Entry 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; AgingBRITE hierarchy
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 ]
K02649 PIK3R1_2_3; phosphoinositide-3-kinase regulatory subunit alpha/beta/delta
K03283 HSPA1_6_8; heat shock 70kDa protein 1/6/8
K03695 clpB; ATP-dependent Clp protease ATP-binding subunit ClpB
K05087 IGF1R, CD221; insulin-like growth factor 1 receptor [EC:2.7.10.1 ]
K05459 IGF1; insulin-like growth factor 1
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
K08035 FOXA2, HNF3B; forkhead box protein A2, hepatocyte nuclear factor 3-beta
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
K11411 SIRT1, SIR2L1; NAD-dependent protein deacetylase sirtuin 1 [EC:2.3.1.286 ]
K12762 GPR1; G protein-coupled receptor GPR1
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
K19805 ILP7; insulin-like peptide 7
Compound C05981 Phosphatidylinositol-3,4,5-trisphosphate
Reference Authors Fontana L, Partridge L, Longo VD
Title Extending healthy life span--from yeast to humans.
Journal Reference Authors Parrella E, Longo VD
Title Insulin/IGF-I and related signaling pathways regulate aging in nondividing cells: from yeast to the mammalian brain.
Journal Reference Authors Santos J, Leitao-Correia F, Sousa MJ, Leao C
Title Dietary Restriction and Nutrient Balance in Aging.
Journal Reference Authors Longo VD, Lieber MR, Vijg J
Title Turning anti-ageing genes against cancer.
Journal Reference Authors Longo VD, Mitteldorf J, Skulachev VP
Title Programmed and altruistic ageing.
Journal Reference Authors Longo VD, Finch CE
Title Evolutionary medicine: from dwarf model systems to healthy centenarians?
Journal Reference Authors Mirzaei H, Suarez JA, Longo VD
Title Protein and amino acid restriction, aging and disease: from yeast to humans.
Journal Reference Authors Kenyon CJ
Title The genetics of ageing.
Journal Reference Authors Longo VD, Fontana L
Title Calorie restriction and cancer prevention: metabolic and molecular mechanisms.
Journal Reference Authors Longo VD, Fabrizio P
Title Chronological aging in Saccharomyces cerevisiae.
Journal Reference Authors Bitto A, Wang AM, Bennett CF, Kaeberlein M
Title Biochemical Genetic Pathways that Modulate Aging in Multiple Species.
Journal Reference Authors Mair W, Dillin A
Title Aging and survival: the genetics of life span extension by dietary restriction.
Journal Reference Authors Dali-Youcef N, Lagouge M, Froelich S, Koehl C, Schoonjans K, Auwerx J
Title Sirtuins: the 'magnificent seven', function, metabolism and longevity.
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 Lee SH, Min KJ
Title Caloric restriction and its mimetics.
Journal Reference Authors Bordone L, Guarente L
Title Calorie restriction, SIRT1 and metabolism: understanding longevity.
Journal Reference Authors Canto C, Auwerx J
Title Calorie restriction: is AMPK a key sensor and effector?
Journal Reference Authors Barbieri M, Bonafe M, Franceschi C, Paolisso G
Title Insulin/IGF-I-signaling pathway: an evolutionarily conserved mechanism of longevity from yeast to humans.
Journal Reference Authors Russell SJ, Kahn CR
Title Endocrine regulation of ageing.
Journal Related ko04211 Longevity regulating pathway
ko04212 Longevity regulating pathway - worm
