KEGG   PATHWAY: pcoo04211
Entry
pcoo04211                   Pathway                                
Name
Longevity regulating pathway - Puma concolor (puma)
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
pcoo04211  Longevity regulating pathway
pcoo04211

Organism
Puma concolor (puma) [GN:pcoo]
Gene
112852904  INSR; insulin receptor [KO:K04527] [EC:2.7.10.1]
112863499  IGF1; insulin-like growth factor I isoform X1 [KO:K05459]
112855479  IGF1R; insulin-like growth factor 1 receptor [KO:K05087] [EC:2.7.10.1]
112859926  insulin receptor substrate 1-like [KO:K17445]
112871206  IRS4; insulin receptor substrate 4 [KO:K17446]
112868012  KRAS; GTPase KRas isoform X1 [KO:K07827]
112848478  NRAS; GTPase NRas [KO:K07828]
112849397  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
112849524  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
112848856  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
112861619  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
112868847  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
112863208  AKT3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
112851313  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
112859788  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
112860207  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
112864041  ADCY3; adenylate cyclase type 3 isoform X1 [KO:K08043] [EC:4.6.1.1]
112855238  ADCY4; adenylate cyclase type 4 [KO:K08044] [EC:4.6.1.1]
112849881  ADCY5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
112867731  ADCY6; adenylate cyclase type 6 [KO:K08046] [EC:4.6.1.1]
112857348  ADCY7; adenylate cyclase type 7 [KO:K08047] [EC:4.6.1.1]
112859389  ADCY8; adenylate cyclase type 8 [KO:K08048] [EC:4.6.1.1]
112853291  ADCY9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
112852313  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
112871920  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
112848555  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
112848765  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
112851773  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048]
112852536  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X1 [KO:K09048]
112865439  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
112871786  CREB3; LOW QUALITY PROTEIN: cyclic AMP-responsive element-binding protein 3 [KO:K09048]
112866754  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
112863930  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
112866756  CREB5; cyclic AMP-responsive element-binding protein 5 [KO:K09047]
112853637  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049]
112853522  EHMT2; histone-lysine N-methyltransferase EHMT2 [KO:K11420] [EC:2.1.1.355]
112860854  EHMT1; histone-lysine N-methyltransferase EHMT1 [KO:K11420] [EC:2.1.1.355]
112860838  FOXO1; forkhead box protein O1 [KO:K07201]
112862093  FOXO3; forkhead box protein O3 [KO:K09408]
112862357  SOD2; superoxide dismutase [Mn], mitochondrial [KO:K04564] [EC:1.15.1.1]
112865557  CAT; catalase [KO:K03781] [EC:1.11.1.6]
112862046  ATG5; autophagy protein 5 [KO:K08339]
112860846  KL; LOW QUALITY PROTEIN: klotho [KO:K14756] [EC:3.2.1.31]
112871843  TSC1; hamartin [KO:K07206]
112853203  TSC2; tuberin [KO:K07207]
112866512  RHEB; GTP-binding protein Rheb [KO:K07208]
112848905  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
112850817  AKT1S1; proline-rich AKT1 substrate 1 [KO:K16184]
112864915  ATG13; autophagy-related protein 13 [KO:K08331]
112859628  RB1CC1; RB1-inducible coiled-coil protein 1 [KO:K17589]
112867375  ATG101; autophagy-related protein 101 [KO:K19730]
112852203  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
112871645  EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X1 [KO:K03259]
112858783  EIF4E; eukaryotic translation initiation factor 4E [KO:K03259]
112860530  EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
112849657  ADIPOQ; adiponectin [KO:K07296]
112857789  ADIPOR1; adiponectin receptor protein 1 [KO:K07297]
112867561  ADIPOR2; adiponectin receptor protein 2 [KO:K07297]
112852486  APPL1; DCC-interacting protein 13-alpha [KO:K08733]
112870127  CAMKK2; calcium/calmodulin-dependent protein kinase kinase 2 [KO:K07359] [EC:2.7.11.17]
112871770  PRKAA2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
112861156  PRKAA1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 isoform X1 [KO:K07198] [EC:2.7.11.31]
112869010  PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X1 [KO:K07199]
112870095  PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
112866705  PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 [KO:K07200]
112867041  PRKAG3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
112867175  PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X1 [KO:K07200]
112854631  SIRT1; NAD-dependent protein deacetylase sirtuin-1 isoform X1 [KO:K11411] [EC:2.3.1.286]
112856999  TP53; LOW QUALITY PROTEIN: cellular tumor antigen p53 [KO:K04451]
112858048  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
112851941  RELA; transcription factor p65 [KO:K04735]
112859366  PPARG; peroxisome proliferator-activated receptor gamma [KO:K08530]
112858075  PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X1 [KO:K07202]
112852775  STK11; serine/threonine-protein kinase STK11 [KO:K07298] [EC:2.7.11.1]
112862925  SESN1; sestrin-1 [KO:K10141]
112865025  SESN3; sestrin-3 isoform X1 [KO:K10141]
112871888  SESN2; sestrin-2 [KO:K20394]
112861108  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
pcoo04064  NF-kappa B signaling pathway
pcoo04068  FoxO signaling pathway
pcoo04115  p53 signaling pathway
pcoo04140  Autophagy - animal
pcoo04150  mTOR signaling pathway
pcoo04151  PI3K-Akt signaling pathway
pcoo04152  AMPK signaling pathway
pcoo04910  Insulin signaling pathway
KO pathway
ko04211   
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