KEGG   PATHWAY: opi04211
Entry
opi04211                    Pathway                                
Name
Longevity regulating pathway - Ochotona princeps (American pika)
Description
Regulation of longevity depends on genetic and environmental factors. Caloric restriction (CR), that is limiting food intake, is recognized in mammals as the best characterized and most reproducible strategy for extending lifespan. Four pathways have been implicated in mediating the CR effect. These are the insulin like growth factor (IGF-1)/insulin signaling pathway, the sirtuin pathway, the adenosine monophosphate (AMP) activated protein kinase (AMPK) pathway and the target of rapamycin (TOR) pathway. The collective response of these pathways to CR is believed to promote cellular fitness and ultimately longevity via activation of autophagy, stress defense mechanisms, and survival pathways while attenuating proinflammatory mediators and cellular growth. Furthermore, there is evidence supporting that life span extension can be achieved with pharmacologic agents that mimic the effects of caloric restriction, such as rapamycin, via mTOR signaling blockade, resveratrol, by activating SIRT1 activity, and metformin, which seems to be a robust stimulator of AMPK activity. As an aging suppressor, Klotho is an important molecule in aging processes and its overexpression results in longevity.
Class
Organismal Systems; Aging
Pathway map
opi04211  Longevity regulating pathway
opi04211

Organism
Ochotona princeps (American pika) [GN:opi]
Gene
101533865  insulin isoform X2 [KO:K04526]
101530887  INSR; insulin receptor [KO:K04527] [EC:2.7.10.1]
101526004  IGF1; insulin-like growth factor I isoform X2 [KO:K05459]
101535483  IGF1R; insulin-like growth factor 1 receptor isoform X1 [KO:K05087] [EC:2.7.10.1]
101526197  IRS1; insulin receptor substrate 1 [KO:K16172]
101527103  IRS2; insulin receptor substrate 2 [KO:K07187]
101525112  insulin receptor substrate 1-like [KO:K17445]
101528328  IRS4; LOW QUALITY PROTEIN: insulin receptor substrate 4 [KO:K17446]
101531636  HRAS; GTPase HRas [KO:K02833]
101534080  KRAS; GTPase KRas isoform X1 [KO:K07827]
101524465  NRAS; GTPase NRas [KO:K07828]
101519449  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
101533851  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X3 [KO:K00922] [EC:2.7.1.153]
101533024  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
101532354  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
101517982  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
101528030  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
101533296  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
101519021  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
101525801  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
101533323  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
101528674  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
101529277  ADCY3; adenylate cyclase type 3 isoform X1 [KO:K08043] [EC:4.6.1.1]
101527552  ADCY4; adenylate cyclase type 4 isoform X2 [KO:K08044] [EC:4.6.1.1]
101526286  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
101528764  ADCY6; adenylate cyclase type 6 isoform X1 [KO:K08046] [EC:4.6.1.1]
101519430  ADCY7; adenylate cyclase type 7 [KO:K08047] [EC:4.6.1.1]
101523667  ADCY8; adenylate cyclase type 8 isoform X1 [KO:K08048] [EC:4.6.1.1]
101517485  ADCY9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
101534210  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
101525119  cAMP-dependent protein kinase catalytic subunit alpha-like [KO:K04345] [EC:2.7.11.11]
101516221  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
101532574  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
101526116  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
101532689  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
101531761  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
101533371  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 [KO:K09048]
101532921  CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
101523446  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
101521567  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
101534608  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
101517365  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049]
101519409  EHMT2; histone-lysine N-methyltransferase EHMT2 isoform X1 [KO:K11420] [EC:2.1.1.355]
101522414  EHMT1; histone-lysine N-methyltransferase EHMT1 [KO:K11420] [EC:2.1.1.355]
101528756  FOXO1; forkhead box protein O1 [KO:K07201]
101521783  FOXO3; forkhead box protein O3 [KO:K09408]
101531538  SOD2; superoxide dismutase [Mn], mitochondrial isoform X1 [KO:K04564] [EC:1.15.1.1]
101520818  CAT; catalase [KO:K03781] [EC:1.11.1.6]
101530742  KL; klotho [KO:K14756] [EC:3.2.1.31]
101520687  TSC1; hamartin [KO:K07206]
101519464  TSC2; tuberin isoform X2 [KO:K07207]
101535564  RHEB; GTP-binding protein Rheb [KO:K07208]
101525384  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
101536034  RPTOR; regulatory-associated protein of mTOR [KO:K07204]
101519220  AKT1S1; proline-rich AKT1 substrate 1 [KO:K16184]
101521994  ULK1; serine/threonine-protein kinase ULK1 isoform X2 [KO:K21357] [EC:2.7.11.1]
101529120  ATG13; autophagy-related protein 13 isoform X1 [KO:K08331]
101534452  RB1CC1; RB1-inducible coiled-coil protein 1 isoform X1 [KO:K17589]
101518211  ATG101; autophagy-related protein 101 [KO:K19730]
101526118  RPS6KB2; ribosomal protein S6 kinase beta-2 [KO:K04688] [EC:2.7.11.1]
101528246  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
101532982  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
101520923  EIF4E; eukaryotic translation initiation factor 4E isoform X1 [KO:K03259]
101518184  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
101528599  LOW QUALITY PROTEIN: eukaryotic translation initiation factor 4E type 1B-like [KO:K03259]
101524098  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
101533464  ADIPOQ; adiponectin [KO:K07296]
101532910  ADIPOR2; adiponectin receptor protein 2 [KO:K07297]
101522527  ADIPOR1; adiponectin receptor protein 1 isoform X2 [KO:K07297]
101518948  LOW QUALITY PROTEIN: adiponectin receptor protein 1-like [KO:K07297]
101525739  APPL1; DCC-interacting protein 13-alpha [KO:K08733]
101535145  CAMKK2; calcium/calmodulin-dependent protein kinase kinase 2 isoform X1 [KO:K07359] [EC:2.7.11.17]
101536083  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
101525509  serine/threonine protein kinase OSK1-like [KO:K07198] [EC:2.7.11.31]
101529543  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
101520164  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X1 [KO:K07199]
101524207  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
101526129  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
101530247  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
101535143  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
101534216  SIRT1; NAD-dependent protein deacetylase sirtuin-1 isoform X1 [KO:K11411] [EC:2.3.1.286]
101517703  BAX; apoptosis regulator BAX [KO:K02159]
101528346  TP53; cellular tumor antigen p53 [KO:K04451]
101531611  NFKB1; LOW QUALITY PROTEIN: nuclear factor NF-kappa-B p105 subunit [KO:K02580]
101530066  RELA; transcription factor p65 [KO:K04735]
101533802  PPARG; peroxisome proliferator-activated receptor gamma isoform X1 [KO:K08530]
101527618  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
101531468  STK11; serine/threonine-protein kinase STK11 [KO:K07298] [EC:2.7.11.1]
101522211  SESN3; sestrin-3 isoform X1 [KO:K10141]
101521048  SESN1; sestrin-1 isoform X1 [KO:K10141]
101530551  SESN2; sestrin-2 [KO:K20394]
101525109  CAMK4; calcium/calmodulin-dependent protein kinase type IV [KO:K05869] [EC:2.7.11.17]
Compound
C00003  NAD+
C00020  AMP
C00076  Calcium cation
C00575  3',5'-Cyclic AMP
C03582  Resveratrol
C05981  Phosphatidylinositol-3,4,5-trisphosphate
C07151  Metformin
C07909  Sirolimus
Reference
PMID:22618766
  Authors
Barzilai N, Huffman DM, Muzumdar RH, Bartke A
  Title
The critical role of metabolic pathways in aging.
  Journal
Diabetes 61:1315-22 (2012)
DOI:10.2337/db11-1300
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:21779512
  Authors
Feng Z, Lin M, Wu R
  Title
The Regulation of Aging and Longevity: A New and Complex Role of p53.
  Journal
Genes Cancer 2:443-52 (2011)
DOI:10.1177/1947601911410223
Reference
PMID:20336132
  Authors
Kenyon CJ
  Title
The genetics of ageing.
  Journal
Nature 464:504-12 (2010)
DOI:10.1038/nature08980
Reference
PMID:24905167
  Authors
Cheng CW, Adams GB, Perin L, Wei M, Zhou X, Lam BS, Da Sacco S, Mirisola M, Quinn DI, Dorff TB, Kopchick JJ, Longo VD
  Title
Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppression.
  Journal
Cell Stem Cell 14:810-23 (2014)
DOI:10.1016/j.stem.2014.04.014
Reference
PMID:25832544
  Authors
Morris BJ, Willcox DC, Donlon TA, Willcox BJ
  Title
FOXO3: A Major Gene for Human Longevity - A Mini-Review.
  Journal
Gerontology 61:515-25 (2015)
DOI:10.1159/000375235
Reference
PMID:23939249
  Authors
Pyo JO, Yoo SM, Ahn HH, Nah J, Hong SH, Kam TI, Jung S, Jung YK
  Title
Overexpression of Atg5 in mice activates autophagy and extends lifespan.
  Journal
Nat Commun 4:2300 (2013)
DOI:10.1038/ncomms3300
Reference
PMID:25654554
  Authors
Madeo F, Zimmermann A, Maiuri MC, Kroemer G
  Title
Essential role for autophagy in life span extension.
  Journal
J Clin Invest 125:85-93 (2015)
DOI:10.1172/JCI73946
Reference
PMID:23061800
  Authors
Passtoors WM, Beekman M, Deelen J, van der Breggen R, Maier AB, Guigas B, Derhovanessian E, van Heemst D, de Craen AJ, Gunn DA, Pawelec G, Slagboom PE
  Title
Gene expression analysis of mTOR pathway: association with human longevity.
  Journal
Aging Cell 12:24-31 (2013)
DOI:10.1111/acel.12015
Reference
PMID:23594965
  Authors
Markaki M, Tavernarakis N
  Title
Metabolic control by target of rapamycin and autophagy during ageing - a mini-review.
  Journal
Gerontology 59:340-8 (2013)
DOI:10.1159/000348599
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:20103737
  Authors
Ruderman NB, Xu XJ, Nelson L, Cacicedo JM, Saha AK, Lan F, Ido Y
  Title
AMPK and SIRT1: a long-standing partnership?
  Journal
Am J Physiol Endocrinol Metab 298:E751-60 (2010)
DOI:10.1152/ajpendo.00745.2009
Reference
PMID:20357764
  Authors
Iwabu M, Yamauchi T, Okada-Iwabu M, Sato K, Nakagawa T, Funata M, Yamaguchi M, Namiki S, Nakayama R, Tabata M, Ogata H, Kubota N, Takamoto I, Hayashi YK, Yamauchi N, Waki H, Fukayama M, Nishino I, Tokuyama K, Ueki K, Oike Y, Ishii S, Hirose K, Shimizu T, Touhara K, Kadowaki T
  Title
Adiponectin and AdipoR1 regulate PGC-1alpha and mitochondria by Ca(2+) and AMPK/SIRT1.
  Journal
Nature 464:1313-9 (2010)
DOI:10.1038/nature08991
Reference
PMID:25824609
  Authors
Ramis MR, Esteban S, Miralles A, Tan DX, Reiter RJ
  Title
Caloric restriction, resveratrol and melatonin: Role of SIRT1 and implications for aging and related-diseases.
  Journal
Mech Ageing Dev 146-148:28-41 (2015)
DOI:10.1016/j.mad.2015.03.008
Reference
PMID:19262508
  Authors
Canto C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, Milne JC, Elliott PJ, Puigserver P, Auwerx J
  Title
AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity.
  Journal
Nature 458:1056-60 (2009)
DOI:10.1038/nature07813
Reference
PMID:24997879
  Authors
Esmaili S, Xu A, George J
  Title
The multifaceted and controversial immunometabolic actions of adiponectin.
  Journal
Trends Endocrinol Metab 25:444-51 (2014)
DOI:10.1016/j.tem.2014.06.001
Reference
PMID:20848587
  Authors
Mouchiroud L, Molin L, Dalliere N, Solari F
  Title
Life span extension by resveratrol, rapamycin, and metformin: The promise of dietary restriction mimetics for an healthy aging.
  Journal
Biofactors 36:377-82 (2010)
DOI:10.1002/biof.127
Reference
PMID:22983298
  Authors
Tucci P
  Title
Caloric restriction: is mammalian life extension linked to p53?
  Journal
Aging (Albany NY) 4:525-34 (2012)
DOI:10.18632/aging.100481
Reference
PMID:18692468
  Authors
Budanov AV, Karin M
  Title
p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling.
  Journal
Cell 134:451-60 (2008)
DOI:10.1016/j.cell.2008.06.028
Reference
PMID:25601466
  Authors
Sopjani M, Rinnerthaler M, Kruja J, Dermaku-Sopjani M
  Title
Intracellular signaling of the aging suppressor protein Klotho.
  Journal
Curr Mol Med 15:27-37 (2015)
DOI:10.2174/1566524015666150114111258
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
Related
pathway
opi04064  NF-kappa B signaling pathway
opi04068  FoxO signaling pathway
opi04115  p53 signaling pathway
opi04140  Autophagy - animal
opi04150  mTOR signaling pathway
opi04151  PI3K-Akt signaling pathway
opi04152  AMPK signaling pathway
opi04910  Insulin signaling pathway
KO pathway
ko04211   
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