ENTRY       hsa04213                    Pathway
NAME        Longevity regulating pathway - multiple species - Homo sapiens (human)
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 hsa04213  Longevity regulating pathway - multiple species
ORGANISM    Homo sapiens (human) [GN:hsa]
GENE        3630  INS; insulin [KO:K04526]
            3643  INSR; insulin receptor [KO:K04527] [EC:2.7.10.1]
            3479  IGF1; insulin like growth factor 1 [KO:K05459]
            3480  IGF1R; insulin like growth factor 1 receptor [KO:K05087] [EC:2.7.10.1]
            3667  IRS1; insulin receptor substrate 1 [KO:K16172]
            8660  IRS2; insulin receptor substrate 2 [KO:K07187]
            8471  IRS4; insulin receptor substrate 4 [KO:K17446]
            3265  HRAS; HRas proto-oncogene, GTPase [KO:K02833]
            3845  KRAS; KRAS proto-oncogene, GTPase [KO:K07827]
            4893  NRAS; NRAS proto-oncogene, GTPase [KO:K07828]
            5290  PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
            5293  PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
            5291  PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153]
            5295  PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
            5296  PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
            8503  PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
            207  AKT1; AKT serine/threonine kinase 1 [KO:K04456] [EC:2.7.11.1]
            208  AKT2; AKT serine/threonine kinase 2 [KO:K04456] [EC:2.7.11.1]
            10000  AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:2.7.11.1]
            107  ADCY1; adenylate cyclase 1 [KO:K08041] [EC:4.6.1.1]
            108  ADCY2; adenylate cyclase 2 [KO:K08042] [EC:4.6.1.1]
            109  ADCY3; adenylate cyclase 3 [KO:K08043] [EC:4.6.1.1]
            196883  ADCY4; adenylate cyclase 4 [KO:K08044] [EC:4.6.1.1]
            111  ADCY5; adenylate cyclase 5 [KO:K08045] [EC:4.6.1.1]
            112  ADCY6; adenylate cyclase 6 [KO:K08046] [EC:4.6.1.1]
            113  ADCY7; adenylate cyclase 7 [KO:K08047] [EC:4.6.1.1]
            114  ADCY8; adenylate cyclase 8 [KO:K08048] [EC:4.6.1.1]
            115  ADCY9; adenylate cyclase 9 [KO:K08049] [EC:4.6.1.1]
            5566  PRKACA; protein kinase cAMP-activated catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
            5567  PRKACB; protein kinase cAMP-activated catalytic subunit beta [KO:K04345] [EC:2.7.11.11]
            5568  PRKACG; protein kinase cAMP-activated catalytic subunit gamma [KO:K04345] [EC:2.7.11.11]
            2308  FOXO1; forkhead box O1 [KO:K07201]
            2309  FOXO3; forkhead box O3 [KO:K09408]
            6648  SOD2; superoxide dismutase 2 [KO:K04564] [EC:1.15.1.1]
            847  CAT; catalase [KO:K03781] [EC:1.11.1.6]
            9474  ATG5; autophagy related 5 [KO:K08339]
            5562  PRKAA1; protein kinase AMP-activated catalytic subunit alpha 1 [KO:K07198] [EC:2.7.11.11]
            5563  PRKAA2; protein kinase AMP-activated catalytic subunit alpha 2 [KO:K07198] [EC:2.7.11.11]
            5564  PRKAB1; protein kinase AMP-activated non-catalytic subunit beta 1 [KO:K07199]
            5565  PRKAB2; protein kinase AMP-activated non-catalytic subunit beta 2 [KO:K07199]
            5571  PRKAG1; protein kinase AMP-activated non-catalytic subunit gamma 1 [KO:K07200]
            53632  PRKAG3; protein kinase AMP-activated non-catalytic subunit gamma 3 [KO:K07200]
            51422  PRKAG2; protein kinase AMP-activated non-catalytic subunit gamma 2 [KO:K07200]
            2475  MTOR; mechanistic target of rapamycin kinase [KO:K07203] [EC:2.7.11.1]
            57521  RPTOR; regulatory associated protein of MTOR complex 1 [KO:K07204]
            84335  AKT1S1; AKT1 substrate 1 [KO:K16184]
            6198  RPS6KB1; ribosomal protein S6 kinase B1 [KO:K04688] [EC:2.7.11.1]
            6199  RPS6KB2; ribosomal protein S6 kinase B2 [KO:K04688] [EC:2.7.11.1]
            23411  SIRT1; sirtuin 1 [KO:K11411] [EC:2.3.1.286]
            6647  SOD1; superoxide dismutase 1 [KO:K04565] [EC:1.15.1.1]
            1979  EIF4EBP2; eukaryotic translation initiation factor 4E binding protein 2 [KO:K18644]
            3312  HSPA8; heat shock protein family A (Hsp70) member 8 [KO:K03283]
            3303  HSPA1A; heat shock protein family A (Hsp70) member 1A [KO:K03283]
            3306  HSPA2; heat shock protein family A (Hsp70) member 2 [KO:K03283]
            3305  HSPA1L; heat shock protein family A (Hsp70) member 1 like [KO:K03283]
            3304  HSPA1B; heat shock protein family A (Hsp70) member 1B [KO:K03283]
            3310  HSPA6; heat shock protein family A (Hsp70) member 6 [KO:K03283]
            1410  CRYAB; crystallin alpha B [KO:K09542]
            3065  HDAC1; histone deacetylase 1 [KO:K06067] [EC:3.5.1.98]
            3066  HDAC2; histone deacetylase 2 [KO:K06067] [EC:3.5.1.98]
            3170  FOXA2; forkhead box A2 [KO:K08035]
            81570  CLPB; caseinolytic mitochondrial matrix peptidase chaperone subunit B [KO:K03695]
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.
  JOURNAL   Science 328:321-6 (2010)
            DOI:10.1126/science.1172539
REFERENCE   PMID:20098959
  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   PMID:26682004
  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   PMID:18946478
  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   PMID:16304601
  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   PMID:12610293
  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   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.
  JOURNAL   BMB Rep 46:181-7 (2013)
            DOI:10.5483/BMBRep.2013.46.4.033
REFERENCE   PMID:15768047
  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   PMID:21841070
  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   PMID:14534077
  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   PMID:17684529
  AUTHORS   Russell SJ, Kahn CR
  TITLE     Endocrine regulation of ageing.
  JOURNAL   Nat Rev Mol Cell Biol 8:681-91 (2007)
            DOI:10.1038/nrm2234
REL_PATHWAY hsa04068  FoxO signaling pathway
            hsa04150  mTOR signaling pathway
            hsa04151  PI3K-Akt signaling pathway
            hsa04152  AMPK signaling pathway
            hsa04211  Longevity regulating pathway
            hsa04910  Insulin signaling pathway
KO_PATHWAY  ko04213
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