Abstract: Compositions and methods are provided for modulation of Target of Rapamycin (TOR) activity. Reduction of TOR blocks insulin resistance and metabolic syndrome phenotypes caused by expression of a constitutively activated version of the insulin responsive transcription factor, FOXO. These TOR-mediated responses are also linked with protection against age-dependent functional organ senescence, e.g., heart decline, as well as increased longevity without changes in resistance to starvation and oxidative stresses.