Entry Name Longevity regulating pathway - multiple species - Homo sapiens (human)
Description Aging is a complex process of accumulation of molecular, cellular, and organ damage, leading to loss of function and increased vulnerability to disease and death. Despite the complexity of aging, recent work has shown that dietary restriction (DR) and genetic down-regulation of nutrient-sensing pathways, namely IIS (insulin/insulin-like growth factor signalling) and TOR (target-of- rapamycin) can substantially increase healthy life span of laboratory model organisms. These nutrient signaling pathways are conserved in various organisms. In worms, flies, and mammals, DR reduces signalling through IIS/TOR pathways, deactivating the PI3K/Akt/TOR intracellular signalling cascade and consequently activating the antiaging FOXO family transcription factor(s). In yeast, the effects of DR on life- span extension are associated with reduced activities of the TOR/Sch9 and Ras/PKA pathways and require the serine-threonine kinase Rim15 and transcription factors Gis1 and Msn2/4. These transcription factors (FOXO, DAF-16, Gis1, and Msn2/4) transactivate genes involved in resistance to oxidative stress, energy metabolism, DNA damage repair, glucose metabolism, autophagy and protection of proteins by chaperones.
Class Organismal Systems; AgingBRITE hierarchy
Pathway map hsa04213 Longevity regulating pathway - multiple species
Drug D11811 Tofersen (JAN/USAN/INN)
Organism Homo sapiens (human) [GN:
hsa ]
Gene 1979 EIF4EBP2; eukaryotic translation initiation factor 4E binding protein 2 [KO:K18644 ]
3265 HRAS; HRas proto-oncogene, GTPase [KO:K02833 ]
3303 HSPA1A; heat shock protein family A (Hsp70) member 1A [KO:K03283 ]
3304 HSPA1B; heat shock protein family A (Hsp70) member 1B [KO:K03283 ]
3305 HSPA1L; heat shock protein family A (Hsp70) member 1 like [KO:K03283 ]
3310 HSPA6; heat shock protein family A (Hsp70) member 6 [KO:K03283 ]
3312 HSPA8; heat shock protein family A (Hsp70) member 8 [KO:K03283 ]
3479 IGF1; insulin like growth factor 1 [KO:K05459 ]
3667 IRS1; insulin receptor substrate 1 [KO:K16172 ]
3845 KRAS; KRAS proto-oncogene, GTPase [KO:K07827 ]
4893 NRAS; NRAS proto-oncogene, GTPase [KO:K07828 ]
51422 PRKAG2; protein kinase AMP-activated non-catalytic subunit gamma 2 [KO:K07200 ]
5290 PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922 ] [EC:2.7.1.153 ]
5291 PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922 ] [EC:2.7.1.153 ]
5293 PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922 ] [EC:2.7.1.153 ]
5295 PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649 ]
5296 PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649 ]
53632 PRKAG3; protein kinase AMP-activated non-catalytic subunit gamma 3 [KO:K07200 ]
5564 PRKAB1; protein kinase AMP-activated non-catalytic subunit beta 1 [KO:K07199 ]
5565 PRKAB2; protein kinase AMP-activated non-catalytic subunit beta 2 [KO:K07199 ]
5571 PRKAG1; protein kinase AMP-activated non-catalytic subunit gamma 1 [KO:K07200 ]
57521 RPTOR; regulatory associated protein of MTOR complex 1 [KO:K07204 ]
81570 CLPB; ClpB family mitochondrial disaggregase [KO:K03695 ]
8471 IRS4; insulin receptor substrate 4 [KO:K17446 ]
8503 PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649 ]
8660 IRS2; insulin receptor substrate 2 [KO:K07187 ]
Compound C05981 Phosphatidylinositol-3,4,5-trisphosphate
Reference Authors Fontana L, Partridge L, Longo VD
Title Extending healthy life span--from yeast to humans.
Journal Reference Authors Parrella E, Longo VD
Title Insulin/IGF-I and related signaling pathways regulate aging in nondividing cells: from yeast to the mammalian brain.
Journal Reference Authors Santos J, Leitao-Correia F, Sousa MJ, Leao C
Title Dietary Restriction and Nutrient Balance in Aging.
Journal Reference Authors Longo VD, Lieber MR, Vijg J
Title Turning anti-ageing genes against cancer.
Journal Reference Authors Longo VD, Mitteldorf J, Skulachev VP
Title Programmed and altruistic ageing.
Journal Reference Authors Longo VD, Finch CE
Title Evolutionary medicine: from dwarf model systems to healthy centenarians?
Journal Reference Authors Mirzaei H, Suarez JA, Longo VD
Title Protein and amino acid restriction, aging and disease: from yeast to humans.
Journal Reference Authors Kenyon CJ
Title The genetics of ageing.
Journal Reference Authors Longo VD, Fontana L
Title Calorie restriction and cancer prevention: metabolic and molecular mechanisms.
Journal Reference Authors Longo VD, Fabrizio P
Title Chronological aging in Saccharomyces cerevisiae.
Journal Reference Authors Bitto A, Wang AM, Bennett CF, Kaeberlein M
Title Biochemical Genetic Pathways that Modulate Aging in Multiple Species.
Journal Reference Authors Mair W, Dillin A
Title Aging and survival: the genetics of life span extension by dietary restriction.
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 Rizki G, Iwata TN, Li J, Riedel CG, Picard CL, Jan M, Murphy CT, Lee SS
Title The evolutionarily conserved longevity determinants HCF-1 and SIR-2.1/SIRT1 collaborate to regulate DAF-16/FOXO.
Journal Reference Authors Lee SH, Min KJ
Title Caloric restriction and its mimetics.
Journal Reference Authors Bordone L, Guarente L
Title Calorie restriction, SIRT1 and metabolism: understanding longevity.
Journal Reference Authors Canto C, Auwerx J
Title Calorie restriction: is AMPK a key sensor and effector?
Journal Reference Authors Barbieri M, Bonafe M, Franceschi C, Paolisso G
Title Insulin/IGF-I-signaling pathway: an evolutionarily conserved mechanism of longevity from yeast to humans.
Journal Reference Authors Russell SJ, Kahn CR
Title Endocrine regulation of ageing.
Journal Related KO pathway 
