Entry Name Longevity regulating pathway
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; AgingBRITE hierarchy
Pathway map ko04211 Longevity regulating pathway
Orthology K00922 PIK3CA_B_D; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:2.7.1.153 ]
K02159 BAX; apoptosis regulator BAX
K02580 NFKB1; nuclear factor NF-kappa-B p105 subunit
K02649 PIK3R1_2_3; phosphoinositide-3-kinase regulatory subunit alpha/beta/delta
K03259 EIF4E; translation initiation factor 4E
K04374 ATF4, CREB2; cyclic AMP-dependent transcription factor ATF-4
K04450 ATF2, CREBP1; cyclic AMP-dependent transcription factor ATF-2
K04451 TP53, P53; tumor protein p53
K04735 RELA; transcription factor p65
K05087 IGF1R, CD221; insulin-like growth factor 1 receptor [EC:2.7.10.1 ]
K05459 IGF1; insulin-like growth factor 1
K05869 CAMK4; calcium/calmodulin-dependent protein kinase IV [EC:2.7.11.17 ]
K05870 CREB1; cyclic AMP-responsive element-binding protein 1
K07187 IRS2; insulin receptor substrate 2
K07198 PRKAA, AMPK; 5'-AMP-activated protein kinase, catalytic alpha subunit [EC:2.7.11.31 ]
K07199 PRKAB; 5'-AMP-activated protein kinase, regulatory beta subunit
K07200 PRKAG; 5'-AMP-activated protein kinase, regulatory gamma subunit
K07201 FOXO1; forkhead box protein O1
K07202 PPARGC1A, PGC1A; alpha peroxisome proliferator-activated receptor gamma coactivator 1-alpha
K07203 MTOR, FRAP, TOR; serine/threonine-protein kinase mTOR [EC:2.7.11.1 ]
K07204 RAPTOR; regulatory associated protein of mTOR
K07205 EIF4EBP1; eukaryotic translation initiation factor 4E binding protein 1
K07206 TSC1; tuberous sclerosis 1
K07207 TSC2; tuberous sclerosis 2
K07208 RHEB; Ras homolog enriched in brain
K07296 ADIPOQ, ACDC; adiponectin
K07297 ADIPOR; adiponectin receptor
K07359 CAMKK2; calcium/calmodulin-dependent protein kinase kinase 2 [EC:2.7.11.17 ]
K07827 KRAS, KRAS2; GTPase KRas
K08331 ATG13; autophagy-related protein 13
K08339 ATG5; autophagy-related protein 5
K08530 NR1C3, PPARG; peroxisome proliferator-activated receptor gamma
K08733 APPL1, DIP13A; DCC-interacting protein 13 alpha
K09047 CREB5, CREBPA; cyclic AMP-responsive element-binding protein 5
K09048 CREB3; cyclic AMP-responsive element-binding protein 3
K09049 ATF6B, CREBL1; cyclic AMP-dependent transcription factor ATF-6 beta
K09408 FOXO3; forkhead box protein O3
K11411 SIRT1, SIR2L1; NAD-dependent protein deacetylase sirtuin 1 [EC:2.3.1.286 ]
K11420 EHMT; [histone H3]-lysine9 N-trimethyltransferase EHMT [EC:2.1.1.355 ]
K16172 IRS1; insulin receptor substrate 1
K16184 AKT1S1, PRAS40; proline-rich AKT1 substrate 1
K17445 IRS3; insulin receptor substrate 3
K17446 IRS4; insulin receptor substrate 4
K17589 RB1CC1; RB1-inducible coiled-coil protein 1
K19730 ATG101; autophagy-related protein 101
Compound C05981 Phosphatidylinositol-3,4,5-trisphosphate
Reference Authors Barzilai N, Huffman DM, Muzumdar RH, Bartke A
Title The critical role of metabolic pathways in aging.
Journal Reference Authors Fontana L, Partridge L, Longo VD
Title Extending healthy life span--from yeast to humans.
Journal Reference Authors Feng Z, Lin M, Wu R
Title The Regulation of Aging and Longevity: A New and Complex Role of p53.
Journal Reference Authors Kenyon CJ
Title The genetics of ageing.
Journal Reference 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 Reference Authors Morris BJ, Willcox DC, Donlon TA, Willcox BJ
Title FOXO3: A Major Gene for Human Longevity - A Mini-Review.
Journal Reference 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 Reference Authors Madeo F, Zimmermann A, Maiuri MC, Kroemer G
Title Essential role for autophagy in life span extension.
Journal Reference 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 Reference Authors Markaki M, Tavernarakis N
Title Metabolic control by target of rapamycin and autophagy during ageing - a mini-review.
Journal Reference Authors Dali-Youcef N, Lagouge M, Froelich S, Koehl C, Schoonjans K, Auwerx J
Title Sirtuins: the 'magnificent seven', function, metabolism and longevity.
Journal Reference Authors Ruderman NB, Xu XJ, Nelson L, Cacicedo JM, Saha AK, Lan F, Ido Y
Title AMPK and SIRT1: a long-standing partnership?
Journal Reference 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 Reference 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 Reference 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 Reference Authors Esmaili S, Xu A, George J
Title The multifaceted and controversial immunometabolic actions of adiponectin.
Journal Reference 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 Reference Authors Tucci P
Title Caloric restriction: is mammalian life extension linked to p53?
Journal Reference Authors Budanov AV, Karin M
Title p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling.
Journal Reference Authors Sopjani M, Rinnerthaler M, Kruja J, Dermaku-Sopjani M
Title Intracellular signaling of the aging suppressor protein Klotho.
Journal Reference Authors Longo VD, Lieber MR, Vijg J
Title Turning anti-ageing genes against cancer.
Journal Related ko04064 NF-kappa B signaling pathway
