extrapolating fromsimplemodelorganismsLife Is Short, if Sw

resistanceandhealthy longevity (Figure1). Analyses of knockout mice and long-lived human cohorts support a link between reduced insulin signaling, FOXO, and longevity (Russell and Kahn, 2007; Lee et al., 2009), suggesting that this longer life might be available not only to simple organisms like nematodes, but also to us. The question remains, however: how can the essential functions of insulin be reconciled with the expected benefits of lowering its activity? In this issue of Cell Metabolism, Lee et al. (2009) begin to unravel how these insulin functions influ-DAF-16 or heat shock factor (HSF-1), which cooperates with DAF-16. Finally, glucose increased expression of several insulin-like genes and led to other gene expression changes that overlapped with effects of inhibiting DAF-16. One of the genes downregulated by both glucose and DAF-16 is aqp-1, which encodes an aquaporin glycerol channel (Lee et al., 2009). Lack of aqp-1mimicked many effects of glucose, including reduc-tion of wild-type but not daf-16() life span, downregulation of DAF-16 and HSF-1 targets, upregulation of ins-7, and bolic pathways on longevity. In the latter study, overexpression of glyoxalase-1 protected against the life span-shortening effects of glucose. This enzyme detoxifies methylglyoxal, a glucose metabolite involved in diabetic complications. This observation should also be explored further, because only one transgenic strain was analyzed, but it suggests that C. elegans might be amenable to analysis of glucose toxicity mechanisms that lead to diabetic complications. While caution should be exercised i