ENTRY ko04213 Pathway NAME Longevity regulating pathway - multiple species DESCRIPTION Aging is a complex process of accumulation of molecular, cellular, and organ damage, leading to loss of function and increased vulnerability to disease and death. Despite the complexity of aging, recent work has shown that dietary restriction (DR) and genetic down-regulation of nutrient-sensing pathways, namely IIS (insulin/insulin-like growth factor signalling) and TOR (target-of- rapamycin) can substantially increase healthy life span of laboratory model organisms. These nutrient signaling pathways are conserved in various organisms. In worms, flies, and mammals, DR reduces signalling through IIS/TOR pathways, deactivating the PI3K/Akt/TOR intracellular signalling cascade and consequently activating the antiaging FOXO family transcription factor(s). In yeast, the effects of DR on life- span extension are associated with reduced activities of the TOR/Sch9 and Ras/PKA pathways and require the serine-threonine kinase Rim15 and transcription factors Gis1 and Msn2/4. These transcription factors (FOXO, DAF-16, Gis1, and Msn2/4) transactivate genes involved in resistance to oxidative stress, energy metabolism, DNA damage repair, glucose metabolism, autophagy and protection of proteins by chaperones. CLASS Organismal Systems; Aging PATHWAY_MAP ko04213 Longevity regulating pathway - multiple species ORTHOLOGY K00922 PIK3CA_B_D; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:2.7.1.153] K01440 PNC1; nicotinamidase [EC:3.5.1.19] K01768 E4.6.1.1; adenylate cyclase [EC:4.6.1.1] K02649 PIK3R1_2_3; phosphoinositide-3-kinase regulatory subunit alpha/beta/delta K02833 HRAS; GTPase HRas K03283 HSPA1_6_8; heat shock 70kDa protein 1/6/8 K03695 clpB; ATP-dependent Clp protease ATP-binding subunit ClpB K03781 katE, CAT, catB, srpA; catalase [EC:1.11.1.6] K04345 PKA; protein kinase A [EC:2.7.11.11] K04456 AKT; RAC serine/threonine-protein kinase [EC:2.7.11.1] K04526 INS; insulin K04527 INSR, CD220; insulin receptor [EC:2.7.10.1] K04564 SOD2; superoxide dismutase, Fe-Mn family [EC:1.15.1.1] K04565 SOD1; superoxide dismutase, Cu-Zn family [EC:1.15.1.1] K04688 RPS6KB; ribosomal protein S6 kinase beta [EC:2.7.11.1] K05087 IGF1R, CD221; insulin-like growth factor 1 receptor [EC:2.7.10.1] K05459 IGF1; insulin-like growth factor 1 K06067 HDAC1_2; histone deacetylase 1/2 [EC:3.5.1.98] K07187 IRS2; insulin receptor substrate 2 K07198 PRKAA, AMPK; 5'-AMP-activated protein kinase, catalytic alpha subunit [EC:2.7.11.31] K07199 PRKAB; 5'-AMP-activated protein kinase, regulatory beta subunit K07200 PRKAG; 5'-AMP-activated protein kinase, regulatory gamma subunit K07201 FOXO1; forkhead box protein O1 K07203 MTOR, FRAP, TOR; serine/threonine-protein kinase mTOR [EC:2.7.11.1] K07204 RAPTOR; regulatory associated protein of mTOR K07827 KRAS, KRAS2; GTPase KRas K07828 NRAS; GTPase NRas K08035 FOXA2, HNF3B; forkhead box protein A2, hepatocyte nuclear factor 3-beta K08041 ADCY1; adenylate cyclase 1 [EC:4.6.1.1] K08042 ADCY2; adenylate cyclase 2 [EC:4.6.1.1] K08043 ADCY3; adenylate cyclase 3 [EC:4.6.1.1] K08044 ADCY4; adenylate cyclase 4 [EC:4.6.1.1] K08045 ADCY5; adenylate cyclase 5 [EC:4.6.1.1] K08046 ADCY6; adenylate cyclase 6 [EC:4.6.1.1] K08047 ADCY7; adenylate cyclase 7 [EC:4.6.1.1] K08048 ADCY8; adenylate cyclase 8 [EC:4.6.1.1] K08049 ADCY9; adenylate cyclase 9 [EC:4.6.1.1] K08339 ATG5; autophagy-related protein 5 K09408 FOXO3; forkhead box protein O3 K09468 MSN2_4; zinc finger protein MSN2/4 K09542 CRYAB; crystallin, alpha B K11121 SIR2; NAD-dependent protein deacetylase SIR2 [EC:2.3.1.286] K11411 SIRT1, SIR2L1; NAD-dependent protein deacetylase sirtuin 1 [EC:2.3.1.286] K12762 GPR1; G protein-coupled receptor GPR1 K12767 RIM15; serine/threonine-protein kinase RIM15 [EC:2.7.11.36] K16172 IRS1; insulin receptor substrate 1 K16184 AKT1S1, PRAS40; proline-rich AKT1 substrate 1 K17445 IRS3; insulin receptor substrate 3 K17446 IRS4; insulin receptor substrate 4 K18644 EIF4EBP2; eukaryotic translation initiation factor 4E binding protein 2 K19764 INS7; insulin-like neuropeptide 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 K19798 GIS1; transcriptional activator/repressor GIS1 K19800 SCH9; serine/threonine protein kinase SCH9 [EC:2.7.11.1] K19805 ILP7; insulin-like peptide 7 COMPOUND C00575 3',5'-Cyclic AMP C05981 Phosphatidylinositol-3,4,5-trisphosphate REFERENCE PMID:20395504 AUTHORS Fontana L, Partridge L, Longo VD TITLE Extending healthy life span--from yeast to humans. 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JOURNAL Science 299:1342-6 (2003) DOI:10.1126/science.1077991 REFERENCE PMID:25153840 AUTHORS Mirzaei H, Suarez JA, Longo VD TITLE Protein and amino acid restriction, aging and disease: from yeast to humans. JOURNAL Trends Endocrinol Metab 25:558-66 (2014) DOI:10.1016/j.tem.2014.07.002 REFERENCE PMID:20336132 AUTHORS Kenyon CJ TITLE The genetics of ageing. JOURNAL Nature 464:504-12 (2010) DOI:10.1038/nature08980 REFERENCE PMID:20097433 AUTHORS Longo VD, Fontana L TITLE Calorie restriction and cancer prevention: metabolic and molecular mechanisms. JOURNAL Trends Pharmacol Sci 31:89-98 (2010) DOI:10.1016/j.tips.2009.11.004 REFERENCE PMID:22094419 AUTHORS Longo VD, Fabrizio P TITLE Chronological aging in Saccharomyces cerevisiae. JOURNAL Subcell Biochem 57:101-21 (2012) DOI:10.1007/978-94-007-2561-4_5 REFERENCE PMID:26525455 AUTHORS Bitto A, Wang AM, Bennett CF, Kaeberlein M TITLE Biochemical Genetic Pathways that Modulate Aging in Multiple Species. JOURNAL Cold Spring Harb Perspect Med 5:a025114 (2015) DOI:10.1101/cshperspect.a025114 REFERENCE PMID:18373439 AUTHORS Mair W, Dillin A TITLE Aging and survival: the genetics of life span extension by dietary restriction. JOURNAL Annu Rev Biochem 77:727-54 (2008) DOI:10.1146/annurev.biochem.77.061206.171059 REFERENCE PMID:17701476 AUTHORS Dali-Youcef N, Lagouge M, Froelich S, Koehl C, Schoonjans K, Auwerx J TITLE Sirtuins: the 'magnificent seven', function, metabolism and longevity. JOURNAL Ann Med 39:335-45 (2007) DOI:10.1080/07853890701408194 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:23615258 AUTHORS Lee SH, Min KJ TITLE Caloric restriction and its mimetics. 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JOURNAL Nat Rev Mol Cell Biol 8:681-91 (2007) DOI:10.1038/nrm2234 REL_PATHWAY ko04068 FoxO signaling pathway ko04150 mTOR signaling pathway ko04151 PI3K-Akt signaling pathway ko04152 AMPK signaling pathway ko04211 Longevity regulating pathway ko04212 Longevity regulating pathway - worm ko04910 Insulin signaling pathway ///