A major obstacle to using bone marrow cell-based therapies for ischemic cardiovascular disease is that transplanted cells must survive in an ischemic microenvironment characterized by low oxygen, glucose, and pH. We demonstrate that treatment of bone marrow-derived angiogenic cells (BMDACs) with dimethyloxalylglycine, an α-ketoglutarate antagonist that induces hypoxia-inducible factor 1 (HIF-1) activity, results in metabolic reprogramming of these cells, with increased glucose uptake, decreased O(2) consumption, increased lactate production, decreased reactive oxygen species, and increased intracellular pH. These effects are dependent on HIF-1, which transactivates target genes encoding metabolic enzymes and membrane transporters. Dimethyloxalylglycine-treated BMDACs have a significant survival advantage under conditions of low O(2) and low pH ex vivo and in ischemic tissue. Combined HIF-1α-based gene and cell therapy reduced tissue necrosis even when BMDAC donors and ischemic recipient mice were 17 months old, suggesting that this approach may have therapeutic utility in elderly patients with critical limb ischemia.