Schematic representation of C.elegans IIS pathway activation

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

  1. 1 2 3 Friedman, D B; Johnson, T E (1988-01-01). "A mutation in the age-1 gene in Caenorhabditis elegans lengthens life and reduces hermaphrodite fertility". Genetics. 118 (1): 75–86. doi:10.1093/genetics/118.1.75. ISSN 1943-2631. PMC 1203268. PMID 8608934.
  2. 1 2 Klass, Michael R. (July 1983). "A method for the isolation of longevity mutants in the nematode Caenorhabditis elegans and initial results". Mechanisms of Ageing and Development. 22 (3–4): 279–286. doi:10.1016/0047-6374(83)90082-9. ISSN 0047-6374. PMID 6632998. S2CID 6870538.
  3. 1 2 "age-1 (gene) - WormBase : Nematode Information Resource". wormbase.org. Retrieved 2021-11-29.
  4. ↑ Luo, Yuan (April 2004). "Long-lived worms and aging". Redox Report. 9 (2): 65–69. doi:10.1179/135100004225004733. ISSN 1351-0002. PMID 15231060. S2CID 9251070.
  5. 1 2 Dorman, J B; Albinder, B; Shroyer, T; Kenyon, C (1995-12-01). "The age-1 and daf-2 genes function in a common pathway to control the lifespan of Caenorhabditis elegans". Genetics. 141 (4): 1399–1406. doi:10.1093/genetics/141.4.1399. ISSN 1943-2631. PMC 1206875. PMID 8601482.
  6. 1 2 Kenyon, Cynthia; Chang, Jean; Gensch, Erin; Rudner, Adam; Tabtiang, Ramon (December 1993). "A C. elegans mutant that lives twice as long as wild type". Nature. 366 (6454): 461–464. Bibcode:1993Natur.366..461K. doi:10.1038/366461a0. ISSN 0028-0836. PMID 8247153. S2CID 4332206.
  7. 1 2 Larsen, P L; Albert, P S; Riddle, D L (1995-04-01). "Genes that regulate both development and longevity in Caenorhabditis elegans". Genetics. 139 (4): 1567–1583. doi:10.1093/genetics/139.4.1567. ISSN 1943-2631. PMC 1206485. PMID 7789761.
  8. 1 2 3 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
  9. ↑ Murphy, Coleen T. (2013-12-26). "Insulin/insulin-like growth factor signaling in C. elegans". WormBook: 1–43. doi:10.1895/wormbook.1.164.1. ISSN 1551-8507. PMC 4780952. PMID 24395814.
  10. ↑ Morris, Jason Z.; Tissenbaum, Heidi A.; Ruvkun, Gary (August 1996). "A phosphatidylinositol-3-OH kinase family member regulating longevity and diapause in Caenorhabditis elegans". Nature. 382 (6591): 536–539. Bibcode:1996Natur.382..536M. doi:10.1038/382536a0. ISSN 0028-0836. PMID 8700226. S2CID 4280752.
  11. ↑ Wolkow, Catherine A.; Muñoz, Manuel J.; Riddle, Donald L.; Ruvkun, Gary (December 2002). "Insulin Receptor Substrate and p55 Orthologous Adaptor Proteins Function in the Caenorhabditis elegans daf-2/Insulin-like Signaling Pathway". Journal of Biological Chemistry. 277 (51): 49591–49597. doi:10.1074/jbc.m207866200. ISSN 0021-9258. PMID 12393910.
  12. ↑ Ogg, Scott; Ruvkun, Gary (December 1998). "The C. elegans PTEN Homolog, DAF-18, Acts in the Insulin Receptor-like Metabolic Signaling Pathway". Molecular Cell. 2 (6): 887–893. doi:10.1016/s1097-2765(00)80303-2. ISSN 1097-2765. PMID 9885576.
  13. ↑ Paradis, S.; Ailion, M.; Toker, A.; Thomas, J. H.; Ruvkun, G. (1999-06-01). "A PDK1 homolog is necessary and sufficient to transduce AGE-1 PI3 kinase signals that regulate diapause in Caenorhabditis elegans". Genes & Development. 13 (11): 1438–1452. doi:10.1101/gad.13.11.1438. ISSN 0890-9369. PMC 316759. PMID 10364160.
  14. ↑ Pearce, Laura R.; Komander, David; Alessi, Dario R. (January 2010). "The nuts and bolts of AGC protein kinases". Nature Reviews Molecular Cell Biology. 11 (1): 9–22. doi:10.1038/nrm2822. ISSN 1471-0072. PMID 20027184. S2CID 1143663.
  15. ↑ Bruhn, Maressa A.; Pearson, Richard B.; Hannan, Ross D.; Sheppard, Karen E. (2010-10-05). "Second AKT: The rise of SGK in cancer signalling". Growth Factors. 28 (6): 394–408. doi:10.3109/08977194.2010.518616. ISSN 0897-7194. PMID 20919962. S2CID 11626509.
  16. ↑ Ogg, Scott; Paradis, Suzanne; Gottlieb, Shoshanna; Patterson, Garth I.; Lee, Linda; Tissenbaum, Heidi A.; Ruvkun, Gary (October 1997). "The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans". Nature. 389 (6654): 994–999. Bibcode:1997Natur.389..994O. doi:10.1038/40194. ISSN 0028-0836. PMID 9353126. S2CID 4412006.
  17. ↑ Lin, Kui; Hsin, Honor; Libina, Natasha; Kenyon, Cynthia (June 2001). "Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling". Nature Genetics. 28 (2): 139–145. doi:10.1038/88850. ISSN 1061-4036. PMID 11381260. S2CID 24436462.
  18. ↑ Medawar, P.B. (1952). An unsolved problem of biology. H.K Lewis for U.C.L. OCLC 940295561.
  19. ↑ Williams, George C. (December 1957). "Pleiotropy, Natural Selection, and the Evolution of Senescence". Evolution. 11 (4): 398–411. doi:10.1111/j.1558-5646.1957.tb02911.x. ISSN 0014-3820. S2CID 84556488.
  20. ↑ Johnson, Thomas E.; Tedesco, Patricia M.; Lithgow, Gordon J. (February 1993). "Comparing mutants, selective breeding, and transgenics in the dissection of aging processes ofCaenorhabditis elegans". Genetica. 91 (1–3): 65–77. doi:10.1007/bf01435988. ISSN 0016-6707. PMID 8125279. S2CID 34272584.
  21. ↑ Kenyon, Cynthia (2011-01-12). "The first long-lived mutants: discovery of the insulin/IGF-1 pathway for ageing". Philosophical Transactions of the Royal Society B: Biological Sciences. 366 (1561): 9–16. doi:10.1098/rstb.2010.0276. ISSN 0962-8436. PMC 3001308. PMID 21115525.
  22. ↑ Carter, Christy S.; Ramsey, Melinda M.; Sonntag, William E. (June 2002). "A critical analysis of the role of growth hormone and IGF-1 in aging and lifespan". Trends in Genetics. 18 (6): 295–301. doi:10.1016/s0168-9525(02)02696-3. ISSN 0168-9525. PMID 12044358.
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