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. The ''age-1'' mutant, first identified by Michael Klass, 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''. Development, metabolism, lifespan, among other processes have been associated with ''age-1'' expression. The ''age-1'' gene is known to share a genetic pathway with ''daf-2'' gene that regulates lifespan in worms. Additionally, both ''age-1'' and ''daf-2'' mutants are dependent on ''daf-16'' and ''daf-18'' genes to promote lifespan extension.

Long-lived ''age-1'' mutants are resistant to oxidative stress and UV light.Hyun M, Lee J, Lee K, May A, Bohr VA, Ahn B. Longevity and resistance to stress correlate with DNA repair capacity in Caenorhabditis elegans. Nucleic Acids Res. 2008 Mar;36(4):1380-9. doi: 10.1093/nar/gkm1161. Epub 2008 Jan 18. PMID: 18203746; PMCID: PMC2275101 ''Age-1'' mutants also have a higher DNA repair capability than wild-type ''C. elegans''. 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.

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. This pathway gets activated upon binding of an insulin-like peptide to the DAF-2/IGF1R receptor. 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 and its adaptor subunit AAP-1. 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). PIP3, causes activation of its major effector PDK-1, which in turn promotes phosphorylation of AKT 1/2, and SGK-1. 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. 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.

History

The ''age-1'' gene was first characterized by Thomas Johnson as a follow up study to Michael Klass's findings on the isolation of long-lived ''C. elegans'' mutants. 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, 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. 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. 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.

References

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Aging-related genes
Caenorhabditis elegans genes