcription factor SKN-1, Nrf-2, promotes mitochondrial biogenesis and this requires its translocation to the nucleus [62]. Notably, the nuclear localization of SKN-1 in C. elegans is inhibited by SGK-1 [63], and more recent data has shown that RICT-1/mTORC2 negatively regulates longevity by inhibiting SKN-1/Nrf in the intestine through the SGK-1 kinase, which phosphorylates and inhibits SKN-1 [49]. This could account for the increased mitochondrial content observed in both, rict-1 and sgk-1 depleted animals. "
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    ABSTRACT: Lifespan regulation by mitochondrial proteins has been well described, however, the mechanism of this regulation is not fully understood. Amongst the mitochondrial proteins profoundly affecting ageing are prohibitins (PHB-1 and PHB-2). Paradoxically, in C. elegans prohibitin depletion shortens the lifespan of wild type animals while dramatically extending that of metabolically compromised animals, such as daf-2-insulin-receptor mutants. Here we show that amongst the three kinases known to act downstream of daf-2, only loss of function of sgk-1 recapitulates the ageing phenotype observed in daf-2 mutants upon prohibitin depletion. Interestingly, signalling through SGK-1 receives input from an additional pathway, parallel to DAF-2, for the prohibitin-mediated lifespan phenotype. We investigated the effect of prohibitin depletion on the mitochondrial unfolded protein response (UPRmt). Remarkably, the lifespan extension upon prohibitin elimination, of both daf-2 and sgk-1 mutants, is accompanied by suppression of the UPRmt induced by lack of prohibitin. On the contrary, gain of function of SGK-1 results in further shortening of lifespan and a further increase of the UPRmt in prohibitin depleted animals. Moreover, SGK-1 interacts with RICT-1 for the regulation of the UPRmt in a parallel pathway to DAF-2. Interestingly, prohibitin depletion in rict-1 loss of function mutant animals also causes lifespan extension. Finally, we reveal an unprecedented role for mTORC2-SGK-1 in the regulation of mitochodrial homeostasis. Together, these results give further insight into the mechanism of lifespan regulation by mitochondrial function and reveal a cross-talk of mitochondria with two key pathways, Insulin/IGF and mTORC2, for the regulation of ageing and stress response.
    PLoS ONE 09/2014; 9(9):e107671. DOI:10.1371/journal.pone.0107671 · 3.23 Impact Factor
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    • "In the animal kingdom, many stress transcription factors are utilized during oxidative stress to activate protective responses (bZIP transcription factors X-BOX BINDING PROTEIN1, ACTIVATING TRANSCRIPTION FACTOR4 [ATF4], NF-E2-RELATED FACTOR1-3, and ATF6; An and Blackwell, 2003; Harding et al., 2003; Glover-Cutter et al., 2013), with many of these factors playing intersecting roles in related cellular stresses, including protein homeostasis and aging (Henis-Korenblit et al., 2010; Kenyon, 2010; Hetz, 2012). The intersection of oxidative stress resistance and longevity is a well-researched field in the animal kingdom (Tullet et al., 2008; Ristow and Schmeisser, 2011; Calabrese et al., 2012; Gems and Partridge, 2013), with many stress and longevity pathways conserved in the plant kingdom. For example, micronutritional depravation of essential nutrients is associated with aging and cognitive decline in animal systems (Chen et al., 2013) and growth and mass decline in plant systems. "
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    ABSTRACT: Identification of viable strategies to increase stress resistance of crops will become increasingly important for the goal of global food security as our population increases and our climate changes. Considering that resistance to oxidative stress is oftentimes an indicator of health and longevity in animal systems, characterizing conserved pathways known to increase oxidative stress resistance could prove fruitful for crop improvement strategies. This report argues for the usefulness and practicality of the model organism Brachypodium distachyon for identifying and validating stress resistance factors. Specifically, we focus on a zinc deficiency transcription factor, BdbZIP10, and its role in oxidative stress in the model organism Brachypodium. When overexpressed, BdbZIP10 protects plants and callus tissue from oxidative stress insults, most likely through distinct and direct activation of protective oxidative stress genes. Increased oxidative stress resistance and cell viability through the overexpression of BdbZIP10 highlight the utility of investigating conserved stress responses between plant and animal systems.
    Plant physiology 09/2014; 166(3). DOI:10.1104/pp.114.240457 · 7.39 Impact Factor
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    • ".3% and 91.0% increase in lifespan upon DR and DD, respectively, these increases were only 20.9% and 13.3% in predicted null skn-1 mutants. (D) Under AL liquid conditions, skn-1 mutants' mean lifespan was equal to that of WT, in contrast to results obtained on plates (Tullet et al., 2008). (E, F) pha-4(zu225) mutation eliminated DR longevity in the control smg- 1(cc546ts) background. "
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    ABSTRACT: Interventions that slow aging and prevent chronic disease may come from an understanding of how dietary restriction (DR) increases lifespan. Mechanisms proposed to mediate DR longevity include reduced mTOR signaling, activation of the NAD+-dependent deacylases known as sirtuins, and increases in NAD+ that derive from higher levels of respiration. Here, we explored these hypotheses in Caenorhabditis elegans using a new liquid feeding protocol. DR lifespan extension depended upon a group of regulators that are involved in stress responses and mTOR signaling, and have been implicated in DR by some other regimens [DAF-16 (FOXO), SKN-1 (Nrf1/2/3), PHA-4 (FOXA), AAK-2 (AMPK)]. Complete DR lifespan extension required the sirtuin SIR-2.1 (SIRT1), the involvement of which in DR has been debated. The nicotinamidase PNC-1, a key NAD+ salvage pathway component, was largely required for DR to increase lifespan but not two healthspan indicators: movement and stress resistance. Independently of pnc-1, DR increased the proportion of respiration that is coupled to ATP production but, surprisingly, reduced overall oxygen consumption. We conclude that stress response and NAD+-dependent mechanisms are each critical for DR lifespan extension, although some healthspan benefits do not require NAD+ salvage. Under DR conditions, NAD+-dependent processes may be supported by a DR-induced shift toward oxidative metabolism rather than an increase in total respiration.
    Aging cell 09/2014; 13(6). DOI:10.1111/acel.12273 · 5.94 Impact Factor
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