Entry 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; AgingBRITE hierarchy
Pathway map Organism Rattus norvegicus (rat) [GN:
rno ]
Gene 116636 Eif4ebp1; eukaryotic translation initiation factor 4E-binding protein 1 [KO:K07205 ]
117045 Eif4e; eukaryotic translation initiation factor 4E [KO:K03259 ]
170911 Pik3ca; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922 ] [EC:2.7.1.153 ]
24482 Igf1; insulin-like growth factor I isoform d preproprotein [KO:K05459 ]
25513 Pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649 ]
25520 Prkag1; 5'-AMP-activated protein kinase subunit gamma-1 [KO:K07200 ]
25664 Pparg; peroxisome proliferator-activated receptor gamma isoform 1 [KO:K08530 ]
25718 Igf1r; insulin-like growth factor 1 receptor isoform 2 precursor [KO:K05087 ] [EC:2.7.10.1 ]
287871 Rptor; regulatory-associated protein of mTOR [KO:K07204 ]
29741 Pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649 ]
298400 Creb3; cyclic AMP-responsive element-binding protein 3 [KO:K09048 ]
300240 Atg101; autophagy-related protein 101 isoform 2 [KO:K19730 ]
301518 Prkag3; 5'-AMP-activated protein kinase subunit gamma-3 [KO:K07200 ]
310616 Creb3l4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform 1 [KO:K09048 ]
312927 Rb1cc1; RB1-inducible coiled-coil protein 1 [KO:K17589 ]
314638 Creb3l3; cyclic AMP-responsive element-binding protein 3-like protein 3 [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 ]
363275 Eif4e2; eukaryotic translation initiation factor 4E type 2 isoform 1 [KO:K03259 ]
366508 Pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922 ] [EC:2.7.1.153 ]
367858 Hrasl1; HRas proto-oncogene, GTPase like 1 [KO:K02833 ]
373545 Prkag2; 5'-AMP-activated protein kinase subunit gamma-2 isoform 1 [KO:K07200 ]
406169 Atf6b; cyclic AMP-dependent transcription factor ATF-6 beta [KO:K09049 ]
500131 Creb5; cyclic AMP-responsive element-binding protein 5 [KO:K09047 ]
60664 Pik3r3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649 ]
64562 Prkab2; 5'-AMP-activated protein kinase subunit beta-2 [KO:K07199 ]
686104 Eif4e1b; eukaryotic translation initiation factor 4E type 1B [KO:K03259 ]
79255 Atf4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374 ]
81646 Creb1; cyclic AMP-responsive element-binding protein 1 isoform A [KO:K05870 ]
81647 Atf2; cyclic AMP-dependent transcription factor ATF-2 [KO:K04450 ]
81736 Nfkb1; nuclear factor NF-kappa-B p105 subunit isoform 2 [KO:K02580 ]
83506 Camkk2; calcium/calmodulin-dependent protein kinase kinase 2 isoform 1 [KO:K07359 ] [EC:2.7.11.17 ]
83516 Ppargc1a; peroxisome proliferator-activated receptor gamma coactivator 1-alpha [KO:K07202 ]
83803 Prkab1; 5'-AMP-activated protein kinase subunit beta-1 [KO:K07199 ]
85243 Pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922 ] [EC:2.7.1.153 ]
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 
