mutationIty. Celecoxib extends the life of the 16 mutations daf depedent manner towards IIS have shown that the life of C. elegans influence. For example, animals with reduced function mutations in daf 2, a homologue of human insulin IGF-1 receptor, or mutations in the downstream components of the PI3K signaling channel 1 PDK act considerably long life. The FOXO transcription factor DAF 16 for IIS mutations increased Hen longevity required. So we next examined whether EPO906 daf 16 is required for celecoxib to affect longevity. We found that treatment with celecoxib was not able to extend the life of the animal with a null mutation of daf-16, suggesting that celecoxib may upstream longevity by inhibiting a component of the path Rts affect DAF 16 DAF IIS or directly Activation 16th We also tested the effect of celecoxib on two daf mutants and found no significant Verl EXTENSIONS of life. Verst again RKT this the idea that celecoxib can life by modulating the activity of t Ngern the IIS pathway to get engaged. Celecoxib extends life span by a mechanism independent Ngig of its inhibitory activity t of COX-2 Although celecoxib was originally developed as a potent inhibitor of COX-2, we found that celecoxib extends life in a way that h on DAF 16 depends erh ht the M possibility that the effect of the longevity of celecoxib can independently ngig t of its COX-2 inhibitory activity. The reason is twofold. First, in S Ugetier models celecoxib other known cellular Ren is having targets. For example, several studies have suggested that it is possible to inhibit tumor growth celecoxib, at least partially.
Through action on a independent COX-2-dependent w During the treatment in a h Heren dose More importantly, no COX isoforms have been identified in unicellular organisms, the kingdom of plants, insects and nematodes, including normal C. elegans. To determine whether the activity of t Celecoxib life of the COX-2 inhibitory activity Separated t k can, We analyzed the lifespan of the animals exposed to OSU 03012, a structural analog of celecoxib in the north Hey, the detectable no activity has t on COX-2 inhibitor up to 50 treatments with SP600125 OSU leased 03,012 Mr. clearly agrees on life without end in a Ma exception Similar to celecoxib, when started from hatching. Wild-type animals treated with 0.5 M OSU 03012 appears the gr Te Verl EXTENSIONS of life. Adult Treatment of 0.5 M OSU Extension 03012 posted yet more lives. Similar to what we observed with celecoxib exposure to 03,012 USO agrees on further ridiculed The lifetime of eating 2 and Cyc 1 mutants, but not Lebensgef HAZARDOUS DAF 16 and 2 mutants. Since OSU 03,012 no detectable COX-2 inhibitor activity of t, our results close to that S that celecoxib and its derivative, OSU 03,012 work on a target other than COX-2 to modulate longevity in C. elegans. It should be noted that we do not, the t M Possibility that k different mutants Can vielf insurance valid drug sensitivity govern exhibit. However, this is not likely to be the case here. Daf mutants 16 not to all three different concentrations of 03 012 OSU we react examined Celecoxib and OSU 03,012 life by inhibiting the activity of PDK 1-t Ngern getting engaged To all potential secondary targets Ren previously reported inhibition of the box ‘Ll PDK 1, a known component of the IIS pathway upstream of DAF 16 by celecoxib is particularly fascinating. I