KEGG   PATHWAY: mmu04213
Entry
mmu04213                    Pathway                                

Name
Longevity regulating pathway - multiple species - Mus musculus (mouse)
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
mmu04213  Longevity regulating pathway - multiple species
mmu04213

Organism
Mus musculus (mouse) [GN:mmu]
Gene
16334  Ins2; insulin II [KO:K04526]
16333  Ins1; insulin I [KO:K04526]
16337  Insr; insulin receptor [KO:K04527] [EC:2.7.10.1]
16000  Igf1; insulin-like growth factor 1 [KO:K05459]
16001  Igf1r; insulin-like growth factor I receptor [KO:K05087] [EC:2.7.10.1]
16367  Irs1; insulin receptor substrate 1 [KO:K16172]
384783  Irs2; insulin receptor substrate 2 [KO:K07187]
16369  Irs3; insulin receptor substrate 3 [KO:K17445]
16370  Irs4; insulin receptor substrate 4 [KO:K17446]
15461  Hras; Harvey rat sarcoma virus oncogene [KO:K02833]
16653  Kras; Kirsten rat sarcoma viral oncogene homolog [KO:K07827]
18176  Nras; neuroblastoma ras oncogene [KO:K07828]
18706  Pik3ca; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
18707  Pik3cd; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
74769  Pik3cb; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153]
18709  Pik3r2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
18708  Pik3r1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
18710  Pik3r3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
11651  Akt1; thymoma viral proto-oncogene 1 [KO:K04456] [EC:2.7.11.1]
11652  Akt2; thymoma viral proto-oncogene 2 [KO:K04456] [EC:2.7.11.1]
23797  Akt3; thymoma viral proto-oncogene 3 [KO:K04456] [EC:2.7.11.1]
432530  Adcy1; adenylate cyclase 1 [KO:K08041] [EC:4.6.1.1]
210044  Adcy2; adenylate cyclase 2 [KO:K08042] [EC:4.6.1.1]
104111  Adcy3; adenylate cyclase 3 [KO:K08043] [EC:4.6.1.1]
104110  Adcy4; adenylate cyclase 4 [KO:K08044] [EC:4.6.1.1]
224129  Adcy5; adenylate cyclase 5 [KO:K08045] [EC:4.6.1.1]
11512  Adcy6; adenylate cyclase 6 [KO:K08046] [EC:4.6.1.1]
11513  Adcy7; adenylate cyclase 7 [KO:K08047] [EC:4.6.1.1]
11514  Adcy8; adenylate cyclase 8 [KO:K08048] [EC:4.6.1.1]
11515  Adcy9; adenylate cyclase 9 [KO:K08049] [EC:4.6.1.1]
18747  Prkaca; protein kinase, cAMP dependent, catalytic, alpha [KO:K04345] [EC:2.7.11.11]
18749  Prkacb; protein kinase, cAMP dependent, catalytic, beta [KO:K04345] [EC:2.7.11.11]
56458  Foxo1; forkhead box O1 [KO:K07201]
56484  Foxo3; forkhead box O3 [KO:K09408]
20656  Sod2; superoxide dismutase 2, mitochondrial [KO:K04564] [EC:1.15.1.1]
12359  Cat; catalase [KO:K03781] [EC:1.11.1.6]
11793  Atg5; autophagy related 5 [KO:K08339]
105787  Prkaa1; protein kinase, AMP-activated, alpha 1 catalytic subunit [KO:K07198] [EC:2.7.11.11]
108079  Prkaa2; protein kinase, AMP-activated, alpha 2 catalytic subunit [KO:K07198] [EC:2.7.11.11]
19079  Prkab1; protein kinase, AMP-activated, beta 1 non-catalytic subunit [KO:K07199]
108097  Prkab2; protein kinase, AMP-activated, beta 2 non-catalytic subunit [KO:K07199]
19082  Prkag1; protein kinase, AMP-activated, gamma 1 non-catalytic subunit [KO:K07200]
241113  Prkag3; protein kinase, AMP-activated, gamma 3 non-catalytic subunit [KO:K07200]
108099  Prkag2; protein kinase, AMP-activated, gamma 2 non-catalytic subunit [KO:K07200]
56717  Mtor; mechanistic target of rapamycin kinase [KO:K07203] [EC:2.7.11.1]
74370  Rptor; regulatory associated protein of MTOR, complex 1 [KO:K07204]
67605  Akt1s1; AKT1 substrate 1 (proline-rich) [KO:K16184]
58988  Rps6kb2; ribosomal protein S6 kinase, polypeptide 2 [KO:K04688] [EC:2.7.11.1]
72508  Rps6kb1; ribosomal protein S6 kinase, polypeptide 1 [KO:K04688] [EC:2.7.11.1]
93759  Sirt1; sirtuin 1 [KO:K11411] [EC:2.3.1.286]
20655  Sod1; superoxide dismutase 1, soluble [KO:K04565] [EC:1.15.1.1]
13688  Eif4ebp2; eukaryotic translation initiation factor 4E binding protein 2 [KO:K18644]
15481  Hspa8; heat shock protein 8 [KO:K03283]
15482  Hspa1l; heat shock protein 1-like [KO:K03283]
193740  Hspa1a; heat shock protein 1A [KO:K03283]
15512  Hspa2; heat shock protein 2 [KO:K03283]
15511  Hspa1b; heat shock protein 1B [KO:K03283]
12955  Cryab; crystallin, alpha B [KO:K09542]
15182  Hdac2; histone deacetylase 2 [KO:K06067] [EC:3.5.1.98]
433759  Hdac1; histone deacetylase 1 [KO:K06067] [EC:3.5.1.98]
15376  Foxa2; forkhead box A2 [KO:K08035]
20480  Clpb; ClpB caseinolytic peptidase B [KO:K03695]
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
mmu04068  FoxO signaling pathway
mmu04150  mTOR signaling pathway
mmu04151  PI3K-Akt signaling pathway
mmu04152  AMPK signaling pathway
mmu04211  Longevity regulating pathway
mmu04910  Insulin signaling pathway
KO pathway
ko04213   

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