Entry Name Longevity regulating pathway - Ursus arctos (brown bear)
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 Ortholog table Organism Ursus arctos (brown bear) [GN:
uah ]
Gene 113254799 PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922 ] [EC:2.7.1.153 ]
113270537 PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922 ] [EC:2.7.1.153 ]
113253989 PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922 ] [EC:2.7.1.153 ]
113256705 PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649 ]
113254730 PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X2 [KO:K02649 ]
113255266 PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649 ]
113250525 CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870 ]
113250749 ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450 ]
113264990 CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048 ]
113264732 CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 isoform X1 [KO:K09048 ]
113245324 CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X1 [KO:K09048 ]
113260470 CREB3; cyclic AMP-responsive element-binding protein 3 [KO:K09048 ]
113242823 CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X2 [KO:K09048 ]
113241758 ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374 ]
113262153 CREB5; cyclic AMP-responsive element-binding protein 5 isoform X2 [KO:K09047 ]
113243741 ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X1 [KO:K09049 ]
113244532 RPTOR; regulatory-associated protein of mTOR isoform X1 [KO:K07204 ]
113268105 RB1CC1; RB1-inducible coiled-coil protein 1 isoform X1 [KO:K17589 ]
113262099 EIF4EBP1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205 ]
113263893 EIF4E1B; eukaryotic translation initiation factor 4E type 1B [KO:K03259 ]
113250342 EIF4E2; eukaryotic translation initiation factor 4E type 2 isoform X2 [KO:K03259 ]
113247754 PRKAB2; 5'-AMP-activated protein kinase subunit beta-2 isoform X2 [KO:K07199 ]
113267029 PRKAB1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199 ]
113257659 PRKAG1; 5'-AMP-activated protein kinase subunit gamma-1 isoform X2 [KO:K07200 ]
113241494 PRKAG2; 5'-AMP-activated protein kinase subunit gamma-2 isoform X7 [KO:K07200 ]
113263101 NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X3 [KO:K02580 ]
113257185 PPARG; peroxisome proliferator-activated receptor gamma isoform X1 [KO:K08530 ]
113266747 PPARGC1A; peroxisome proliferator-activated receptor gamma coactivator 1-alpha isoform X4 [KO:K07202 ]
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 KO pathway LinkDB All DBs
