KEGG   PATHWAY: dnm04211
Entry
dnm04211                    Pathway                                
Name
Longevity regulating pathway - Dasypus novemcinctus (nine-banded armadillo)
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
dnm04211  Longevity regulating pathway
dnm04211

Organism
Dasypus novemcinctus (nine-banded armadillo) [GN:dnm]
Gene
101431970  INSR; insulin receptor isoform X1 [KO:K04527] [EC:2.7.10.1]
101440893  IGF1; insulin-like growth factor I isoform X1 [KO:K05459]
101416767  IGF1R; insulin-like growth factor 1 receptor [KO:K05087] [EC:2.7.10.1]
101437367  IRS1; insulin receptor substrate 1 [KO:K16172]
101425165  IRS2; LOW QUALITY PROTEIN: insulin receptor substrate 2 [KO:K07187]
101416233  IRS4; insulin receptor substrate 4 [KO:K17446]
101419480  HRAS; GTPase HRas isoform X1 [KO:K02833]
101412233  KRAS; GTPase KRas isoform X4 [KO:K07827]
101430817  NRAS; GTPase NRas [KO:K07828]
101414240  LOW QUALITY PROTEIN: GTPase NRas-like [KO:K07828]
101444276  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
101443761  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
101426945  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
101423744  phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
101435351  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
101433347  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
101419022  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
101428799  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
101445813  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
101411559  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
101411573  ADCY3; adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
101419332  ADCY4; adenylate cyclase type 4 [KO:K08044] [EC:4.6.1.1]
101417345  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
101442950  ADCY6; adenylate cyclase type 6 [KO:K08046] [EC:4.6.1.1]
101427927  ADCY7; LOW QUALITY PROTEIN: adenylate cyclase type 7 [KO:K08047] [EC:4.6.1.1]
101422732  adenylate cyclase type 8 [KO:K08048] [EC:4.6.1.1]
101442901  ADCY9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
101413809  cAMP-dependent protein kinase type 2 [KO:K04345] [EC:2.7.11.11]
101423692  PRKACB; LOW QUALITY PROTEIN: cAMP-dependent protein kinase catalytic subunit beta [KO:K04345] [EC:2.7.11.11]
101445596  uncharacterized protein LOC101445596 [KO:K04345] [EC:2.7.11.11]
101434860  CREB1; cyclic AMP-responsive element-binding protein 1 [KO:K05870]
101414225  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
101414637  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
101424631  CREB3L3; LOW QUALITY PROTEIN: cyclic AMP-responsive element-binding protein 3-like protein 3 [KO:K09048]
101411890  CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
101435604  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 isoform X1 [KO:K09048]
101442310  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
101410933  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
101410879  cyclic AMP-dependent transcription factor ATF-4-like [KO:K04374]
101426399  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
101425452  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta [KO:K09049]
101435395  EHMT2; histone-lysine N-methyltransferase EHMT2 [KO:K11420] [EC:2.1.1.355]
101444858  EHMT1; histone-lysine N-methyltransferase EHMT1 [KO:K11420] [EC:2.1.1.355]
105745292  LOW QUALITY PROTEIN: forkhead box protein O1-like [KO:K07201]
101412377  FOXO1; forkhead box protein O1 [KO:K07201]
101419568  FOXO3; forkhead box protein O3 [KO:K09408]
101426028  SOD2; superoxide dismutase [Mn], mitochondrial [KO:K04564] [EC:1.15.1.1]
101411637  CAT; catalase [KO:K03781] [EC:1.11.1.6]
101444274  ATG5; autophagy protein 5 [KO:K08339]
101434074  KL; klotho [KO:K14756] [EC:3.2.1.31]
101446801  TSC1; hamartin isoform X1 [KO:K07206]
101413281  TSC2; tuberin [KO:K07207]
101417998  RHEB; GTP-binding protein Rheb [KO:K07208]
101434069  MTOR; LOW QUALITY PROTEIN: serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
101433259  RPTOR; regulatory-associated protein of mTOR [KO:K07204]
101423988  ULK1; serine/threonine-protein kinase ULK1 [KO:K21357] [EC:2.7.11.1]
101418297  ATG13; autophagy-related protein 13 isoform X1 [KO:K08331]
101437295  RB1CC1; RB1-inducible coiled-coil protein 1 isoform X2 [KO:K17589]
101414072  ATG101; autophagy-related protein 101 [KO:K19730]
101439255  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
101434210  RPS6KB2; ribosomal protein S6 kinase beta-2 [KO:K04688] [EC:2.7.11.1]
101428978  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
101434873  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
101423038  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
101424862  eukaryotic translation initiation factor 4E [KO:K03259]
101442588  ADIPOQ; adiponectin isoform X3 [KO:K07296]
101440107  ADIPOR2; adiponectin receptor protein 2 [KO:K07297]
101436347  ADIPOR1; adiponectin receptor protein 1 [KO:K07297]
101423339  APPL1; DCC-interacting protein 13-alpha [KO:K08733]
101412193  CAMKK2; calcium/calmodulin-dependent protein kinase kinase 2 isoform X1 [KO:K07359] [EC:2.7.11.17]
101446858  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
101429267  LOW QUALITY PROTEIN: 5'-AMP-activated protein kinase catalytic subunit alpha-2-like [KO:K07198] [EC:2.7.11.31]
101425404  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
101440900  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
101430169  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
101431993  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
101418750  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
101414148  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 isoform X2 [KO:K07200]
101424120  SIRT1; LOW QUALITY PROTEIN: NAD-dependent protein deacetylase sirtuin-1 [KO:K11411] [EC:2.3.1.286]
101432154  BAX; apoptosis regulator BAX [KO:K02159]
101416069  TP53; cellular tumor antigen p53 [KO:K04451]
101437556  NFKB1; LOW QUALITY PROTEIN: nuclear factor NF-kappa-B p105 subunit [KO:K02580]
101417885  RELA; transcription factor p65 [KO:K04735]
101418117  PPARG; peroxisome proliferator-activated receptor gamma isoform X1 [KO:K08530]
101441748  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
101426791  serine/threonine-protein kinase STK11-like [KO:K07298] [EC:2.7.11.1]
101445640  SESN3; sestrin-3 isoform X3 [KO:K10141]
101417806  SESN1; sestrin-1 isoform X1 [KO:K10141]
101427253  SESN2; sestrin-2 [KO:K20394]
101428221  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
dnm04064  NF-kappa B signaling pathway
dnm04068  FoxO signaling pathway
dnm04115  p53 signaling pathway
dnm04140  Autophagy - animal
dnm04150  mTOR signaling pathway
dnm04151  PI3K-Akt signaling pathway
dnm04152  AMPK signaling pathway
dnm04910  Insulin signaling pathway
KO pathway
ko04211   
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