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: 31.96). 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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    ABSTRACT: Lowering caloric intake, a dietary process known as caloric restriction (CR) is the only reproducible non-genetic method that extends lifespan for most of the organisms tested, yet our understanding of how this diet works remains poor. One group of enzymes, the sirtuins, has recently emerged as leading candidates for mediators of the benefits of CR across species. In Chapter 1, the sirtuin family of deacetylase enzymes is reviewed within the context of CR-mediated biological effects in organisms. The mammalian sirtuins have emerging roles in a variety of important basic and age-associated processes like cancer, diabetes, obesity, inflammation, muscle differentiation, heart failure, and neurodegeneration, thereby attracting wide interest for promising therapeutic intervention. However, many of the mammalian sirtuins remain poorly characterized, such as the case of the mitochondrial sirtuin SIRT3. In human cell-culture studies, as discussed in Chapter 2, a new biological role is elucidated for SIRT3 as an anti-apoptotic sirtuin that protects against stress/nutrient deprivation. Prior to this work, virtually no connection existed between this sirtuin, the unique biochemical microenvironment inside of mitochondria, and cellular survival. Furthermore, in skeletal muscle studies explained in Chapter 3, a new biological role for SIRT3 is also described. As detailed in this Chapter, exercise training and CR raise SIRT3 expression in vivo, which leads to downstream activation of key pathways affecting muscle energy homeostasis. In Chapter 4, the role of sirtuins and PNC-1/nicotinamidase is considered in the model organism C. elegans. In this Chapter, it is demonstrated that the nematode PNC-1 has robust nicotinamidase enzymatic activity in vitro and that over-expression in vivo protects against stress and extends lifespan by mimicking the effects of CR. Lastly, evidence is presented that some of the sirtuins in this organism mediate the effects of CR-induced longevity, contrary to some past literature. Collectively, all of these biochemical and genetic studies, as summarized and discussed in Chapter 5, will help to further explain sirtuin-mediated mechanisms of homeostasis and aging in animals, thereby opening new routes for potential therapeutic intervention and for studying the biology of aging in vivo.
    02/2010, Degree: Ph.D., Supervisor: David A. Sinclair
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    ABSTRACT: Background Little is known about the role of amino acids in cellular signaling pathways, especially as it pertains to pathways that regulate the rate of aging. However, it has been shown that methionine or tryptophan restriction extends lifespan in higher eukaryotes and increased proline or tryptophan levels increase longevity in C. elegans. In addition, leucine strongly activates the TOR signaling pathway, which when inhibited increases lifespan.ResultsTherefore each of the 20 proteogenic amino acids was individually supplemented to C. elegans and the effects on lifespan were determined. All amino acids except phenylalanine and aspartate extended lifespan at least to a small extent at one or more of the 3 concentrations tested with serine and proline showing the largest effects. 11 of the amino acids were less potent at higher doses, while 5 even decreased lifespan. Serine, proline, or histidine-mediated lifespan extension was greatly inhibited in eat-2 worms, a model of dietary restriction, in daf-16/FOXO, sir-2.1, rsks-1 (ribosomal S6 kinase), gcn-2, and aak-2 (AMPK) longevity pathway mutants, and in bec-1 autophagy-defective knockdown worms. 8 of 10 longevity-promoting amino acids tested activated a SKN-1/Nrf2 reporter strain, while serine and histidine were the only amino acids from those to activate a hypoxia-inducible factor (HIF-1) reporter strain. Thermotolerance was increased by proline or tryptophan supplementation, while tryptophan-mediated lifespan extension was independent of DAF-16/FOXO and SKN-1/Nrf2 signaling, but tryptophan and several related pyridine-containing compounds induced the mitochondrial unfolded protein response and an ER stress response. High glucose levels or mutations affecting electron transport chain (ETC) function inhibited amino acid-mediated lifespan extension suggesting that metabolism plays an important role. Providing many other cellular metabolites to C. elegans also increased longevity suggesting that anaplerosis of tricarboxylic acid (TCA) cycle substrates likely plays a role in lifespan extension.Conclusions Supplementation of C. elegans with 18 of the 20 individual amino acids extended lifespan, but lifespan often decreased with increasing concentration suggesting hormesis. Lifespan extension appears to be caused by altered mitochondrial TCA cycle metabolism and respiratory substrate utilization resulting in the activation of the DAF-16/FOXO and SKN-1/Nrf2 stress response pathways.
    BMC Genetics 02/2015; 16(1):8. DOI:10.1186/s12863-015-0167-2 · 2.36 Impact Factor
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    ABSTRACT: RIO protein kinases (RIOKs) are a relatively conserved family of enzymes implicated in cell cycle control and ribosomal RNA processing. Despite their functional importance, they remain a poorly understood group of kinases in multicellular organisms. Here, we show that the C. elegans genome contains one member of each of the three RIOK sub-families and that each of the genes coding for them has a unique tissue expression pattern. Our analysis showed that the gene encoding RIOK-1 (riok-1) was broadly and strongly expressed. Interestingly, the intestinal expression of riok-1 was dependent upon two putative binding sites for the oxidative and xenobiotic stress response transcription factor SKN-1. RNA interference (RNAi)-mediated knock down of riok-1 resulted in germline defects, including defects in germ line stem cell proliferation, oocyte maturation and the production of endomitotic oocytes. Taken together, our findings indicate new functions for RIOK-1 in post mitotic tissues and in reproduction.
    PLoS ONE 02/2015; 10(2):e0117444. DOI:10.1371/journal.pone.0117444 · 3.53 Impact Factor

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