Fig. 6. A model for regulation of C. elegans larval development, metabolism and longevity. Proposed wild-type functions are shown, with arrows indicating stimulation of activities and T-bars indicating inhibition, but the steps do not indicate direct protein interactions. Bold arrows represent changes in wild-type activities. Both daf-15 and daf-2 pathways are essential for larval development. Null mutations result in larval lethality. (A) When food is abundant, LET-363/DAF-15 transduces a sufficient nutrient signal to permit growth to the reproductive adult. This signal is also required for DAF-2/insulin signaling to stimulate growth. Disruption of either pathway will cause larval arrest at the second molt. Food availability could also regulate the DAF-2/insulin pathway. (B) When nutrients are limited, the LET-363/DAF-15 signal is insufficient to prevent larval arrest. With concomitant down regulation of the DAF-2 pathway, animals will enter the dauer stage. When DAF-16 activity is high, TOR activity is low, and vice versa. However, in a daf-15 or let-363 mutant TOR activity is low even when insulin/IGF signaling is high, resulting in activation of some target functions, such as autophagy, but the reduced activity of DAF-16 fails to activate other functions needed to complete dauer morphogenesis. daf-15 is epistatic to daf-2 because some targets of TOR that are essential for dauer morphogenesis fail to be activated in the absence of DAF-15 function. Essentially, knockout of LET-363/DAF-15 activity results in dauer-like arrest regardless of DAF-2 signaling because LET-363/DAF-15 is required for both dauer and non-dauer development. TOR regulates autophagy, which is required for dauer morphogenesis and for the increased longevity of daf-2 adults, but TOR activity is also required for maturation to the adult. DAF-16 and LET-363/DAF-15 have other downstream targets not shown here.