Purpose AMR show strikingly similar molecular mechanisms (chronic inflammation, fibrogenesis, and others processes) to conditions that accelerate lung aging. Clinically, both AMR and age acceleration manifest as progressive loss of lung function leading us to hypothesize that AMR is associated with age acceleration. Age acceleration triggers signature methylation changes at cytosine-guanosine (CpGs) motifs of “aging” genes. Thus, to test this hypothesis, we used unbiased bisulfite sequencing. Methods Six lung transplant patients with AMR (positive allograft dysfunction, DSA and histopathology and/or C4d) were identified. Two bronchoalveolar (BAL) samples were collected from each patient, one pre-AMR control (no rejection, no infection) and one at AMR diagnosis. BAL cells were used for DNA isolation, bisulfite treatment, and sequencing. Sequences were analyzed via a custom-built computation workflow (bismark, bsseq, bumphunter) that assigns CpGs to DNA regions, normalizes data for cell composition, performs paired analysis to identify differentially methylated regions (DMRs), and maps the DMRs to genes for pathway enrichment analysis. Thresholds for CpG coverage (6X) and DMR mean difference (10%) were arbitrarily selected. P-values were corrected for multiple analyses. Results We identified 900K DMRs between AMR and control. Average DMR length was 238 base pairs with median 4.7 CpGs per DMR (range 3-64). 38.8K DMRs showed 10% or higher methylation difference between AMR and control, with 67% of the DMRs mapped to genes within 1 Killobase. “Aging” genes were overrepresented (q=2.880 × 10−13): genes that promote lung age acceleration (n=370) were predominantly hypo-methylated in AMR, while genes that inhibit lung age acceleration (n=454) were predominantly hyper-methylated. Antibody-mediated pathways such as macrophage activation, Fc-gamma-mediated cell-death, and cytotoxic T-cell activation were also overrepresented (q=0.0007 - 0.0040). Conclusion Both antibody-mediated pathways and “aging” genes were differentially methylated in AMR suggesting epigenetic regulation of these processes and a strong association between AMR and age acceleration. Future studies are needed to validate these findings and assess whether age acceleration contribute to the progressive loss of lung function often observed with AMR. AMR show strikingly similar molecular mechanisms (chronic inflammation, fibrogenesis, and others processes) to conditions that accelerate lung aging. Clinically, both AMR and age acceleration manifest as progressive loss of lung function leading us to hypothesize that AMR is associated with age acceleration. Age acceleration triggers signature methylation changes at cytosine-guanosine (CpGs) motifs of “aging” genes. Thus, to test this hypothesis, we used unbiased bisulfite sequencing. Six lung transplant patients with AMR (positive allograft dysfunction, DSA and histopathology and/or C4d) were identified. Two bronchoalveolar (BAL) samples were collected from each patient, one pre-AMR control (no rejection, no infection) and one at AMR diagnosis. BAL cells were used for DNA isolation, bisulfite treatment, and sequencing. Sequences were analyzed via a custom-built computation workflow (bismark, bsseq, bumphunter) that assigns CpGs to DNA regions, normalizes data for cell composition, performs paired analysis to identify differentially methylated regions (DMRs), and maps the DMRs to genes for pathway enrichment analysis. Thresholds for CpG coverage (6X) and DMR mean difference (10%) were arbitrarily selected. P-values were corrected for multiple analyses. We identified 900K DMRs between AMR and control. Average DMR length was 238 base pairs with median 4.7 CpGs per DMR (range 3-64). 38.8K DMRs showed 10% or higher methylation difference between AMR and control, with 67% of the DMRs mapped to genes within 1 Killobase. “Aging” genes were overrepresented (q=2.880 × 10−13): genes that promote lung age acceleration (n=370) were predominantly hypo-methylated in AMR, while genes that inhibit lung age acceleration (n=454) were predominantly hyper-methylated. Antibody-mediated pathways such as macrophage activation, Fc-gamma-mediated cell-death, and cytotoxic T-cell activation were also overrepresented (q=0.0007 - 0.0040). Both antibody-mediated pathways and “aging” genes were differentially methylated in AMR suggesting epigenetic regulation of these processes and a strong association between AMR and age acceleration. Future studies are needed to validate these findings and assess whether age acceleration contribute to the progressive loss of lung function often observed with AMR.