KEGG   PATHWAY: mlf04211
Entry
mlf04211                    Pathway                                
Name
Longevity regulating pathway - Myotis lucifugus (little brown bat)
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
mlf04211  Longevity regulating pathway
mlf04211

Organism
Myotis lucifugus (little brown bat) [GN:mlf]
Gene
102430737  INS; insulin [KO:K04526]
102437355  INSR; LOW QUALITY PROTEIN: insulin receptor [KO:K04527] [EC:2.7.10.1]
102424041  IGF1; insulin-like growth factor I isoform X1 [KO:K05459]
102430595  IGF1R; LOW QUALITY PROTEIN: insulin-like growth factor 1 receptor [KO:K05087] [EC:2.7.10.1]
102442509  IRS1; insulin receptor substrate 1 [KO:K16172]
102429074  IRS2; LOW QUALITY PROTEIN: insulin receptor substrate 2 [KO:K07187]
102418401  IRS4; LOW QUALITY PROTEIN: insulin receptor substrate 4 [KO:K17446]
102431999  KRAS; GTPase KRas isoform X1 [KO:K07827]
102430744  NRAS; GTPase NRas [KO:K07828]
102422649  PIK3CD; LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
102441064  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
102433534  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
102427890  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X2 [KO:K02649]
102441522  LOW QUALITY PROTEIN: phosphatidylinositol 3-kinase regulatory subunit beta-like [KO:K02649]
102429230  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
102426106  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
102419324  LOW QUALITY PROTEIN: phosphatidylinositol 3-kinase regulatory subunit beta-like [KO:K02649]
102443221  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
102439923  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
102430354  ADCY2; adenylate cyclase type 2 isoform X2 [KO:K08042] [EC:4.6.1.1]
102442682  ADCY3; adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
102417969  ADCY4; adenylate cyclase type 4 isoform X1 [KO:K08044] [EC:4.6.1.1]
102425254  ADCY5; LOW QUALITY PROTEIN: adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
102433159  ADCY6; LOW QUALITY PROTEIN: adenylate cyclase type 6 [KO:K08046] [EC:4.6.1.1]
102423495  ADCY8; adenylate cyclase type 8 isoform X1 [KO:K08048] [EC:4.6.1.1]
102422477  ADCY9; adenylate cyclase type 9 isoform X1 [KO:K08049] [EC:4.6.1.1]
102437773  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
102417960  PRKACA; LOW QUALITY PROTEIN: cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
102428529  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
102418405  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
102431250  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
102416978  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 isoform X2 [KO:K09048]
102443216  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
102427186  CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048]
102421849  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
102429560  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
102439961  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
102428756  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta [KO:K09049]
102417065  EHMT1; histone-lysine N-methyltransferase EHMT1 isoform X1 [KO:K11420] [EC:2.1.1.355]
102416827  EHMT2; LOW QUALITY PROTEIN: histone-lysine N-methyltransferase EHMT2 [KO:K11420] [EC:2.1.1.355]
102432268  FOXO1; LOW QUALITY PROTEIN: forkhead box protein O1 [KO:K07201]
102440021  FOXO3; forkhead box protein O3 [KO:K09408]
102424669  SOD2; superoxide dismutase [Mn], mitochondrial isoform X1 [KO:K04564] [EC:1.15.1.1]
102422808  CAT; LOW QUALITY PROTEIN: catalase [KO:K03781] [EC:1.11.1.6]
102428926  ATG5; autophagy protein 5 [KO:K08339]
102436510  KL; LOW QUALITY PROTEIN: klotho [KO:K14756] [EC:3.2.1.31]
102440346  TSC1; hamartin [KO:K07206]
102422720  TSC2; tuberin isoform X1 [KO:K07207]
102422024  LOW QUALITY PROTEIN: GTP-binding protein Rheb-like [KO:K07208]
102441557  RHEB; GTP-binding protein Rheb [KO:K07208]
102434974  MTOR; LOW QUALITY PROTEIN: serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
102430610  RPTOR; regulatory-associated protein of mTOR [KO:K07204]
102424796  AKT1S1; LOW QUALITY PROTEIN: proline-rich AKT1 substrate 1 [KO:K16184]
102429007  ATG13; autophagy-related protein 13 isoform X4 [KO:K08331]
102420949  RB1CC1; RB1-inducible coiled-coil protein 1 isoform X1 [KO:K17589]
102429721  ATG101; autophagy-related protein 101 [KO:K19730]
102429245  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X2 [KO:K04688] [EC:2.7.11.1]
102433676  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
102418433  EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
102437938  eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
102433516  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
102416807  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
102431191  EIF4E; eukaryotic translation initiation factor 4E isoform X1 [KO:K03259]
102429555  ADIPOQ; adiponectin [KO:K07296]
102437976  ADIPOR1; adiponectin receptor protein 1 [KO:K07297]
102425347  ADIPOR2; adiponectin receptor protein 2 [KO:K07297]
102438518  APPL1; DCC-interacting protein 13-alpha isoform X1 [KO:K08733]
102421841  CAMKK2; LOW QUALITY PROTEIN: calcium/calmodulin-dependent protein kinase kinase 2 [KO:K07359] [EC:2.7.11.17]
102440094  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
102438720  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
102430132  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
106695632  5'-AMP-activated protein kinase subunit beta-2-like [KO:K07199]
102430862  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
102428212  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X1 [KO:K07200]
102425288  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
102436674  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
102421566  SIRT1; NAD-dependent protein deacetylase sirtuin-1 [KO:K11411] [EC:2.3.1.286]
102417074  BAX; apoptosis regulator BAX [KO:K02159]
102431418  TP53; cellular tumor antigen p53 isoform X2 [KO:K04451]
102435748  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
102424236  RELA; transcription factor p65 [KO:K04735]
102435787  PPARG; peroxisome proliferator-activated receptor gamma isoform X1 [KO:K08530]
102417838  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha [KO:K07202]
102421316  STK11; serine/threonine-protein kinase STK11 isoform X1 [KO:K07298] [EC:2.7.11.1]
102438956  SESN1; sestrin-1 isoform X1 [KO:K10141]
102428802  SESN3; sestrin-3 [KO:K10141]
102426630  SESN2; sestrin-2 isoform X2 [KO:K20394]
102433506  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
mlf04064  NF-kappa B signaling pathway
mlf04068  FoxO signaling pathway
mlf04115  p53 signaling pathway
mlf04140  Autophagy - animal
mlf04150  mTOR signaling pathway
mlf04151  PI3K-Akt signaling pathway
mlf04152  AMPK signaling pathway
mlf04910  Insulin signaling pathway
KO pathway
ko04211   
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