KEGG   PATHWAY: cfa04211
Entry
cfa04211                    Pathway                                
Name
Longevity regulating pathway - Canis lupus familiaris (dog)
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
cfa04211  Longevity regulating pathway
cfa04211

Organism
Canis lupus familiaris (dog) [GN:cfa]
Gene
483665  INS; insulin precursor [KO:K04526]
484990  INSR; insulin receptor isoform X3 [KO:K04527] [EC:2.7.10.1]
610255  IGF1; insulin-like growth factor I precursor [KO:K05459]
442951  IGF1R; insulin-like growth factor 1 receptor isoform X1 [KO:K05087] [EC:2.7.10.1]
486148  IRS1; insulin receptor substrate 1 [KO:K16172]
485548  IRS2; insulin receptor substrate 2 isoform X8 [KO:K07187]
492059  IRS4; insulin receptor substrate 4 [KO:K17446]
403735  HRAS; GTPase HRas isoform 1 [KO:K02833]
403871  KRAS; GTPase KRas isoform X1 [KO:K07827]
403872  NRAS; GTPase NRas [KO:K07828]
488084  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
489644  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X3 [KO:K00922] [EC:2.7.1.153]
477085  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
609956  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
487235  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
100856339  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
442964  AKT3; RAC-gamma serine/threonine-protein kinase isoform X8 [KO:K04456] [EC:2.7.11.1]
449021  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
490878  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
607357  ADCY1; LOW QUALITY PROTEIN: adenylate cyclase type 1 isoform X5 [KO:K08041] [EC:4.6.1.1]
478624  ADCY2; adenylate cyclase type 2 isoform X1 [KO:K08042] [EC:4.6.1.1]
482994  ADCY3; adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
480271  ADCY4; adenylate cyclase type 4 isoform X2 [KO:K08044] [EC:4.6.1.1]
403859  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
477625  ADCY6; adenylate cyclase type 6 [KO:K08046] [EC:4.6.1.1]
487289  ADCY7; adenylate cyclase type 7 isoform X1 [KO:K08047] [EC:4.6.1.1]
482045  ADCY8; adenylate cyclase type 8 isoform X2 [KO:K08048] [EC:4.6.1.1]
490031  ADCY9; adenylate cyclase type 9 isoform X2 [KO:K08049] [EC:4.6.1.1]
403556  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
479975  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X2 [KO:K04345] [EC:2.7.11.11]
607922  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
478806  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
611934  CREB3; cyclic AMP-responsive element-binding protein 3 isoform X2 [KO:K09048]
483636  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
491369  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
485046  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
612303  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 [KO:K09048]
474503  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
475266  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X5 [KO:K09047]
474855  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049]
474851  EHMT2; histone-lysine N-methyltransferase EHMT2 isoform X1 [KO:K11420] [EC:2.1.1.355]
491224  EHMT1; histone-lysine N-methyltransferase EHMT1 isoform X3 [KO:K11420] [EC:2.1.1.355]
477295  FOXO1; forkhead box protein O1 [KO:K07201]
481954  FOXO3; forkhead box protein O3 [KO:K09408]
476258  SOD2; superoxide dismutase [Mn], mitochondrial [KO:K04564] [EC:1.15.1.1]
403474  CAT; catalase [KO:K03781] [EC:1.11.1.6]
610868  ATG5; autophagy protein 5 isoform X1 [KO:K08339]
100685604  KL; klotho isoform X3 [KO:K14756] [EC:3.2.1.31]
480688  TSC1; hamartin isoform X1 [KO:K07206]
479883  TSC2; tuberin isoform X1 [KO:K07207]
475545  RHEB; GTP-binding protein Rheb isoform X2 [KO:K07208]
478232  MTOR; serine/threonine-protein kinase mTOR isoform X5 [KO:K07203] [EC:2.7.11.1]
608378  RPTOR; regulatory-associated protein of mTOR isoform X2 [KO:K07204]
610130  AKT1S1; proline-rich AKT1 substrate 1 isoform X1 [KO:K16184]
477437  ULK1; serine/threonine-protein kinase ULK1 isoform X3 [KO:K21357] [EC:2.7.11.1]
483632  ATG13; autophagy-related protein 13 isoform X1 [KO:K08331]
477876  RB1CC1; RB1-inducible coiled-coil protein 1 isoform X1 [KO:K17589]
486535  ATG101; autophagy-related protein 101 [KO:K19730]
480580  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X3 [KO:K04688] [EC:2.7.11.1]
610499  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X2 [KO:K04688] [EC:2.7.11.1]
475590  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
487870  EIF4E; eukaryotic translation initiation factor 4E isoform X1 [KO:K03259]
610238  EIF4E2; eukaryotic translation initiation factor 4E type 2 [KO:K03259]
489099  EIF4E1B; eukaryotic translation initiation factor 4E type 1B isoform X1 [KO:K03259]
611215  LOW QUALITY PROTEIN: eukaryotic translation initiation factor 4E type 2-like [KO:K03259]
100685582  eukaryotic translation initiation factor 4E type 2-like [KO:K03259]
403625  ADIPOQ; adiponectin precursor [KO:K07296]
477732  ADIPOR2; adiponectin receptor protein 2 isoform X1 [KO:K07297]
479995  ADIPOR1; adiponectin receptor protein 1 [KO:K07297]
484716  APPL1; DCC-interacting protein 13-alpha isoform X2 [KO:K08733]
486263  CAMKK2; calcium/calmodulin-dependent protein kinase kinase 2 isoform X1 [KO:K07359] [EC:2.7.11.17]
479351  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
489571  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 isoform X2 [KO:K07198] [EC:2.7.11.31]
486295  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
100856379  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X1 [KO:K07199]
475546  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
486559  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
488526  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 isoform X1 [KO:K07200]
489012  SIRT1; NAD-dependent protein deacetylase sirtuin-1 isoform X2 [KO:K11411] [EC:2.3.1.286]
403523  BAX; apoptosis regulator BAX [KO:K02159]
403869  TP53; cellular tumor antigen p53 [KO:K04451]
442859  NFKB1; nuclear factor NF-kappa-B p105 subunit [KO:K02580]
483729  RELA; transcription factor p65 isoform X2 [KO:K04735]
403606  PPARG; peroxisome proliferator-activated receptor gamma [KO:K08530]
479127  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X3 [KO:K07202]
485088  STK11; serine/threonine-protein kinase STK11 isoform X1 [KO:K07298] [EC:2.7.11.1]
481956  SESN1; sestrin-1 isoform X2 [KO:K10141]
485118  SESN3; sestrin-3 isoform X2 [KO:K10141]
487335  SESN2; sestrin-2 [KO:K20394]
100684140  CAMK4; calcium/calmodulin-dependent protein kinase type IV isoform X1 [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
cfa04064  NF-kappa B signaling pathway
cfa04068  FoxO signaling pathway
cfa04115  p53 signaling pathway
cfa04140  Autophagy - animal
cfa04150  mTOR signaling pathway
cfa04151  PI3K-Akt signaling pathway
cfa04152  AMPK signaling pathway
cfa04910  Insulin signaling pathway
KO pathway
ko04211   
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