Isobaric labeling quantitative phospho proteomics uncovered differential site-specific protein phosphorylation within mTOR, Rho GTPase and MAPK systems in platelets from aged donors. Western blot confirmed constitutive activation of the mTOR pathway in platelets from both aged humans and mice, which was associated with increased aggregation compared to young controls. Inhibition of mTOR either with Torin 1 in aged humans, or genetic deletion in aged mice, reversed platelet hyperreactivity. Mechanistically, we noted increased levels of mitochondrial reactive oxygen species and Rac1 activation in resting platelets from aged mice, as well as increased p38 phosphorylation upstream of thromboxane generation following agonist stimulation.