Age-1
The age-1 gene is located on chromosome 2 in C.elegans. It gained attention in 1983 for its ability to induce long-lived C. elegans mutants.[1] The age-1 mutant, first identified by Michael Klass,[2] was reported to extend mean lifespan by over 50% at 25 °C when compared to the wild type worm (N2) in 1987 by Johnson et al.[1] Development, metabolism, lifespan, among other processes have been associated with age-1 expression.[3] The age-1 gene is known to share a genetic pathway with daf-2 gene that regulates lifespan in worms.[4][5] Additionally, both age-1 and daf-2 mutants are dependent on daf-16 and daf-18 genes to promote lifespan extension.[5][6][7]
Long-lived age-1 mutants are resistant to oxidative stress and UV light.[8] Age-1 mutants also have a higher DNA repair capability than wild-type C. elegans.[8] Knockdown of the nucleotide excision repair gene Xpa-1 increases sensitivity to UV and reduces the life span of the long-lived mutants. These findings support the hypothesis that DNA repair capability underlies longevity.[8]
Insulin/IGF-1 signaling (IIS) pathway
The age-1 gene is said to encode for AGE-1, the catalytic subunit ortholog to phosphoinositide 3-kinase in C.elegans, which plays an important role in the insulin/IGF-1(IIS) signaling pathway.[3] This pathway gets activated upon binding of an insulin-like peptide to the DAF-2/IGF1R receptor.[9] Binding causes dimerization and phosphorylation of the receptor, which induces recruitment of the DAF-2 receptor substrate IST-1. Subsequently, IST-1 promotes activation of both AGE-1/PI3K[10] and its adaptor subunit AAP-1.[11] AGE-1 then induces conversion of phosphatidylinositol- 4,5-biphosphate (PIP2) to phosphatidylinositol-3,4,5-triphosphate (PIP3). This conversion can be reversed by DAF-18 (PTEN in humans).[12] PIP3, causes activation of its major effector PDK-1, which in turn promotes phosphorylation of AKT 1/2,[13] and SGK-1.[14][15] This phosphorylation causes inhibition of the transcription factor DAF-16/FoXO and glucocorticoid-inducible kinase-1(SKN-1), preventing the expression of downstream genes involved in longevity.[6][7][16] In other words, activation of the IIS pathway blocks expression of genes known to extend lifespan by preventing DAF-16 from translocating to the nucleus and activating them.[17]
History
The age-1 gene was first characterized by Thomas Johnson as a follow up study to Michael Klass's findings[2] on the isolation of long-lived C. elegans mutants.[1] Johnson demonstrated that long-lived age-1 (hx546) mutants did not have significant differences in growth rate or development. Additionally, all age-1 isolates were also fer-15 (mutants sensitive to temperature), suggesting that both genes were inherited together. This result suggested that the age phenotype was caused by a single mutation. Johnson proposed a negative pleiotropy theory,[18][19] in which the age-1 gene is beneficial early in life but harmful at a later stage, on the basis that the long-lived mutants had decreased self-fertility compared to controls. This theory was contradicted in 1993 by Johnson himself when he ablated the fertility defect on the mutant, and the animals still lived long.[20] After the age-1 gene was discovered, Cynthia Kenyon published groundbreaking research on doubling the lifespan of C. elegans by the insulin/IGF-1 pathway.[21] The age-1 gene plays a pivotal role in the IGF-1 pathway and encodes the homolog of phosphatidylinositol-3-OH kinase (PI3K) catalytic subunits in mammals.[22]
See also
References
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