Age-1
{{short description|Gene}}
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.{{cite journal|last1=Friedman|first1=D B|last2=Johnson|first2=T E|date=1988-01-01|title=A mutation in the age-1 gene in Caenorhabditis elegans lengthens life and reduces hermaphrodite fertility. |journal=Genetics|volume=118|issue=1|pages=75–86|doi=10.1093/genetics/118.1.75|pmid=8608934 |pmc=1203268 |issn=1943-2631}} The age-1 mutant, first identified by Michael Klass,{{cite journal|last=Klass|first=Michael R.|date=July 1983|title=A method for the isolation of longevity mutants in the nematode Caenorhabditis elegans and initial results|journal=Mechanisms of Ageing and Development|volume=22|issue=3–4|pages=279–286|doi=10.1016/0047-6374(83)90082-9|pmid=6632998 |s2cid=6870538 |issn=0047-6374}} 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.{{cite web|title=age-1 (gene) - WormBase : Nematode Information Resource|url=https://wormbase.org/species/c_elegans/gene/WBGene00000090#d-j0-10-d.|access-date=2021-11-29|website=wormbase.org}} The age-1 gene is known to share a genetic pathway with daf-2 gene that regulates lifespan in worms.{{cite journal|last=Luo|first=Yuan|date=April 2004|title=Long-lived worms and aging|journal=Redox Report|volume=9|issue=2|pages=65–69|doi=10.1179/135100004225004733|pmid=15231060 |s2cid=9251070 |issn=1351-0002|doi-access=free}}{{cite journal|last1=Dorman|first1=J B|last2=Albinder|first2=B|last3=Shroyer|first3=T|last4=Kenyon|first4=C|date=1995-12-01|title=The age-1 and daf-2 genes function in a common pathway to control the lifespan of Caenorhabditis elegans|journal=Genetics|volume=141|issue=4|pages=1399–1406|doi=10.1093/genetics/141.4.1399|pmid=8601482 |pmc=1206875 |issn=1943-2631}} Additionally, both age-1 and daf-2 mutants are dependent on daf-16 and daf-18 genes to promote lifespan extension.{{cite journal|last1=Kenyon|first1=Cynthia|last2=Chang|first2=Jean|last3=Gensch|first3=Erin|last4=Rudner|first4=Adam|last5=Tabtiang|first5=Ramon|date=December 1993|title=A C. elegans mutant that lives twice as long as wild type |journal=Nature|volume=366|issue=6454|pages=461–4|doi=10.1038/366461a0|pmid=8247153 |bibcode=1993Natur.366..461K |s2cid=4332206 |issn=0028-0836}}{{cite journal|last1=Larsen|first1=P L|last2=Albert|first2=P S|last3=Riddle|first3=D L|date=1995-04-01|title=Genes that regulate both development and longevity in Caenorhabditis elegans |journal=Genetics|volume=139|issue=4|pages=1567–83|doi=10.1093/genetics/139.4.1567|pmid=7789761 |pmc=1206485 |issn=1943-2631}}
Long-lived age-1 mutants are resistant to oxidative stress and UV light.{{cite journal |vauthors=Hyun M, Lee J, Lee K, May A, Bohr VA, Ahn B |title=Longevity and resistance to stress correlate with DNA repair capacity in Caenorhabditis elegans |journal=Nucleic Acids Res |volume=36 |issue=4 |pages=1380–9 |date=March 2008 |pmid=18203746 |pmc=2275101 |doi=10.1093/nar/gkm1161 }} 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.{{cite journal|last=Murphy|first=Coleen T.|date=2013-12-26|title=Insulin/insulin-like growth factor signaling in C. elegans |journal=WormBook|pages=1–43|pmid=24395814 |doi=10.1895/wormbook.1.164.1|pmc=4780952 |issn=1551-8507}} 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{{cite journal|last1=Morris|first1=Jason Z.|last2=Tissenbaum|first2=Heidi A.|last3=Ruvkun|first3=Gary|date=August 1996|title=A phosphatidylinositol-3-OH kinase family member regulating longevity and diapause in Caenorhabditis elegans |journal=Nature|volume=382|issue=6591|pages=536–|doi=10.1038/382536a0|pmid=8700226 |bibcode=1996Natur.382..536M |s2cid=4280752 |issn=0028-0836}} and its adaptor subunit AAP-1.{{cite journal|last1=Wolkow|first1=Catherine A.|last2=Muñoz|first2=Manuel J.|last3=Riddle|first3=Donald L.|last4=Ruvkun|first4=Gary|date=December 2002|title=Insulin Receptor Substrate and p55 Orthologous Adaptor Proteins Function in the Caenorhabditis elegans daf-2/Insulin-like Signaling Pathway|journal=Journal of Biological Chemistry|volume=277|issue=51|pages=49591–7|doi=10.1074/jbc.m207866200|pmid=12393910 |issn=0021-9258|doi-access=free }} 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).{{cite journal|last1=Ogg|first1=Scott|last2=Ruvkun|first2=Gary|date=December 1998|title=The C. elegans PTEN Homolog, DAF-18, Acts in the Insulin Receptor-like Metabolic Signaling Pathway|journal=Molecular Cell|volume=2|issue=6|pages=887–893|doi=10.1016/s1097-2765(00)80303-2|pmid=9885576 |issn=1097-2765|doi-access=free}} PIP3, causes activation of its major effector PDK-1, which in turn promotes phosphorylation of AKT 1/2,{{cite journal|last1=Paradis|first1=S.|last2=Ailion|first2=M.|last3=Toker|first3=A.|last4=Thomas|first4=J. H.|last5=Ruvkun|first5=G.|date=1999-06-01|title=A PDK1 homolog is necessary and sufficient to transduce AGE-1 PI3 kinase signals that regulate diapause in Caenorhabditis elegans |journal=Genes & Development|volume=13|issue=11|pages=1438–52|pmc=316759 |doi=10.1101/gad.13.11.1438|pmid=10364160 }} and SGK-1.{{cite journal|last1=Pearce|first1=Laura R.|last2=Komander|first2=David|last3=Alessi|first3=Dario R.|date=January 2010|title=The nuts and bolts of AGC protein kinases |journal=Nature Reviews Molecular Cell Biology|volume=11|issue=1|pages=9–22|doi=10.1038/nrm2822|pmid=20027184 |s2cid=1143663 |issn=1471-0072}}{{cite journal|last1=Bruhn|first1=Maressa A.|last2=Pearson|first2=Richard B.|last3=Hannan|first3=Ross D.|last4=Sheppard|first4=Karen E.|date=2010-10-05|title=Second AKT: The rise of SGK in cancer signalling |journal=Growth Factors|volume=28|issue=6|pages=394–408|doi=10.3109/08977194.2010.518616|pmid=20919962 |s2cid=11626509 |issn=0897-7194}} 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.{{cite journal|last1=Ogg|first1=Scott|last2=Paradis|first2=Suzanne|last3=Gottlieb|first3=Shoshanna|last4=Patterson|first4=Garth I.|last5=Lee|first5=Linda|last6=Tissenbaum|first6=Heidi A.|last7=Ruvkun|first7=Gary|date=October 1997|title=The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans |journal=Nature|volume=389|issue=6654|pages=994–9|doi=10.1038/40194|pmid=9353126 |bibcode=1997Natur.389..994O |s2cid=4412006 |issn=0028-0836}} 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.{{cite journal|last1=Lin|first1=Kui|last2=Hsin|first2=Honor|last3=Libina|first3=Natasha|last4=Kenyon|first4=Cynthia|date=June 2001|title=Regulation of the Caenorhabditis elegans longevity protein DAF-16 by insulin/IGF-1 and germline signaling |journal=Nature Genetics|volume=28|issue=2|pages=139–145|doi=10.1038/88850|pmid=11381260 |s2cid=24436462 |issn=1061-4036}}
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,{{cite book|last=Medawar|first=P.B.|url=http://worldcat.org/oclc/940295561|title=An unsolved problem of biology|date=1952|publisher=H.K Lewis for U.C.L|oclc=940295561}}{{cite journal|last=Williams|first=George C.|title=Pleiotropy, Natural Selection, and the Evolution of Senescence |date=December 1957 |journal=Evolution|volume=11|issue=4|pages=398–411|doi=10.1111/j.1558-5646.1957.tb02911.x|s2cid=84556488 |issn=0014-3820}} 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.{{cite journal|last1=Johnson|first1=Thomas E.|last2=Tedesco|first2=Patricia M.|last3=Lithgow|first3=Gordon J.|date=February 1993|title=Comparing mutants, selective breeding, and transgenics in the dissection of aging processes of Caenorhabditis elegans |journal=Genetica|volume=91|issue=1–3|pages=65–77|doi=10.1007/bf01435988|pmid=8125279 |s2cid=34272584 |issn=0016-6707}} 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.{{cite journal|last=Kenyon|first=Cynthia|date=2011-01-12|title=The first long-lived mutants: discovery of the insulin/IGF-1 pathway for ageing |journal=Philosophical Transactions of the Royal Society B: Biological Sciences|volume=366|issue=1561|pages=9–16|pmc=3001308| doi=10.1098/rstb.2010.0276|pmid=21115525 |issn=0962-8436}} 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.{{cite journal|last1=Carter|first1=Christy S.|last2=Ramsey|first2=Melinda M.|last3=Sonntag|first3=William E.|date=June 2002|title=A critical analysis of the role of growth hormone and IGF-1 in aging and lifespan |journal=Trends in Genetics|volume=18|issue=6|pages=295–301|doi=10.1016/s0168-9525(02)02696-3|pmid=12044358 |issn=0168-9525}}