KEGG   PATHWAY: ko04213
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
ko04213

Orthology
K04526  insulin
K04527  insulin receptor [EC:2.7.10.1]
K05459  insulin-like growth factor 1
K05087  insulin-like growth factor 1 receptor [EC:2.7.10.1]
K16172  insulin receptor substrate 1
K07187  insulin receptor substrate 2
K17445  insulin receptor substrate 3
K17446  insulin receptor substrate 4
K02833  GTPase HRas
K07827  GTPase KRas
K07828  GTPase NRas
K00922  phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:2.7.1.153]
K02649  phosphoinositide-3-kinase regulatory subunit alpha/beta/delta
K04456  RAC serine/threonine-protein kinase [EC:2.7.11.1]
K08041  adenylate cyclase 1 [EC:4.6.1.1]
K08042  adenylate cyclase 2 [EC:4.6.1.1]
K08043  adenylate cyclase 3 [EC:4.6.1.1]
K08044  adenylate cyclase 4 [EC:4.6.1.1]
K08045  adenylate cyclase 5 [EC:4.6.1.1]
K08046  adenylate cyclase 6 [EC:4.6.1.1]
K08047  adenylate cyclase 7 [EC:4.6.1.1]
K08048  adenylate cyclase 8 [EC:4.6.1.1]
K08049  adenylate cyclase 9 [EC:4.6.1.1]
K04345  protein kinase A [EC:2.7.11.11]
K07201  forkhead box protein O1
K09408  forkhead box protein O3
K04564  superoxide dismutase, Fe-Mn family [EC:1.15.1.1]
K03781  catalase [EC:1.11.1.6]
K08339  autophagy-related protein 5
K07198  5'-AMP-activated protein kinase, catalytic alpha subunit [EC:2.7.11.11]
K07199  5'-AMP-activated protein kinase, regulatory beta subunit
K07200  5'-AMP-activated protein kinase, regulatory gamma subunit
K07203  serine/threonine-protein kinase mTOR [EC:2.7.11.1]
K07204  regulatory associated protein of mTOR
K16184  proline-rich AKT1 substrate 1
K04688  ribosomal protein S6 kinase beta [EC:2.7.11.1]
K11411  NAD+-dependent protein deacetylase sirtuin 1 [EC:2.3.1.286]
K19805  insulin-like peptide 7
K04565  superoxide dismutase, Cu-Zn family [EC:1.15.1.1]
K18644  eukaryotic translation initiation factor 4E binding protein 2
K03283  heat shock 70kDa protein 1/2/6/8
K09542  crystallin, alpha B
K06067  histone deacetylase 1/2 [EC:3.5.1.98]
K19764  insulin-like neuropeptide
K08035  forkhead box protein A2, hepatocyte nuclear factor 3-beta
K19766  heat shock protein Hsp-16.1/Hsp-16.11
K19767  heat shock protein Hsp-16.48/Hsp-16.49
K19768  heat shock protein 12.6
K19769  stress-induced protein 1
K12762  G protein-coupled receptor GPR1
K01768  adenylate cyclase [EC:4.6.1.1]
K09468  zinc finger protein MSN2/4
K12767  serine/threonine-protein kinase RIM15 [EC:2.7.11.1]
K19798  transcriptional activator/repressor GIS1
K19800  serine/threonine protein kinase SCH9 [EC:2.7.11.1]
K03695  ATP-dependent Clp protease ATP-binding subunit ClpB
K01440  nicotinamidase [EC:3.5.1.19]
K11121  NAD+-dependent protein deacetylase SIR2 [EC:2.3.1.286]
Compound
C00575  3',5'-Cyclic AMP
C05981  Phosphatidylinositol-3,4,5-trisphosphate
Reference
  Authors
Fontana L, Partridge L, Longo VD
  Title
Extending healthy life span--from yeast to humans.
  Journal
Science 328:321-6 (2010)
DOI:10.1126/science.1172539
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
ScientificWorldJournal 10:161-77 (2010)
DOI:10.1100/tsw.2010.8
Reference
  Authors
Santos J, Leitao-Correia F, Sousa MJ, Leao C
  Title
Dietary Restriction and Nutrient Balance in Aging.
  Journal
Oxid Med Cell Longev 2016:4010357 (2016)
DOI:10.1155/2016/4010357
Reference
  Authors
Longo VD, Lieber MR, Vijg J
  Title
Turning anti-ageing genes against cancer.
  Journal
Nat Rev Mol Cell Biol 9:903-10 (2008)
DOI:10.1038/nrm2526
Reference
  Authors
Longo VD, Mitteldorf J, Skulachev VP
  Title
Programmed and altruistic ageing.
  Journal
Nat Rev Genet 6:866-72 (2005)
DOI:10.1038/nrg1706
Reference
  Authors
Longo VD, Finch CE
  Title
Evolutionary medicine: from dwarf model systems to healthy centenarians?
  Journal
Science 299:1342-6 (2003)
DOI:10.1126/science.1077991
Reference
  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
  Authors
Kenyon CJ
  Title
The genetics of ageing.
  Journal
Nature 464:504-12 (2010)
DOI:10.1038/nature08980
Reference
  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
  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
  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
  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
  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
  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
  Authors
Lee SH, Min KJ
  Title
Caloric restriction and its mimetics.
  Journal
BMB Rep 46:181-7 (2013)
DOI:10.5483/BMBRep.2013.46.4.033
Reference
  Authors
Bordone L, Guarente L
  Title
Calorie restriction, SIRT1 and metabolism: understanding longevity.
  Journal
Nat Rev Mol Cell Biol 6:298-305 (2005)
DOI:10.1038/nrm1616
Reference
  Authors
Canto C, Auwerx J
  Title
Calorie restriction: is AMPK a key sensor and effector?
  Journal
Physiology (Bethesda) 26:214-24 (2011)
DOI:10.1152/physiol.00010.2011
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
Am J Physiol Endocrinol Metab 285:E1064-71 (2003)
DOI:10.1152/ajpendo.00296.2003
Reference
  Authors
Russell SJ, Kahn CR
  Title
Endocrine regulation of ageing.
  Journal
Nat Rev Mol Cell Biol 8:681-91 (2007)
DOI:10.1038/nrm2234
Related
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
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