KEGG   PATHWAY: pon04211
Entry
pon04211                    Pathway                                
Name
Longevity regulating pathway - Pongo abelii (Sumatran orangutan)
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
pon04211  Longevity regulating pathway
pon04211

Organism
Pongo abelii (Sumatran orangutan) [GN:pon]
Gene
100451422  INSR; insulin receptor isoform X1 [KO:K04527] [EC:2.7.10.1]
100444645  IGF1; insulin-like growth factor I isoform X2 [KO:K05459]
100172156  IGF1R; insulin-like growth factor 1 receptor [KO:K05087] [EC:2.7.10.1]
100442255  IRS1; insulin receptor substrate 1 [KO:K16172]
100452233  IRS2; insulin receptor substrate 2 [KO:K07187]
100458662  IRS4; insulin receptor substrate 4 [KO:K17446]
100459427  HRAS; GTPase HRas [KO:K02833]
100462513  KRAS; GTPase KRas isoform X1 [KO:K07827]
100174317  NRAS; GTPase NRas precursor [KO:K07828]
100432846  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
100453779  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
103889133  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
100174298  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
100173589  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]
100437617  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
100454279  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
100448114  AKT3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100442100  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
100449504  ADCY1; adenylate cyclase type 1 isoform X1 [KO:K08041] [EC:4.6.1.1]
100445431  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
100431221  ADCY3; adenylate cyclase type 3 isoform X1 [KO:K08043] [EC:4.6.1.1]
100460806  ADCY4; adenylate cyclase type 4 isoform X1 [KO:K08044] [EC:4.6.1.1]
100454138  ADCY5; adenylate cyclase type 5 isoform X1 [KO:K08045] [EC:4.6.1.1]
100438178  ADCY6; adenylate cyclase type 6 isoform X1 [KO:K08046] [EC:4.6.1.1]
100436577  ADCY7; adenylate cyclase type 7 [KO:K08047] [EC:4.6.1.1]
100461383  ADCY8; adenylate cyclase type 8 isoform X1 [KO:K08048] [EC:4.6.1.1]
103889530  ADCY9; adenylate cyclase type 9 isoform X1 [KO:K08049] [EC:4.6.1.1]
100174748  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform 2 [KO:K04345] [EC:2.7.11.11]
100431906  PRKACG; cAMP-dependent protein kinase catalytic subunit gamma isoform X1 [KO:K04345] [EC:2.7.11.11]
100437102  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
100294619  CREB1; cyclic AMP-responsive element-binding protein 1 [KO:K05870]
100450554  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
100432292  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 isoform X1 [KO:K09048]
100436186  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
100438869  CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
100127093  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
100441756  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
100462459  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
100431578  cyclic AMP-dependent transcription factor ATF-4-like [KO:K04374]
100439720  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
100172895  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta [KO:K09049]
100449422  EHMT1; histone-lysine N-methyltransferase EHMT1 isoform X1 [KO:K11420] [EC:2.1.1.355]
100460372  EHMT2; histone-lysine N-methyltransferase EHMT2 isoform X1 [KO:K11420] [EC:2.1.1.355]
100460676  FOXO1; forkhead box protein O1 [KO:K07201]
100451077  FOXO3; forkhead box protein O3 [KO:K09408]
100174061  SOD2; superoxide dismutase [Mn], mitochondrial [KO:K04564] [EC:1.15.1.1]
100171588  CAT; catalase [KO:K03781] [EC:1.11.1.6]
100173376  ATG5; autophagy protein 5 [KO:K08339]
100439507  KL; klotho [KO:K14756] [EC:3.2.1.31]
100147742  TSC1; hamartin [KO:K07206]
100441126  TSC2; tuberin isoform X1 [KO:K07207]
100447214  RHEB; GTP-binding protein Rheb [KO:K07208]
100456786  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
100434731  RPTOR; regulatory-associated protein of mTOR isoform X1 [KO:K07204]
100449244  AKT1S1; proline-rich AKT1 substrate 1 isoform X1 [KO:K16184]
100450395  ULK1; serine/threonine-protein kinase ULK1 [KO:K21357] [EC:2.7.11.1]
100171805  ATG13; autophagy-related protein 13 [KO:K08331]
100172027  RB1CC1; RB1-inducible coiled-coil protein 1 isoform X1 [KO:K17589]
100443914  ATG101; autophagy-related protein 101 [KO:K19730]
100462008  LOW QUALITY PROTEIN: ribosomal protein S6 kinase beta-1 [KO:K04688] [EC:2.7.11.1]
100459428  RPS6KB2; ribosomal protein S6 kinase beta-2 [KO:K04688] [EC:2.7.11.1]
100456988  RPS6KB1; LOW QUALITY PROTEIN: ribosomal protein S6 kinase beta-1 [KO:K04688] [EC:2.7.11.1]
100455169  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
100173976  EIF4E2; eukaryotic translation initiation factor 4E type 2 [KO:K03259]
100448282  EIF4E; eukaryotic translation initiation factor 4E isoform X1 [KO:K03259]
100456700  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
100437367  ADIPOQ; adiponectin [KO:K07296]
100440372  ADIPOR2; adiponectin receptor protein 2 [KO:K07297]
100442095  ADIPOR1; adiponectin receptor protein 1 [KO:K07297]
100442490  APPL1; DCC-interacting protein 13-alpha isoform X1 [KO:K08733]
100459439  CAMKK2; calcium/calmodulin-dependent protein kinase kinase 2 isoform X1 [KO:K07359] [EC:2.7.11.17]
100172060  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
100174304  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 [KO:K07198] [EC:2.7.11.31]
100173201  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
100172154  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
100173926  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 [KO:K07200]
100442951  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 [KO:K07200]
100440280  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
100443901  SIRT1; NAD-dependent protein deacetylase sirtuin-1 isoform X1 [KO:K11411] [EC:2.3.1.286]
100450682  BAX; apoptosis regulator BAX isoform X1 [KO:K02159]
100435218  TP53; cellular tumor antigen p53 [KO:K04451]
100461595  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
100456049  RELA; transcription factor p65 [KO:K04735]
100171496  PPARG; peroxisome proliferator-activated receptor gamma [KO:K08530]
100172312  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha [KO:K07202]
100460337  STK11; serine/threonine-protein kinase STK11 isoform X1 [KO:K07298] [EC:2.7.11.1]
100174188  SESN1; sestrin-1 [KO:K10141]
100445126  SESN3; sestrin-3 [KO:K10141]
100172219  SESN2; sestrin-2 [KO:K20394]
100461605  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
pon04064  NF-kappa B signaling pathway
pon04068  FoxO signaling pathway
pon04115  p53 signaling pathway
pon04140  Autophagy - animal
pon04150  mTOR signaling pathway
pon04151  PI3K-Akt signaling pathway
pon04152  AMPK signaling pathway
pon04910  Insulin signaling pathway
KO pathway
ko04211   
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