Entry 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; AgingBRITE hierarchy
Pathway map ko04212 Longevity regulating pathway - worm
Orthology K00507 SCD, desC; stearoyl-CoA desaturase (Delta-9 desaturase) [EC:1.14.19.1 ]
K00922 PIK3CA_B_D; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:2.7.1.153 ]
K03871 VHL; von Hippel-Lindau disease tumor supressor
K04043 dnaK, HSPA9; molecular chaperone DnaK
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 ]
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
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
K14035 NR1IN; nuclear receptor subfamily 1 group I
K14739 MT1_2; metallothionein 1/2
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.-.-]
K19772 LIPS17; triacylglycerol lipase
K19773 NHR80; nuclear hormone receptor family member NHR-80
K19774 DVE1; homeobox domain-containing protein
K24070 PARP1; poly [ADP-ribose] polymerase 1
K27390 HCFC2; host cell factor 2
Compound C03150 Nicotinamide-beta-riboside
C05981 Phosphatidylinositol-3,4,5-trisphosphate
C21076 Delta4-Dafachronic acid
C21077 Delta7-Dafachronic acid
D09692 Veliparib (JAN/USAN/INN)
D09730 Olaparib (JAN/USAN/INN)
Reference Authors Lapierre LR, Hansen M
Title Lessons from C. elegans: signaling pathways for longevity.
Journal Reference Authors Yanos ME, Bennett CF, Kaeberlein M
Title Genome-Wide RNAi Longevity Screens in Caenorhabditis elegans.
Journal Reference Authors Antebi A
Title Regulation of longevity by the reproductive system.
Journal Reference Authors Khodakarami A, Saez I, Mels J, Vilchez D
Title Mediation of organismal aging and somatic proteostasis by the germline.
Journal Reference Authors Hansen M, Flatt T, Aguilaniu H
Title Reproduction, fat metabolism, and life span: what is the connection?
Journal Reference 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 Reference Authors Jasper H
Title Sirtuins: Longevity focuses on NAD+.
Journal Reference Authors Karpac J, Jasper H
Title Aging: seeking mitonuclear balance.
Journal Reference Authors Jensen MB, Jasper H
Title Mitochondrial proteostasis in the control of aging and longevity.
Journal Reference Authors Munkacsy E, Rea SL
Title The paradox of mitochondrial dysfunction and extended longevity.
Journal Reference 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 Reference 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 Reference 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 Reference 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 Reference 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 Reference Authors Hsu AL, Murphy CT, Kenyon C
Title Regulation of aging and age-related disease by DAF-16 and heat-shock factor.
Journal Reference 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 Reference 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 Reference Authors Leiser SF, Begun A, Kaeberlein M
Title HIF-1 modulates longevity and healthspan in a temperature-dependent manner.
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