Age-1

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

• Unfolded protein response
• Genetics of aging

References

1. 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. 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. "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. 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. 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): 461–4. Bibcode:1993Natur.366..461K. doi:10.1038/366461a0. ISSN 0028-0836. PMID 8247153. S2CID 4332206.
7. 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): 1567–83. doi:10.1093/genetics/139.4.1567. ISSN 1943-2631. PMC 1206485. PMID 7789761.
8. Hyun M, Lee J, Lee K, May A, Bohr VA, Ahn B (March 2008). "Longevity and resistance to stress correlate with DNA repair capacity in Caenorhabditis elegans". Nucleic Acids Res. 36 (4): 1380–9. doi:10.1093/nar/gkm1161. PMC 2275101. PMID 18203746.
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–. 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): 49591–7. 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): 1438–52. doi:10.1101/gad.13.11.1438. 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): 994–9. 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 of Caenorhabditis 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.