KEGG   PATHWAY: cel04212
Entry
cel04212                    Pathway                                
Name
Longevity regulating pathway - worm - Caenorhabditis elegans (nematode)
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
cel04212  Longevity regulating pathway - worm
cel04212

Organism
Caenorhabditis elegans (nematode) [GN:cel]
Gene
CELE_F35C8.3  jkk-1; Dual specificity mitogen-activated protein kinase kinase jkk-1 [KO:K19763] [EC:2.7.12.2]
CELE_B0478.1  jnk-1; Stress-activated protein kinase jnk-1 [KO:K04440] [EC:2.7.11.24]
CELE_T07A9.3  kgb-1; GLH-binding kinase 1 [KO:K04440] [EC:2.7.11.24]
CELE_ZC416.4  kgb-2; Stress-activated protein kinase JNK [KO:K04440] [EC:2.7.11.24]
CELE_ZK1251.2  ins-7; putative insulin-like peptide beta-type 4 [KO:K19764]
CELE_Y55D5A.5  daf-2; Insulin-like receptor subunit beta [KO:K04527] [EC:2.7.10.1]
CELE_C54D1.3  ist-1; IRS-type PTB domain-containing protein [KO:K16172]
CELE_B0334.8  age-1; Phosphatidylinositol 3-kinase age-1 [KO:K00922] [EC:2.7.1.153]
CELE_T07A9.6  daf-18; Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase daf-18 [KO:K01110] [EC:3.1.3.16 3.1.3.48 3.1.3.67]
CELE_F28H6.1  akt-2; Serine/threonine-protein kinase akt-2 [KO:K04456] [EC:2.7.11.1]
CELE_C12D8.10  akt-1; Serine/threonine-protein kinase akt-1 [KO:K04456] [EC:2.7.11.1]
CELE_R13H8.1  daf-16; Forkhead box protein O [KO:K09408]
CELE_R11A8.4  sir-2.1; NAD-dependent protein deacetylase sir-2.1 [KO:K11411] [EC:2.3.1.286]
CELE_C46A5.9  hcf-1; Host cell factor homolog hcf-1 [KO:K27390]
CELE_F41E6.4  smk-1; Serine/threonine-protein phosphatase 4 regulatory subunit 3-like central domain-containing protein [KO:K17491]
CELE_K11G9.6  mtl-1; Metallothionein-1 [KO:K14739]
CELE_F10D11.1  sod-2; Superoxide dismutase [Mn] 1, mitochondrial [KO:K04564] [EC:1.15.1.1]
CELE_C08A9.1  sod-3; Superoxide dismutase [Mn] 2, mitochondrial [KO:K04564] [EC:1.15.1.1]
CELE_Y54G11A.13  ctl-3; Catalase [KO:K03781] [EC:1.11.1.6]
CELE_Y54G11A.5  ctl-2; Peroxisomal catalase 1 [KO:K03781] [EC:1.11.1.6]
CELE_Y54G11A.6  ctl-1; Catalase-2 [KO:K03781] [EC:1.11.1.6]
CELE_F11G11.3  gst-6; putative glutathione S-transferase 6 [KO:K00799] [EC:2.5.1.18]
CELE_R03D7.6  gst-5; putative glutathione S-transferase 5 [KO:K00799] [EC:2.5.1.18]
CELE_R07B1.4  gst-36; putative glutathione S-transferase gst-36 [KO:K00799] [EC:2.5.1.18]
CELE_F11G11.1  gst-8; putative glutathione S-transferase 8 [KO:K00799] [EC:2.5.1.18]
CELE_F11G11.2  gst-7; putative glutathione S-transferase 7 [KO:K00799] [EC:2.5.1.18]
CELE_F35E8.8  gst-38; Glutathione transferase [KO:K00799] [EC:2.5.1.18]
CELE_K08F4.7  gst-4; Glutathione S-transferase 4 [KO:K00799] [EC:2.5.1.18]
CELE_K08F4.6  gst-2; Glutathione S-transferase 2 [KO:K00799] [EC:2.5.1.18]
CELE_K08F4.11  gst-3; Glutathione S-transferase 3 [KO:K00799] [EC:2.5.1.18]
CELE_C29E4.7  gsto-1; Glutathione transferase omega-1 [KO:K00799] [EC:2.5.1.18]
CELE_C02D5.3  gsto-2; putative glutathione transferase omega-2 [KO:K00799] [EC:2.5.1.18]
CELE_C02D5.4  C02D5.4; Glutathione S-transferase omega [KO:K00799] [EC:2.5.1.18]
CELE_F13A7.10  gst-44; Glutathione S-transferase omega [KO:K00799] [EC:2.5.1.18]
CELE_R05F9.5  gst-9; putative glutathione S-transferase 9 [KO:K00799] [EC:2.5.1.18]
CELE_F37B1.1  gst-24; Glutathione S-transferase [KO:K00799] [EC:2.5.1.18]
CELE_Y48E1B.10  gst-20; Glutathione S-transferase [KO:K00799] [EC:2.5.1.18]
CELE_Y53F4B.31  gst-28; Glutathione S-Transferase [KO:K00799] [EC:2.5.1.18]
CELE_Y53F4B.33  gst-39; Glutathione S-Transferase [KO:K00799] [EC:2.5.1.18]
CELE_W10C8.4  W10C8.4; Glutathione S-transferase [KO:K00799] [EC:2.5.1.18]
CELE_K08E7.2  hsb-1; Heat shock factor-binding protein 1 [KO:K19765]
CELE_F59E12.10  ddl-1; WASH complex subunit homolog 3 [KO:K18463]
CELE_Y48E1B.1  ddl-2; WASH complex subunit homolog 1 [KO:K18461]
CELE_Y53C10A.12  hsf-1; Heat shock transcription factor hsf-1 [KO:K09414]
CELE_T27E4.8  hsp-16.1; Heat shock protein Hsp-16.1/Hsp-16.11 [KO:K19766]
CELE_T27E4.2  hsp-16.11; Heat shock protein Hsp-16.1/Hsp-16.11 [KO:K19766]
CELE_T27E4.9  hsp-16.49; Heat shock protein Hsp-16.48/Hsp-16.49 [KO:K19767]
CELE_T27E4.3  hsp-16.48; Heat shock protein Hsp-16.48/Hsp-16.49 [KO:K19767]
CELE_F38E11.2  hsp-12.6; SHSP domain-containing protein [KO:K19768]
CELE_F43D9.4  sip-1; Stress-induced protein 1 [KO:K19769]
CELE_R03G5.2  sek-1; Dual specificity mitogen-activated protein kinase kinase sek-1 [KO:K04433] [EC:2.7.12.2]
CELE_F42G8.3  pmk-2; Mitogen-activated protein kinase pmk-2 [KO:K04441] [EC:2.7.11.24]
CELE_B0218.3  pmk-1; Mitogen-activated protein kinase pmk-1 [KO:K04441] [EC:2.7.11.24]
CELE_F42G8.4  pmk-3; Mitogen-activated protein kinase pmk-3 [KO:K04441] [EC:2.7.11.24]
CELE_T19E7.2  skn-1; Protein skinhead-1 [KO:K05638]
CELE_F37B12.2  gcs-1; Glutamate--cysteine ligase [KO:K11204] [EC:6.3.2.2]
CELE_B0261.2  let-363; Target of rapamycin homolog [KO:K07203] [EC:2.7.11.1]
CELE_R04A9.7  R04A9.7; Non-specific serine/threonine protein kinase [KO:K04688] [EC:2.7.11.1]
CELE_Y47D3A.16  rsks-1; Ribosomal protein S6 kinase beta [KO:K04688] [EC:2.7.11.1]
CELE_F38A6.1  pha-4; Defective pharyngeal development protein 4 [KO:K08035]
CELE_Y60A3A.1  unc-51; Serine/threonine-protein kinase unc-51 [KO:K08269] [EC:2.7.11.1]
CELE_C32D5.9  lgg-1; Protein lgg-1 [KO:K08341]
CELE_F52D10.3  ftt-2; 14-3-3 domain-containing protein [KO:K16197]
CELE_M117.2  par-5; 14-3-3-like protein 1 [KO:K16197]
CELE_F49C12.12  F49C12.12; Ribonuclease kappa [KO:K19770] [EC:3.1.-.-]
CELE_C46G7.1  C46G7.1; Ribonuclease kappa [KO:K19770] [EC:3.1.-.-]
CELE_ZK1127.9  tcer-1; WW domain-containing protein [KO:K12824]
CELE_ZK265.1  kri-1; FERM domain-containing protein [KO:K17705]
CELE_K04A8.5  lipl-4; Lipase lipl-4 [KO:K19771]
CELE_R07G3.2  lips-17; LIPaSe related [KO:K19772]
CELE_C12D8.5  daf-36; Cholesterol 7-desaturase [KO:K14938] [EC:1.14.19.21]
CELE_T13C5.1  daf-9; 3-ketosteroid oxygenase [KO:K22878] [EC:1.14.15.15]
CELE_F11A1.3  daf-12; Nuclear hormone receptor family member daf-12 [KO:K14035]
CELE_Y71H10A.2  fard-1; Fatty acyl-CoA reductase [KO:K13356] [EC:1.2.1.84]
CELE_H10E21.3  nhr-80; Nuclear hormone receptor family member nhr-80 [KO:K19773]
CELE_F10D2.9  fat-7; Delta(9)-fatty-acid desaturase fat-7 [KO:K00507] [EC:1.14.19.1]
CELE_VZK822L.1  fat-6; Delta(9)-fatty-acid desaturase fat-6 [KO:K00507] [EC:1.14.19.1]
CELE_W06D12.3  fat-5; Delta(9)-fatty-acid desaturase fat-5 [KO:K00507] [EC:1.14.19.1]
CELE_F08G12.4  vhl-1; von Hippel-Lindau tumor suppressor homolog [KO:K03871]
CELE_F38A6.3  hif-1; Hypoxia-inducible factor 1 [KO:K08268]
CELE_Y71F9AL.18  parp-1; Poly [ADP-ribose] polymerase 1 [KO:K24070] [EC:2.4.2.30]
CELE_E02H1.4  parp-2; Poly [ADP-ribose] polymerase 2 [KO:K10798] [EC:2.4.2.30]
CELE_ZK970.2  clpp-1; ATP-dependent Clp protease proteolytic subunit 1, mitochondrial [KO:K01358] [EC:3.4.21.92]
CELE_C30H6.6  haf-1; HAlF transporter (PGP related) [KO:K19762]
CELE_ZK1193.5  dve-1; Homeobox protein dve-1 [KO:K19774]
CELE_F46F11.4  ubl-5; Ubiquitin-like protein 5 [KO:K13113]
CELE_T04C10.4  atf-4; Transcription factor atf-4 homolog [KO:K04374]
CELE_F15D3.7  timm-23; Mitochondrial import inner membrane translocase subunit TIM23 [KO:K17794]
CELE_C37H5.8  hsp-6; Heat shock protein hsp-6 [KO:K04043]
CELE_Y22D7AL.5  hsp-60; Chaperonin homolog Hsp-60, mitochondrial [KO:K04077] [EC:5.6.1.7]
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
Related
pathway
cel04140  Autophagy - animal
cel04150  mTOR signaling pathway
KO pathway
ko04212   
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