ENTRY ko04212 Pathway NAME Longevity regulating pathway - worm DESCRIPTION The nematode Caenorhabditis elegans has proven to be a very useful tool for studying the genetics of longevity due to its simple biology. Over 70 genes have been found to influence lifespan in this worm. The majority of the genes could be placed into canonical longevity pathways including insulin/IGF, germline, TOR signaling, and mitochondrial respiration. The insulin/IGF-1 signaling (IIS) pathway is a central regulator of life span. Transcription factors regulated by the IIS and the TOR-S6K pathways are implicated in the anti-aging effects of Dietary restriction (DR). Lifespan extension via germline removal depends on at least four signaling mechanisms: reduced TOR signaling, DAF-16/FOXO regulation, increased steroid signaling via the DAF-36/DAF-9/DAF-12 pathway, and increased NHR-80/HNF-4 signaling. The mitochondrial unfolded protein response (UPRmt), a mitochondrial stress response, can be regarded as a hormetic mechanism that extends lifespan in spite of mitochondrial dysfunction. Longevity- promoting compounds such as rapamycin and resveratrol also induce mitonuclear imbalance that activates the UPRmt. CLASS Organismal Systems; Aging PATHWAY_MAP ko04212 Longevity regulating pathway - worm ORTHOLOGY K00507 SCD, desC; stearoyl-CoA desaturase (Delta-9 desaturase) [EC:1.14.19.1] K00799 GST; glutathione S-transferase [EC:2.5.1.18] K00922 PIK3CA_B_D; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:2.7.1.153] K01110 PTEN; phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN [EC:3.1.3.16 3.1.3.48 3.1.3.67] K01358 clpP; ATP-dependent Clp protease, protease subunit [EC:3.4.21.92] K03781 katE, CAT, catB, srpA; catalase [EC:1.11.1.6] K03871 VHL; von Hippel-Lindau disease tumor supressor K04043 dnaK, HSPA9; molecular chaperone DnaK K04077 groEL, HSPD1, HSP60, CPN60; chaperonin GroEL [EC:5.6.1.7] K04374 ATF4, CREB2; cyclic AMP-dependent transcription factor ATF-4 K04433 MAP2K6, MKK6; mitogen-activated protein kinase kinase 6 [EC:2.7.12.2] K04440 JNK; mitogen-activated protein kinase 8/9/10 (c-Jun N-terminal kinase) [EC:2.7.11.24] K04441 P38; p38 MAP kinase [EC:2.7.11.24] K04456 AKT; RAC serine/threonine-protein kinase [EC:2.7.11.1] K04527 INSR, CD220; insulin receptor [EC:2.7.10.1] K04564 SOD2; superoxide dismutase, Fe-Mn family [EC:1.15.1.1] K04688 RPS6KB; ribosomal protein S6 kinase beta [EC:2.7.11.1] K05638 NFE2L2, NRF2; nuclear factor erythroid 2-related factor 2 K07203 MTOR, FRAP, TOR; serine/threonine-protein kinase mTOR [EC:2.7.11.1] K08035 FOXA2, HNF3B; forkhead box protein A2, hepatocyte nuclear factor 3-beta K08268 HIF1A; hypoxia-inducible factor 1 alpha K08269 ULK2, ATG1; serine/threonine-protein kinase ULK2 [EC:2.7.11.1] K08341 GABARAP, ATG8, LC3; GABA(A) receptor-associated protein K09408 FOXO3; forkhead box protein O3 K09414 HSF1; heat shock transcription factor 1 K11204 GCLC; glutamate--cysteine ligase catalytic subunit [EC:6.3.2.2] K11411 SIRT1, SIR2L1; NAD-dependent protein deacetylase sirtuin 1 [EC:2.3.1.286] K12824 TCERG1, CA150; transcription elongation regulator 1 K13113 UBL5, HUB1; ubiquitin-like protein 5 K13356 FAR; alcohol-forming fatty acyl-CoA reductase [EC:1.2.1.84] K14035 NR1IN; nuclear receptor subfamily 1 group I K14739 MT1_2; metallothionein 1/2 K14938 NVD, DAF36; cholesterol 7-desaturase [EC:1.14.19.21] K16172 IRS1; insulin receptor substrate 1 K16197 YWHAB_Q_Z; 14-3-3 protein beta/theta/zeta K17491 SMEK, PPP4R3; protein phosphatase 4 regulatory subunit 3 K17705 KRIT1, CCM1; Krev interaction trapped protein 1 K17794 TIM23; mitochondrial import inner membrane translocase subunit TIM23 K18461 WASH1; WAS protein family homolog 1 K18463 CCDC53; WASH complex subunit CCDC53 K19762 HAF1; ATP-binding cassette, subfamily B, HAIF transporter K19763 JKK1; dual specificity mitogen-activated protein kinase kinase JKK-1 [EC:2.7.12.2] K19764 INS7; insulin-like neuropeptide K19765 HSBP1; heat shock factor-binding protein 1 K19766 HSP16.1; heat shock protein Hsp-16.1/Hsp-16.11 K19767 HSP16.49; heat shock protein Hsp-16.48/Hsp-16.49 K19768 HSP12.6; heat shock protein 12.6 K19769 SIP1; stress-induced protein 1 K19770 RNASEK; ribonuclease kappa [EC:3.1.-.-] K19771 LIPL4; lipase K19772 LIPS17; triacylglycerol lipase K19773 NHR80; nuclear hormone receptor family member NHR-80 K19774 DVE1; homeobox domain-containing protein K22878 DAF9; cytochrome P450 daf-9 [EC:1.14.15.15] K24070 PARP1; poly [ADP-ribose] polymerase 1 K27390 HCFC2; host cell factor 2 COMPOUND C00003 NAD+ C00153 Nicotinamide C00704 Superoxide C00712 (9Z)-Octadecenoic acid C03150 Nicotinamide-beta-riboside C03582 Resveratrol C05981 Phosphatidylinositol-3,4,5-trisphosphate C07909 Sirolimus C21076 Delta4-Dafachronic acid C21077 Delta7-Dafachronic acid D09692 Veliparib (JAN/USAN/INN) D09730 Olaparib (JAN/USAN/INN) REFERENCE PMID:22939742 AUTHORS Lapierre LR, Hansen M TITLE Lessons from C. elegans: signaling pathways for longevity. JOURNAL Trends Endocrinol Metab 23:637-44 (2012) DOI:10.1016/j.tem.2012.07.007 REFERENCE PMID:23633911 AUTHORS Yanos ME, Bennett CF, Kaeberlein M TITLE Genome-Wide RNAi Longevity Screens in Caenorhabditis elegans. JOURNAL Curr Genomics 13:508-18 (2012) DOI:10.2174/138920212803251391 REFERENCE PMID:23063987 AUTHORS Antebi A TITLE Regulation of longevity by the reproductive system. JOURNAL Exp Gerontol 48:596-602 (2013) DOI:10.1016/j.exger.2012.09.009 REFERENCE PMID:25988171 AUTHORS Khodakarami A, Saez I, Mels J, Vilchez D TITLE Mediation of organismal aging and somatic proteostasis by the germline. JOURNAL Front Mol Biosci 2:3 (2015) DOI:10.3389/fmolb.2015.00003 REFERENCE PMID:23312280 AUTHORS Hansen M, Flatt T, Aguilaniu H TITLE Reproduction, fat metabolism, and life span: what is the connection? JOURNAL Cell Metab 17:10-9 (2013) DOI:10.1016/j.cmet.2012.12.003 REFERENCE PMID:23870130 AUTHORS Mouchiroud L, Houtkooper RH, Moullan N, Katsyuba E, Ryu D, Canto C, Mottis A, Jo YS, Viswanathan M, Schoonjans K, Guarente L, Auwerx J TITLE The NAD(+)/Sirtuin Pathway Modulates Longevity through Activation of Mitochondrial UPR and FOXO Signaling. JOURNAL Cell 154:430-41 (2013) DOI:10.1016/j.cell.2013.06.016 REFERENCE PMID:24141218 AUTHORS Jasper H TITLE Sirtuins: Longevity focuses on NAD+. JOURNAL Nat Chem Biol 9:666-7 (2013) DOI:10.1038/nchembio.1369 REFERENCE PMID:23870118 AUTHORS Karpac J, Jasper H TITLE Aging: seeking mitonuclear balance. JOURNAL Cell 154:271-3 (2013) DOI:10.1016/j.cell.2013.06.046 REFERENCE PMID:24930971 AUTHORS Jensen MB, Jasper H TITLE Mitochondrial proteostasis in the control of aging and longevity. JOURNAL Cell Metab 20:214-25 (2014) DOI:10.1016/j.cmet.2014.05.006 REFERENCE PMID:24699406 AUTHORS Munkacsy E, Rea SL TITLE The paradox of mitochondrial dysfunction and extended longevity. JOURNAL Exp Gerontol 56:221-33 (2014) DOI:10.1016/j.exger.2014.03.016 REFERENCE PMID:15767565 AUTHORS Oh SW, Mukhopadhyay A, Svrzikapa N, Jiang F, Davis RJ, Tissenbaum HA TITLE JNK regulates lifespan in Caenorhabditis elegans by modulating nuclear translocation of forkhead transcription factor/DAF-16. JOURNAL Proc Natl Acad Sci U S A 102:4494-9 (2005) DOI:10.1073/pnas.0500749102 REFERENCE PMID:12845331 AUTHORS Murphy CT, McCarroll SA, Bargmann CI, Fraser A, Kamath RS, Ahringer J, Li H, Kenyon C TITLE Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans. JOURNAL Nature 424:277-83 (2003) DOI:10.1038/nature01789 REFERENCE PMID:21909281 AUTHORS Rizki G, Iwata TN, Li J, Riedel CG, Picard CL, Jan M, Murphy CT, Lee SS TITLE The evolutionarily conserved longevity determinants HCF-1 and SIR-2.1/SIRT1 collaborate to regulate DAF-16/FOXO. JOURNAL PLoS Genet 7:e1002235 (2011) DOI:10.1371/journal.pgen.1002235 REFERENCE PMID:16530049 AUTHORS Wolff S, Ma H, Burch D, Maciel GA, Hunter T, Dillin A TITLE SMK-1, an essential regulator of DAF-16-mediated longevity. JOURNAL Cell 124:1039-53 (2006) DOI:10.1016/j.cell.2005.12.042 REFERENCE PMID:23116063 AUTHORS Barna J, Princz A, Kosztelnik M, Hargitai B, Takacs-Vellai K, Vellai T TITLE Heat shock factor-1 intertwines insulin/IGF-1, TGF-beta and cGMP signaling to control development and aging. JOURNAL BMC Dev Biol 12:32 (2012) DOI:10.1186/1471-213X-12-32 REFERENCE PMID:12750521 AUTHORS Hsu AL, Murphy CT, Kenyon C TITLE Regulation of aging and age-related disease by DAF-16 and heat-shock factor. JOURNAL Science 300:1142-5 (2003) DOI:10.1126/science.1083701 REFERENCE PMID:16251270 AUTHORS An JH, Vranas K, Lucke M, Inoue H, Hisamoto N, Matsumoto K, Blackwell TK TITLE Regulation of the Caenorhabditis elegans oxidative stress defense protein SKN-1 by glycogen synthase kinase-3. JOURNAL Proc Natl Acad Sci U S A 102:16275-80 (2005) DOI:10.1073/pnas.0508105102 REFERENCE PMID:16166371 AUTHORS Inoue H, Hisamoto N, An JH, Oliveira RP, Nishida E, Blackwell TK, Matsumoto K TITLE The C. elegans p38 MAPK pathway regulates nuclear localization of the transcription factor SKN-1 in oxidative stress response. JOURNAL Genes Dev 19:2278-83 (2005) DOI:10.1101/gad.1324805 REFERENCE PMID:21241450 AUTHORS Leiser SF, Begun A, Kaeberlein M TITLE HIF-1 modulates longevity and healthspan in a temperature-dependent manner. JOURNAL Aging Cell 10:318-26 (2011) DOI:10.1111/j.1474-9726.2011.00672.x REL_PATHWAY ko04066 HIF-1 signaling pathway ko04140 Autophagy - animal ko04150 mTOR signaling pathway ko04151 PI3K-Akt signaling pathway ko04910 Insulin signaling pathway ///