Role of IGF1 in aging remains controversial. Aging is associated with suppression of mitophagy and mitochondrial dysfunction. As we reported IGF1 activated autophagy, however, IGF1 effect on mitophagy is unknown. We hypothesized that IGF1 activates mitophagy and via this mechanism IGF1 suppresses cellular aging. Aortic SMC were maintained at passage 5 (P5th) and 20 (P20th). Compared to P5, P20 have ~3-fold increase in senescence-associated beta-galactosidase (SA-ß-gal), 2.6-fold elevation of SA-ß-gal activity, 44±6% decrease in cell proliferation, 35±8% decrease in migration and 36±12% decrease in ATP (bioluminescent assay) indicating that P20th cells acquired aging phenotype. Mitophagy was suppressed in P20 (% area overlapping mitochondria and lysosomes, P20, 0.7±0.3 vs. P5, 3.4±0.6). P20 had decreased LC3II/I conversion ratio (autophagy marker, P20, 0.33±0.11 vs. P5, 0.87±0.13), increased mitochondrial markers Tom20 (P20, 0.67±0.1 vs. P5, 0.34±0.1) and TIM23 (P20, 0.83±0.13 vs. P5, 0.44±0.09), elevated mtDNA damage (AP site number/10bp, P20, 88.3±11.6 vs. P5, 45.5±7.9) suggesting reduced mitochondrial biogenesis. IGF1 (25ng/mL, 6h) reduced SA-ß-gal level and activity in P20 (47±14% and 50±19% decrease, respectively), stimulated cell proliferation (44±9% increase) and migration (34±15% increase), increased ATP (59±13% increase) and reduced mtDNA damage (IGF1, 42±9 vs. control, 89±11) showing that IGF-1 reversed aging phenotype. IGF1 activated mitophagy in P20 (IGF-1, 2.7±0.6 vs. control, 0.6±0.4). PINK1 siRNA-induced inhibition of mitophagy blocked IGF-1 effects on SA-ß-gal, migration, proliferation and ATP showing that mitophagy mediates these effects. IGF1 induced 44±9% increase in activity of NRF2 (redox transcription factor) and 60±10% increase in Sirt3 (mitophagy activator) in P20th and either NRF2 or Sirt3 siRNA blunted the mitophagy activation indicating that NRF2/Sirt3 pathway mediated this IGF-1 effect. In summary, we found that IGF1 exerts array of potentially anti-aging effects in SMC and IGF1 activates mitophagy via NRF2/Sirt3 pathway. We have shown that mitophagy activation mediated IGF1-induced effects. These data suggest novel IGF1-based anti-aging therapy.