Researcher Mode A.: The daf-16 gene plays a crucial role in regulating lifespan in Caenorhabditis elegans through its involvement in the insulin/IGF-1 signaling (IIS) pathway. DAF-16 is the C. elegans homolog of the forkhead box FoxO transcription factor, which is pivotal in mediating the effects of reduced IIS signaling1 . When IIS activity is low, DAF-16 translocates to the nucleus where it activates or represses genes involved in stress response, metabolism, and autophagy, resulting in lifespan extension1.
Moreover, DAF-16 does not act alone; it requires other factors for full activation. For example, the overexpression of DAF-16 alone only slightly increases lifespan, and its nuclear localization is necessary but not sufficient for lifespan extension1. Other proteins such as JNK-1 and CST-1, which modify DAF-16 post-translationally, can stimulate its activity, leading to lifespan extension1. Additionally, DAF-16 cooperates with other transcription factors like HSF-1, SKN-1, and PQM-1, which regulate overlapping pro-longevity genes1.
DAF-16’s role in lifespan extension is also influenced by dietary restriction (DR). Under DR, DAF-16 activity becomes a robust predictor of lifespan in C. elegans, with its nuclear localization indicating strong endogenous activity2. The largest contributions to this activity under DR conditions come from the intestine and neurons, and DAF-16 also shows activity in the germline and intestinal nucleoli3.
Furthermore, DAF-16 mediates longevity effects associated with specific dietary restriction regimens but is dispensable for longevity induced by chronic calorie restriction or continuous fasting4. This suggests that DAF-16 activation is sensitive to the type of dietary restriction and the timing or duration of exposure4
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