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Inflammation is a critical component of chronic diseases, aging progression, and lifespan. Omics signatures may characterize inflammation status beyond blood biomarkers. We leveraged genetics (polygenic risk score [PRS]), metabolomics (metabolomic risk score [MRS]), and epigenetics (epigenetic risk score [ERS]) to build multi-omics-multi-marker risk scores for inflammation status represented by the level of circulating C-reactive protein (CRP), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-α). We found that multi-omics risk scores generally outperformed single-omics risk scores in predicting all-cause mortality in the Canadian Longitudinal Study on Aging. Compared with circulating inflammation biomarkers, some multi-omics risk scores had a higher hazard ratio (HR) for all-cause mortality when including both score and circulating IL-6 in the same model (1-SD IL-6 MRS-ERS: HR = 2.20 [1.55-3.13] vs. 1-SD circulating IL-6 HR = 0.94 [0.67,1.32]. 1-SD IL-6 PRS-MRS: HR = 1.47 [1.35,1.59] vs. 1-SD circulating IL-6 HR = 1.33 [1.18, 1.51]. 1-SD PRS-MRS-ERS: HR = 1.95 [1.40, 2.70] vs. 1-SD circulating IL-6: HR = 0.99 [0.71, 1.39]). In the Nurses' Health Study (NHS), NHS II, and Health Professional Follow-up Study with available omics, 1 SD of IL-6 PRS and 1-SD IL-6 PRS-MRS had HR = 1.12 [1.00,1.26] and HR = 1.13 [1.01,1.26] among individuals >65 years old without mutual adjustment of the score and circulating IL-6. Our study demonstrates that some multi-omics scores for inflammation markers may characterize important inflammation burden for an individual beyond those represented by blood biomarkers and improve our prediction capability for the aging process and lifespan.