KEGG   PATHWAY: rno04211
Entry
rno04211                    Pathway                                
Name
Longevity regulating pathway - Rattus norvegicus (rat)
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
rno04211  Longevity regulating pathway
rno04211

Organism
Rattus norvegicus (rat) [GN:rno]
Gene
24506  Ins2; insulin-2 preproprotein [KO:K04526]
24505  Ins1; insulin-1 preproprotein [KO:K04526]
24954  Insr; insulin receptor preproprotein [KO:K04527] [EC:2.7.10.1]
24482  Igf1; insulin-like growth factor I isoform d preproprotein [KO:K05459]
25718  Igf1r; insulin-like growth factor 1 receptor isoform 2 precursor [KO:K05087] [EC:2.7.10.1]
25467  Irs1; insulin receptor substrate 1 [KO:K16172]
29376  Irs2; insulin receptor substrate 2 [KO:K07187]
84021  Irs3; insulin receptor substrate 3 [KO:K17445]
315350  Irs4; insulin receptor substrate 4 [KO:K17446]
293621  Hras; GTPase HRas [KO:K02833]
367858  Hrasl1; HRas proto-oncogene, GTPase like 1 [KO:K02833]
24525  Kras; GTPase KRas [KO:K07827]
24605  Nras; GTPase NRas [KO:K07828]
85243  Pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
170911  Pik3ca; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
366508  Pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
134484121  LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform-like [KO:K00922] [EC:2.7.1.153]
25513  Pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]
60664  Pik3r3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
29741  Pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
24185  Akt1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
25233  Akt2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
29414  Akt3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
305509  Adcy1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
81636  Adcy2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
64508  Adcy3; adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
54223  Adcy4; adenylate cyclase type 4 [KO:K08044] [EC:4.6.1.1]
64532  Adcy5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
25289  Adcy6; adenylate cyclase type 6 isoform 2 [KO:K08046] [EC:4.6.1.1]
84420  Adcy7; adenylate cyclase type 7 [KO:K08047] [EC:4.6.1.1]
29241  Adcy8; adenylate cyclase type 8 [KO:K08048] [EC:4.6.1.1]
302950  Adcy9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
25636  Prkaca; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
293508  Prkacb; cAMP-dependent protein kinase catalytic subunit beta [KO:K04345] [EC:2.7.11.11]
81646  Creb1; cyclic AMP-responsive element-binding protein 1 isoform A [KO:K05870]
81647  Atf2; cyclic AMP-dependent transcription factor ATF-2 [KO:K04450]
310616  Creb3l4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform 1 [KO:K09048]
362165  Creb3l1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
362339  Creb3l2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
314638  Creb3l3; cyclic AMP-responsive element-binding protein 3-like protein 3 [KO:K09048]
79255  Atf4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
500131  Creb5; cyclic AMP-responsive element-binding protein 5 [KO:K09047]
406169  Atf6b; cyclic AMP-dependent transcription factor ATF-6 beta [KO:K09049]
361798  Ehmt2; histone-lysine N-methyltransferase EHMT2 [KO:K11420] [EC:2.1.1.355]
362078  Ehmt1; histone-lysine N-methyltransferase EHMT1 isoform 1 [KO:K11420] [EC:2.1.1.355]
84482  Foxo1; forkhead box protein O1 [KO:K07201]
294515  Foxo3; forkhead box protein O3 [KO:K09408]
24787  Sod2; superoxide dismutase [Mn], mitochondrial precursor [KO:K04564] [EC:1.15.1.1]
24248  Cat; catalase [KO:K03781] [EC:1.11.1.6]
365601  Atg5; autophagy protein 5 isoform 1 [KO:K08339]
83504  Kl; klotho precursor [KO:K14756] [EC:3.2.1.31]
60445  Tsc1; hamartin [KO:K07206]
24855  Tsc2; tuberin [KO:K07207]
26954  Rheb; GTP-binding protein Rheb [KO:K07208]
56718  Mtor; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
287871  Rptor; regulatory-associated protein of mTOR [KO:K07204]
292887  Akt1s1; proline-rich AKT1 substrate 1 [KO:K16184]
360827  Ulk1; serine/threonine-protein kinase ULK1 [KO:K21357] [EC:2.7.11.1]
362164  Atg13; autophagy-related protein 13 [KO:K08331]
312927  Rb1cc1; RB1-inducible coiled-coil protein 1 [KO:K17589]
300240  Atg101; autophagy-related protein 101 isoform 2 [KO:K19730]
83840  Rps6kb1; ribosomal protein S6 kinase beta-1 [KO:K04688] [EC:2.7.11.1]
361696  Rps6kb2; ribosomal protein S6 kinase beta-2 [KO:K04688] [EC:2.7.11.1]
116636  Eif4ebp1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205]
117045  Eif4e; eukaryotic translation initiation factor 4E [KO:K03259]
686104  Eif4e1b; eukaryotic translation initiation factor 4E type 1B [KO:K03259]
363275  Eif4e2; eukaryotic translation initiation factor 4E type 2 isoform 1 [KO:K03259]
246253  Adipoq; adiponectin precursor [KO:K07296]
312670  Adipor2; adiponectin receptor protein 2 [KO:K07297]
289036  Adipor1; adiponectin receptor protein 1 [KO:K07297]
290537  Appl1; DCC-interacting protein 13-alpha [KO:K08733]
83506  Camkk2; calcium/calmodulin-dependent protein kinase kinase 2 isoform 1 [KO:K07359] [EC:2.7.11.17]
65248  Prkaa1; 5'-AMP-activated protein kinase catalytic subunit alpha-1 [KO:K07198] [EC:2.7.11.31]
78975  Prkaa2; 5'-AMP-activated protein kinase catalytic subunit alpha-2 [KO:K07198] [EC:2.7.11.31]
83803  Prkab1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199]
64562  Prkab2; 5'-AMP-activated protein kinase subunit beta-2 [KO:K07199]
25520  Prkag1; 5'-AMP-activated protein kinase subunit gamma-1 [KO:K07200]
301518  Prkag3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200]
373545  Prkag2; 5'-AMP-activated protein kinase subunit gamma-2 isoform 1 [KO:K07200]
309757  Sirt1; NAD-dependent protein deacetylase sirtuin-1 [KO:K11411] [EC:2.3.1.286]
24887  Bax; apoptosis regulator BAX [KO:K02159]
367149  Bax-ps1; apoptosis regulator BAX-like [KO:K02159]
681314  apoptosis regulator BAX-like [KO:K02159]
24842  Tp53; cellular tumor antigen p53 [KO:K04451]
81736  Nfkb1; nuclear factor NF-kappa-B p105 subunit isoform 2 [KO:K02580]
309165  Rela; transcription factor p65 [KO:K04735]
25664  Pparg; peroxisome proliferator-activated receptor gamma isoform 1 [KO:K08530]
83516  Ppargc1a; peroxisome proliferator-activated receptor gamma coactivator 1-alpha [KO:K07202]
314621  Stk11; serine/threonine-protein kinase STK11 [KO:K07298] [EC:2.7.11.1]
315427  Sesn3; sestrin-3 [KO:K10141]
294518  Sesn1; sestrin-1 [KO:K10141]
502988  Sesn2; sestrin-2 [KO:K20394]
25050  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
rno04064  NF-kappa B signaling pathway
rno04068  FoxO signaling pathway
rno04115  p53 signaling pathway
rno04140  Autophagy - animal
rno04150  mTOR signaling pathway
rno04151  PI3K-Akt signaling pathway
rno04152  AMPK signaling pathway
rno04910  Insulin signaling pathway
KO pathway
ko04211   
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