KEGG   PATHWAY: pcoq04211
Entry
pcoq04211                   Pathway                                
Name
Longevity regulating pathway - Propithecus coquereli (Coquerel's sifaka)
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
pcoq04211  Longevity regulating pathway
pcoq04211

Organism
Propithecus coquereli (Coquerel's sifaka) [GN:pcoq]
Gene
105816531  INS; insulin [KO:K04526]
105811840  INSR; insulin receptor [KO:K04527] [EC:2.7.10.1]
105815122  IGF1; insulin-like growth factor I [KO:K05459]
105809892  IGF1R; insulin-like growth factor 1 receptor [KO:K05087] [EC:2.7.10.1]
105808835  IRS1; insulin receptor substrate 1 [KO:K16172]
105805133  IRS2; insulin receptor substrate 2 isoform X1 [KO:K07187]
105806007  insulin receptor substrate 1-like [KO:K17445]
105810971  IRS4; insulin receptor substrate 4 [KO:K17446]
105816561  HRAS; GTPase HRas isoform X1 [KO:K02833]
105807545  KRAS; GTPase KRas [KO:K07827]
105810591  NRAS; GTPase NRas [KO:K07828]
105824997  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
105826540  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
105806240  PIK3CA; LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
105826612  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
105818191  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
105814042  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
105820591  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
105812606  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
105810397  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
105812499  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
105821322  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
105816960  ADCY3; adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
105812764  ADCY4; adenylate cyclase type 4 [KO:K08044] [EC:4.6.1.1]
105808688  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
105818188  ADCY6; adenylate cyclase type 6 [KO:K08046] [EC:4.6.1.1]
105808848  ADCY7; adenylate cyclase type 7 [KO:K08047] [EC:4.6.1.1]
105813348  ADCY8; adenylate cyclase type 8 isoform X1 [KO:K08048] [EC:4.6.1.1]
105813177  ADCY9; adenylate cyclase type 9 isoform X1 [KO:K08049] [EC:4.6.1.1]
105823839  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
105807940  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha isoform X1 [KO:K04345] [EC:2.7.11.11]
105823945  CREB1; cyclic AMP-responsive element-binding protein 1 [KO:K05870]
105815570  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
105820021  CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
105821904  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 [KO:K09048]
105811984  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 [KO:K09048]
105809025  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
105811104  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
105805232  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
105807372  cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
105817861  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049]
105818718  EHMT1; histone-lysine N-methyltransferase EHMT1 isoform X1 [KO:K11420] [EC:2.1.1.355]
105817873  EHMT2; histone-lysine N-methyltransferase EHMT2 isoform X1 [KO:K11420] [EC:2.1.1.355]
105809929  FOXO1; forkhead box protein O1 [KO:K07201]
105815931  FOXO3; forkhead box protein O3 [KO:K09408]
105812396  SOD2; superoxide dismutase [Mn], mitochondrial [KO:K04564] [EC:1.15.1.1]
105814601  CAT; catalase [KO:K03781] [EC:1.11.1.6]
105815928  ATG5; autophagy protein 5 isoform X1 [KO:K08339]
105808479  KL; klotho [KO:K14756] [EC:3.2.1.31]
105806636  TSC1; hamartin [KO:K07206]
105813061  TSC2; tuberin isoform X1 [KO:K07207]
105824616  RHEB; GTP-binding protein Rheb [KO:K07208]
105824883  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
105826235  RPTOR; regulatory-associated protein of mTOR [KO:K07204]
105809369  AKT1S1; proline-rich AKT1 substrate 1 isoform X1 [KO:K16184]
105820727  ULK1; serine/threonine-protein kinase ULK1 isoform X1 [KO:K21357] [EC:2.7.11.1]
105811079  ATG13; autophagy-related protein 13 isoform X1 [KO:K08331]
105824092  RB1CC1; RB1-inducible coiled-coil protein 1 isoform X1 [KO:K17589]
105817917  ATG101; autophagy-related protein 101 [KO:K19730]
105827360  RPS6KB2; ribosomal protein S6 kinase beta-2 [KO:K04688] [EC:2.7.11.1]
105813657  RPS6KB1; ribosomal protein S6 kinase beta-1 [KO:K04688] [EC:2.7.11.1]
105815840  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
105822359  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
105822497  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
105807639  EIF4E; eukaryotic translation initiation factor 4E [KO:K03259]
105807279  ADIPOQ; adiponectin [KO:K07296]
105819636  ADIPOR1; adiponectin receptor protein 1 [KO:K07297]
105812920  ADIPOR2; adiponectin receptor protein 2 [KO:K07297]
105807446  APPL1; DCC-interacting protein 13-alpha [KO:K08733]
105825619  CAMKK2; calcium/calmodulin-dependent protein kinase kinase 2 isoform X1 [KO:K07359] [EC:2.7.11.17]
105806302  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
105814830  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
105815079  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
105809631  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
105824627  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 [KO:K07200]
105808834  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
105817615  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 [KO:K07200]
105821946  SIRT1; NAD-dependent protein deacetylase sirtuin-1 isoform X1 [KO:K11411] [EC:2.3.1.286]
105809316  BAX; apoptosis regulator BAX [KO:K02159]
105819395  TP53; cellular tumor antigen p53 [KO:K04451]
105819191  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
105827383  RELA; transcription factor p65 isoform X1 [KO:K04735]
105819019  PPARG; peroxisome proliferator-activated receptor gamma [KO:K08530]
105826255  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
105811307  STK11; serine/threonine-protein kinase STK11 isoform X1 [KO:K07298] [EC:2.7.11.1]
105822993  SESN3; sestrin-3 isoform X1 [KO:K10141]
105815940  SESN1; sestrin-1 isoform X1 [KO:K10141]
105811735  SESN2; sestrin-2 [KO:K20394]
105822534  CAMK4; LOW QUALITY PROTEIN: 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
pcoq04064  NF-kappa B signaling pathway
pcoq04068  FoxO signaling pathway
pcoq04115  p53 signaling pathway
pcoq04140  Autophagy - animal
pcoq04150  mTOR signaling pathway
pcoq04151  PI3K-Akt signaling pathway
pcoq04152  AMPK signaling pathway
pcoq04910  Insulin signaling pathway
KO pathway
ko04211   
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