The senescence-accelerated mouse (SAM) model has been extensively used to study neurological alterations associated with aging. Although the SAM model is also useful to study vascular aging, there is still work to be done to better define its utility as a model of atherosclerosis, since contradictory data have been published and sex seems to play a crucial role in potential divergences. With this in mind, we aimed to decipher the molecular mechanisms underlying the potentially higher atherogenesis risk of SAMP8 mice, analyzing the aorta of 10 months-old animals by means of in-depth proteomic analysis, considering sex- specific differences. Validation of the results obtained were performed by western blot in an independent cohort of mice, as well as in human aortic smooth muscle cells (HASMC). Besides, an exhaustive lipoprotein and glycoprotein analysis was performed in plasma. Distinct proteomic, lipoprotein and glycoprotein profiles have been found in SAMP8 mice, according to sex. Male SAMP8 mice evidenced increased atherogenesis susceptibility due to several sex- specific alterations: 1) increased number of VLDLs, as well as in their cholesterol and TG content; 2) upregulation of inflammatory glycoproteins in plasma; and 3) increased features of SASP and vascular calcification: upregulation of exocytic vesicular transport and downregulation of the protein Gas6. On the contrary, female mice showed a much better proteomic and lipoprotein profile and only the decrease of the atheroprotective protein NRP1 as a sex-specific pathological feature. The results obtained suggest that male SAMP8 mice can develop atherosclerosis under a HFD while female SAMP8 mice may be less susceptible to atherogenesis.