Age-1 Explained

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. 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.[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. 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.[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 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,[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

Notes and 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. 10.1093/genetics/118.1.75. 8608934 . 1203268 . 1943-2631.
  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. 10.1016/0047-6374(83)90082-9. 6632998 . 6870538 . 0047-6374.
  3. Web site: age-1 (gene) - WormBase : Nematode Information Resource. 2021-11-29. wormbase.org.
  4. Luo. Yuan. April 2004. Long-lived worms and aging. Redox Report. 9. 2. 65–69. 10.1179/135100004225004733. 15231060 . 9251070 . 1351-0002. free.
  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. 10.1093/genetics/141.4.1399. 8601482 . 1206875 . 1943-2631.
  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. 461–464. 10.1038/366461a0. 8247153 . 1993Natur.366..461K . 4332206 . 0028-0836.
  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. 1567–1583. 10.1093/genetics/139.4.1567. 7789761 . 1206485 . 1943-2631.
  8. 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. ; PMCID: PMC2275101
  9. Murphy. Coleen T.. 2013-12-26. Insulin/insulin-like growth factor signaling in C. elegans. WormBook. 1–43. 24395814 . 10.1895/wormbook.1.164.1. 4780952 . 1551-8507.
  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. 10.1038/382536a0. 8700226 . 1996Natur.382..536M . 4280752 . 0028-0836.
  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. 10.1074/jbc.m207866200. 12393910 . 0021-9258. free .
  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. 10.1016/s1097-2765(00)80303-2. 9885576 . 1097-2765. free.
  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. 316759 . 10.1101/gad.13.11.1438. 10364160 . 0890-9369.
  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. 10.1038/nrm2822. 20027184 . 1143663 . 1471-0072.
  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. 10.3109/08977194.2010.518616. 20919962 . 11626509 . 0897-7194.
  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. 10.1038/40194. 9353126 . 1997Natur.389..994O . 4412006 . 0028-0836.
  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. 10.1038/88850. 11381260 . 24436462 . 1061-4036.
  18. Book: Medawar, P.B.. An unsolved problem of biology. 1952. H.K Lewis for U.C.L. 940295561.
  19. Williams. George C.. Pleiotropy, Natural Selection, and the Evolution of Senescence . December 1957. Evolution. 11. 4. 398–411. 10.1111/j.1558-5646.1957.tb02911.x. 84556488 . 0014-3820.
  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. 10.1007/bf01435988. 8125279 . 34272584 . 0016-6707.
  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. 3001308. 10.1098/rstb.2010.0276. 21115525 . 0962-8436.
  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. 10.1016/s0168-9525(02)02696-3. 12044358 . 0168-9525.

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