Peripheral blood mononuclear-cells (PBMNC) senescence in relation to coronary-artery-disease (CAD) severity, and factors influencing senescence and severity are limited. Here, we explored the association of PBMNC-senescence with the extent of coronary stenosis and methylation-cycle; and methylation-cycle with severity. We assessed telomerase activity (TA) and cell cycle arrest (CCA) in PBMNC as senescence-indicators; plasma concentrations of analytes (asymmetric-dimethylarginine:ADMA, homocysteine:HCY) and SAM-dependent-methyltransferase activity in PBMNC for methylation-cycle. Based on Gensini scores (GS), 45 participants were assigned to either insignificant CAD (with <= 50% stenosis) or established CAD (with > 50% stenosis) group. Using LC-ESI-MS, HTRF-assay, propidium-iodide flow-cytometry and PCR-ELISA approaches, concentrations of analytes, methyltransferase-activity, CCA and TA were assessed. There were significant differences in senescence indicators, methylation-cycle and GS among the groups (P < 0.05). GS has positive correlation (P = 0.0001) with CCA, methyltransferase-activity and analytes concentrations; negative correlation (P = 0.0001) with TA. Additionally, methyltransferase-activity and analytes' concentrations are positively correlated (P = 0.0001) with CCA; negatively correlated (P = 0.0001) with TA. Together, senescence indicators and methylation-cycle elements were altered in patients with or without stenosis. This study shows that PBMNC-senescence signatures can be defined for GS; CCA can be developed as a non-invasive tool to assess CAD severity as CCA distinguishes patients with and without significant coronary artery stenosis.