The sporadic and familial forms of Creutzfeldt-Jacob disease (sCJD and fCJD) usually appear at older ages (60-70 years and ∼ 50, respectively). Nevertheless, infectious forms such as Kuru and variant CJD (vCJD) present mostly at a much earlier age. To study the effect of age on the pathogenesis of infectious prion disease, we inoculated young and aged mice intraperitoneally with RML prions, followed them to disease end point and studied their disease characteristics. We now show that mice infected at older age present a significantly longer incubation time then mice infected at young age. Additionally, brains of mice infected at older age present significantly less disease-specific pathological markers such as gliosis, vacuolation and PrP(Sc) accumulation. Concomitantly, gene expression analysis revealed that the upregulation of disease-associated inflammatory and stress-response genes, was significantly less pronounced in the brains of mice infected at older age. Based on this data, we suggest that alterations associated with aging, are accountable for the delay in the disease onset and the milder pathology in prion-infected aged mice.