Transgenic mice, containing a chimeric gene in which the cDNA for phosphoenolpyruvate carboxykinase (GTP) (PEPCK-C) (EC 4.1.1.32) was linked to the -skeletal actin gene promoter, express PEPCK-C in skeletal muscle (1~3 units/g). Breeding two founder lines together produced mice with an activity of PEPCK-C of 9 units/g muscle (PEPCK-C^mus mice). These mice were seven times more active in their cages than controls. On a mouse treadmill, PEPCK-C^mus mice ran up to 6 km at a speed of 20 m/min while controls stopped at 0.2 km. PEPCK-C ^mus mice had an enhanced running ability, with a VO₂ max of 156 ± 8.0 ml/kg/min, a maximal Respiratory Exchange Ratio (RER) of 0.91 ± 0.03 and a blood lactate concentration of 3.7 ± 1.0 mM after running for 32 min at a 25º grade; the values for control animals were 112 ± 21 ml/kg/min, 0.99 ± 0.08, and 8.1 ± 5.0 mM respectively. The PEPCK-C^mus mice eat 60% more than controls, but had half the body weight and 10% the body fat as determined by MRI. In addition, the number of mitochondria and the content of triglyceride in the skeletal muscle of PEPCK-C^mus mice was greatly increased as compared to controls. PEPCK-C^mus mice had an extended life span relative to control animals; mice up to an age of 2.5 years ran twice as fast as 6-12 month old control animals. We conclude that over-expression of PEPCK-C repatterns energy metabolism and leads to greater longevity.