More Than You Ever Wanted to Know About DAF Gene Pathways

Daf-2 was one of the original longevity genes uncovered in nematode worms. Here, Ouroboros looks at the knowledge spiraling out from that discovery: "The insulin-like growth factor (IGF) pathway is one of the longest-known and well-studied regulators of longevity. Extracellular signals (insulin-like peptides) activate insulin-receptor homologs (in worm, DAF-2) which in turn recruit and activate phosphoinositol 3-kinases (AGE-1). PI3Ks convert PIP2 into PIP3, which tethers and recruits other kinases such as AKT-1. Eventually, activation of these upstream kinases results in phosphorylation and inactivation of the longevity assurance gene DAF-16, which encodes a transcription factor that activates (among many other things) stress resistance genes. ... And what does DAF-16 do? It heads to the nucleus and transcriptionally silences the genes encoding the upstream kinases DAF-2, AGE-1 and others - in other words, DAF-16 turns off the genes that could turn off DAF-16. It's a feedback loop! ... The authors argue that this arrangement represents a biological switch between a short-lived 'reproductive state' and a non-reproducing 'longevity state', characterized by DAF-16 activation of stress-resistance and other types of longevity assurance genes."


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