Caloric restriction (CR) is the only intervention shown to extend lifespan and retard age-related declines in function in mammals. Mutations that extend lifespan in C. elegans suggest that insulin/IGF-1 signaling (IS) pathway may play a key role in retarding aging and extending the lifespan by CR. To evaluate this hypothesis, we subjected male F-344 rats to 2 mo or 25 mo CR (starting at 28 days old, 40% of control level) and then assessed the effects of CR on early events in the IS pathway in liver and muscle. The results indicated that aging was accompanied by significant reduction in insulin receptor tyrosine phosphorylation (pY-IR) in response to insulin in both tissues, which was correlated with significantly increased activity of protein tyrosine phosphatase 1B (PTP-1B). However, these alterations with age were attenuated by 25CR. Furthermore, a significant increase in the amount of IR protein was evident in liver and muscle of 2CR rats. Expression profile of liver mRNA revealed that the expression of mRNAs for IR and IGF-1 receptors were significantly increased by CR, but increased expression of IR mRNA in 25CR rats was disassociated with IR protein level. We also analyzed expression of genes involved in lipid metabolism in liver, which is likely to contribute to altered PTP-1B activity during aging and CR. Expression of peroxisome proliferator-activated receptors (PPARs), with several target genes, were reciprocally regulated during aging and CR. PPAR alpha, delta, and gamma and PGC-1 were significantly increased by 25CR. SREBP-1c and fatty acid synthase were reduced as was hormone sensitive lipase genes increased by CR. In conclusion, CR improved PTP-1B activity and prevented the age-related decline in pY-IR in aged rats. CR also enhanced IR mRNA consistent with increased IR protein in young rats. An altered expression of transcription of a number of genes involved in lipid metabolism may also contribute to the regulation of the early events in the IS pathway during aging and CR.