Daf-16

DAF-16 is the sole ortholog of the FOXO family of transcription factors in the nematode Caenorhabditis elegans. It is responsible for activating genes involved in longevity, lipogenesis, heat shock survival and oxidative stress responses. It also protects C.elegans during food deprivation, causing it to transform into a hibernation - like state, known as a Dauer. DAF-16 is notable for being the primary transcription factor required for the profound lifespan extension observed upon mutation of the insulin-like receptor DAF-2. The gene has played a large role in research into longevity and the insulin signalling pathway as it is located in C. elegans, a successful ageing model organism. DAF-16 is the sole ortholog of the FOXO family of transcription factors in the nematode Caenorhabditis elegans. It is responsible for activating genes involved in longevity, lipogenesis, heat shock survival and oxidative stress responses. It also protects C.elegans during food deprivation, causing it to transform into a hibernation - like state, known as a Dauer. DAF-16 is notable for being the primary transcription factor required for the profound lifespan extension observed upon mutation of the insulin-like receptor DAF-2. The gene has played a large role in research into longevity and the insulin signalling pathway as it is located in C. elegans, a successful ageing model organism. DAF-16 is a gene conserved across species, with homologs being found in C. elegans, humans, mice, and Drosophila (fruit flies). In C. elegans, DAF-16 is located on Chromosome 1, at position 175-268. It is made up of 15 exons. DAF-16 is also located downstream of DAF-2, which signals in the IIS pathway. Mutants in this pathway age slower and have a lifespan up to twice as long as normal. Further studies have demonstrated that the lifespan extension is dependent on DAF-16. Other consequences of mutations in the DAF-16 gene is the inability to form dauers. DAF-16 encodes FOXO (Forkhead box protein O), which binds to gene promoters that contain the sequence TTGTTTAC in their regulatory region – this is the DAF-16 binding element (DBE). FOXO is involved in the Insulin / IGF1 signalling pathway (IIS) which affects longevity, lipogenesis, dauer formation, heat shock and oxidative stress responses, by activating proteins such as MnSOD and Catalase. Expression of FOXO in the intestine normally leads to longevity signalling. FOXO has been shown to have a protective role against cancer, as it regulates and suppresses genes involved in tumour formation. It also has a protective role against muscular dystrophy. FOXO is also important in embryonic development, as it promotes apoptosis. Insulin Signalling Insulin and IGF1 are peptide hormones dictating energy functions such as glucose and lipid metabolism. The signalling pathway is evolutionary conserved and found across species. Signalling occurs through kinases such as PI3K to produce phospholipid products such as AKT. This causes downstream phosphorylation of targets such as DAF-16 by a phosphorylation cascade, blocking nuclear entry. Therefore a reduction in insulin signalling generally leads to an increase in FOXO expression, as DAF-16 is no longer inhibited by AKT. When not phosphorylated, DAF-16 is active and present in the nucleus, so FOXO can be transcribed and can up-regulate production of about 100 beneficial proteins that increase longevity. C. elegans is the only known species to contain the DAF-16 gene, although orthologs are conserved across species. DAF-16 may localise to the nucleus or cytoplasm, depending on resources. In nutrient rich conditions, DAF-2 and AKT-1/AKT-2 in the insulin pathway inhibits entry of DAF-16 to the nucleus as it is phosphorylated. However starvation, heat and oxidative stress inhibit phosphorylation by AKT and allow the localisation of DAF-16 to the nucleus. DAF-16 is sequestered in the cytoplasm when associated with ftt-2. Translocation to the nucleus and translation of longevity genes occurs after DAF-16 associates with prmpt-1 Translocation to the nucleus is also promoted by jnk-1 in heat stress and sek-1 in oxidative stress. Expression Isoform b and Isoform c are expressed in muscles, ectoderm, the intestine and neurones. Isoform b is additionally expressed in the pharynx. Expression can be induced by quinic acid. Implication in Aging