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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 ''Caenorhabditis elegans'' () is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a blend of the Greek ''caeno-'' (recent), ''rhabditis'' ( ...
'' 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 The DAF-2 gene encodes for the insulin-like growth factor 1 (IGF-1) receptor in the worm ''Caenorhabditis elegans''. DAF-2 is part of the first metabolic pathway discovered to regulate the rate of aging. DAF-2 is also known to regulate reproducti ...
'' gene that regulates lifespan in worms. Additionally, both ''age-1'' and ''
daf-2 The DAF-2 gene encodes for the insulin-like growth factor 1 (IGF-1) receptor in the worm ''Caenorhabditis elegans''. DAF-2 is part of the first metabolic pathway discovered to regulate the rate of aging. DAF-2 is also known to regulate reproducti ...
'' mutants are dependent on ''daf-16'' and ''daf-18'' genes to promote lifespan extension. Long-lived ''age-1''
mutant In biology, and especially in genetics, a mutant is an organism or a new genetic character arising or resulting from an instance of mutation, which is generally an alteration of the DNA sequence of the genome or chromosome of an organism. It i ...
s are resistant to
oxidative stress Oxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal ...
and
UV light Ultraviolet radiation, also known as simply UV, is electromagnetic radiation of wavelengths of 10–400 nanometers, shorter than that of visible light, but longer than X-rays. UV radiation is present in sunlight and constitutes about 10% of t ...
. ''Age-1'' mutants also have a higher
DNA repair DNA repair is a collection of processes by which a cell (biology), cell identifies and corrects damage to the DNA molecules that encode its genome. A weakened capacity for DNA repair is a risk factor for the development of cancer. DNA is cons ...
capability than wild-type ''C. elegans''. Knockdown of the
nucleotide excision repair Nucleotide excision repair is a DNA repair mechanism. DNA damage occurs constantly because of chemicals (e.g. Intercalation (biochemistry), intercalating agents), radiation and other mutagens. Three excision repair pathways exist to repair single ...
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 DAF-16 is the sole Homology (biology)#Orthology, ortholog of the FOX proteins, FOXO family of transcription factors in the nematode ''Caenorhabditis elegans''. It is responsible for activating genes involved in longevity, lipogenesis, heat shock ...
/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 ''Caenorhabditis elegans'' () is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a blend of the Greek ''caeno-'' (recent), ''rhabditis'' ( ...
'' 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 Cynthia Jane Kenyon (born February 21, 1954) is an American molecular biologist and biogerontologist known for her genetic dissection of aging in a widely used model organism, the roundworm ''Caenorhabditis elegans''. She is the vice president of ...
published groundbreaking research on doubling the lifespan of ''
C. elegans ''Caenorhabditis elegans'' () is a free-living transparent nematode about 1 mm in length that lives in temperate soil environments. It is the type species of its genus. The name is a blend of the Greek ''caeno-'' (recent), ''rhabditis'' ( ...
'' 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 Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...
) catalytic subunits in mammals.


See also

*
Unfolded protein response The unfolded protein response (UPR) is a cellular stress response related to the endoplasmic reticulum (ER) stress. It has been found to be conserved between mammalian species, as well as yeast and worm organisms. The UPR is activated in response t ...
*
Genetics of aging Genetics of aging is generally concerned with life extension associated with genetic alterations, rather than with accelerated aging diseases leading to reduction in lifespan. The first mutation found to increase longevity in an animal was the '' ...


References

{{reflist Aging-related genes Caenorhabditis elegans genes