KEGG   PATHWAY: cimi04211
Entry
cimi04211                   Pathway                                
Name
Longevity regulating pathway - Cebus imitator (Panamanian white-faced capuchin)
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
cimi04211  Longevity regulating pathway
cimi04211

Organism
Cebus imitator (Panamanian white-faced capuchin) [GN:cimi]
Gene
108288726  INS; insulin [KO:K04526]
108304133  INSR; insulin receptor [KO:K04527] [EC:2.7.10.1]
108294842  IGF1; insulin-like growth factor I isoform X2 [KO:K05459]
108294997  IGF1R; insulin-like growth factor 1 receptor [KO:K05087] [EC:2.7.10.1]
108304802  IRS1; insulin receptor substrate 1 [KO:K16172]
108284872  IRS2; insulin receptor substrate 2 [KO:K07187]
108316556  IRS4; insulin receptor substrate 4 [KO:K17446]
108288791  HRAS; GTPase HRas isoform X1 [KO:K02833]
108300272  KRAS; GTPase KRas isoform X2 [KO:K07827]
108289201  GTPase NRas-like [KO:K07828]
108301162  NRAS; GTPase NRas isoform X2 [KO:K07828]
108287732  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
108300786  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
108286022  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
108312772  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
108284538  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
108295514  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
108285792  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
108306856  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
108287186  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
108301433  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
108281387  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
108303190  ADCY3; adenylate cyclase type 3 isoform X1 [KO:K08043] [EC:4.6.1.1]
108297937  ADCY4; adenylate cyclase type 4 isoform X2 [KO:K08044] [EC:4.6.1.1]
108288965  ADCY5; adenylate cyclase type 5 isoform X1 [KO:K08045] [EC:4.6.1.1]
108316024  ADCY6; LOW QUALITY PROTEIN: adenylate cyclase type 6 [KO:K08046] [EC:4.6.1.1]
108305477  ADCY7; adenylate cyclase type 7 [KO:K08047] [EC:4.6.1.1]
108283815  ADCY8; adenylate cyclase type 8 isoform X1 [KO:K08048] [EC:4.6.1.1]
108286553  ADCY9; adenylate cyclase type 9 isoform X1 [KO:K08049] [EC:4.6.1.1]
108309036  LOW QUALITY PROTEIN: cAMP-dependent protein kinase catalytic subunit gamma-like [KO:K04345] [EC:2.7.11.11]
108284294  LOW QUALITY PROTEIN: cAMP-dependent protein kinase catalytic subunit gamma-like [KO:K04345] [EC:2.7.11.11]
108281936  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
108283458  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
108314512  PRKACG; LOW QUALITY PROTEIN: cAMP-dependent protein kinase catalytic subunit gamma [KO:K04345] [EC:2.7.11.11]
108316708  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
108311016  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
108288452  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
108292437  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 [KO:K09048]
108314253  CREB3; cyclic AMP-responsive element-binding protein 3 isoform X1 [KO:K09048]
108304874  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
108286451  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 isoform X1 [KO:K09048]
108293817  cyclic AMP-dependent transcription factor ATF-4-like [KO:K04374]
108315292  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
108303281  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X2 [KO:K09047]
108299802  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049]
108299809  EHMT2; histone-lysine N-methyltransferase EHMT2 isoform X1 [KO:K11420] [EC:2.1.1.355]
108287299  EHMT1; histone-lysine N-methyltransferase EHMT1 isoform X1 [KO:K11420] [EC:2.1.1.355]
108313887  FOXO1; forkhead box protein O1 [KO:K07201]
108314715  FOXO3; forkhead box protein O3 [KO:K09408]
108310971  SOD2; superoxide dismutase [Mn], mitochondrial [KO:K04564] [EC:1.15.1.1]
108305771  CAT; catalase [KO:K03781] [EC:1.11.1.6]
108314738  ATG5; autophagy protein 5 isoform X1 [KO:K08339]
108310801  KL; klotho [KO:K14756] [EC:3.2.1.31]
108295422  TSC1; hamartin [KO:K07206]
108290925  TSC2; tuberin isoform X1 [KO:K07207]
108297459  RHEB; GTP-binding protein Rheb [KO:K07208]
108285700  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
108301563  RPTOR; regulatory-associated protein of mTOR [KO:K07204]
108292019  AKT1S1; proline-rich AKT1 substrate 1 isoform X3 [KO:K16184]
108292658  ULK1; serine/threonine-protein kinase ULK1 [KO:K21357] [EC:2.7.11.1]
108304864  ATG13; autophagy-related protein 13 isoform X1 [KO:K08331]
108306695  RB1CC1; RB1-inducible coiled-coil protein 1 isoform X1 [KO:K17589]
108299074  autophagy-related protein 101-like [KO:K19730]
108316111  ATG101; autophagy-related protein 101 [KO:K19730]
108310354  RPS6KB2; ribosomal protein S6 kinase beta-2 [KO:K04688] [EC:2.7.11.1]
108312078  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
108309889  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
108292177  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
108294345  EIF4E; eukaryotic translation initiation factor 4E [KO:K03259]
108294625  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
108311122  ADIPOQ; adiponectin [KO:K07296]
108301996  ADIPOR1; adiponectin receptor protein 1 isoform X1 [KO:K07297]
108303554  adiponectin receptor protein 1-like [KO:K07297]
108315843  ADIPOR2; adiponectin receptor protein 2 isoform X1 [KO:K07297]
108303557  APPL1; DCC-interacting protein 13-alpha [KO:K08733]
108315123  CAMKK2; calcium/calmodulin-dependent protein kinase kinase 2 isoform X1 [KO:K07359] [EC:2.7.11.17]
108314880  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
108307684  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
108290415  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
108293690  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X1 [KO:K07199]
108297422  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
108309073  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
108316036  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 [KO:K07200]
108285090  SIRT1; NAD-dependent protein deacetylase sirtuin-1 [KO:K11411] [EC:2.3.1.286]
108287107  apoptosis regulator BAX-like [KO:K02159]
108283911  BAX; apoptosis regulator BAX [KO:K02159]
108306559  TP53; cellular tumor antigen p53 isoform X1 [KO:K04451]
108289254  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
108310400  RELA; transcription factor p65 isoform X2 [KO:K04735]
108284639  PPARG; peroxisome proliferator-activated receptor gamma isoform X1 [KO:K08530]
108290096  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
108293173  STK11; serine/threonine-protein kinase STK11 isoform X1 [KO:K07298] [EC:2.7.11.1]
108281719  SESN1; sestrin-1 [KO:K10141]
108287097  SESN3; sestrin-3 isoform X1 [KO:K10141]
108308764  SESN2; sestrin-2 [KO:K20394]
108303390  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
cimi04064  NF-kappa B signaling pathway
cimi04068  FoxO signaling pathway
cimi04115  p53 signaling pathway
cimi04140  Autophagy - animal
cimi04150  mTOR signaling pathway
cimi04151  PI3K-Akt signaling pathway
cimi04152  AMPK signaling pathway
cimi04910  Insulin signaling pathway
KO pathway
ko04211   
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