**Background:** Obesity affects 650 million adults worldwide and is associated with increased DNA damage, oxidative stress, inflammation, and elevated risk for cancer, cardiovascular disease, and diabetes. Bariatric surgery (BS) is an effective intervention for severe obesity, but its effects on genomic stability—particularly DNA repair mechanisms and telomere length—have been poorly characterized. This study aimed to comprehensively evaluate the impact of BS-induced weight loss on DNA stability, oxidative DNA damage, DNA repair (base excision repair [BER] and nucleotide excision repair [NER]), telomere length, antioxidant enzyme activities, lipid peroxidation, and the plasma proteome.
**Methods:** Thirty-five patients (mean age 41.3 ± 13.3 years, 29 female/6 male, mean BMI 45.4 ± 6.6 kg/m²) were recruited from the Department of Surgery, Medical University of Vienna. Exclusion criteria included chronic diseases (diabetes type II, cystic fibrosis, arthritis, asthma), intake of food supplements before surgery, and anti-inflammatory or antioxidant medications. Patients underwent RYGB (n=11), OAGB (n=19), GS (n=2), or SADI-S (n=3). Blood samples were collected one day before surgery (T0) and at 1 month (T1) and 6 months (T2) post-surgery. All patients received a standard nutritional supplement (WLS Forte) after surgery. DNA damage and oxidized purines were measured using the single-cell gel electrophoresis (SCGE/comet) assay in lymphocytes. BER and NER activities were assessed using a modified comet assay with lymphocyte protein extracts applied to pre-damaged substrate cells (A549 line). Superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities were measured spectrophotometrically. Malondialdehyde (MDA) was quantified by HPLC. Telomere length was determined by monochrome multiplex qPCR (T/S ratio using ALB and 36B4 as reference genes). Plasma proteomics (410 proteins from 3182 peptides) was performed using LC-MS/MS. Statistical analyses used a general linear model with age, sex, smoking status, and baseline BMI as covariates, with Bonferroni correction.
**Key Results:** Body weight decreased by 27.5% and BMI by 28% at 6 months (both p < 0.001). DNA damage under standard comet assay conditions decreased significantly by 54% at 6 months (p = 0.009). Oxidized purines (FPG-sensitive sites) showed a time-dependent decline (trend p < 0.001) but did not reach significance at individual time points. BER activity decreased significantly at 6 months (p = 0.001), and NER activity also decreased (p = 0.049). Both repair systems showed non-significant declines at 1 month (NER 16.5%, BER 7%). In the OAGB subgroup (n=19), DNA damage decreased by 50% (p = 0.0002) and BER was significantly reduced (p = 0.008) at 6 months. SOD and GPx activities showed non-significant declines at both time points (SOD: −6.4% at 1 month, −1.9% at 6 months; GPx: −7.3% at 1 month, −2.5% at 6 months). MDA levels decreased significantly from 4.42 ± 0.72 μM/L at baseline to 2.60 ± 0.89 μM/L at 6 months. Telomere length (ALB assay) increased significantly between 1 and 6 months in the overall group (+12.1%, p = 0.022) and OAGB subgroup (+18.0%, p = 0.046); the 36B4 assay showed a similar but non-significant trend. Proteomic analysis identified four downregulated proteins at 6 months: serum amyloid A1 (SAA1), C-reactive protein (CRP), and hemoglobin subunits HBB and HBA1. Apolipoprotein A-IV (APOA4) was significantly upregulated at 1 month compared to 6 months.
**Clinical Implications:** This study provides evidence that bariatric surgery-induced weight loss substantially reduces DNA damage and oxidative DNA damage, likely mediated by decreased inflammation (reflected by reduced CRP and SAA1) and reduced lipid peroxidation (MDA decreased by 41% at 6 months). The unexpected decrease in BER and NER activities may reflect an adaptive downregulation in response to reduced DNA damage levels, possibly influenced by post-surgery nutritional supplementation. The increase in telomere length between 1 and 6 months suggests potential reversal of obesity-related cellular aging. These findings support the hypothesis that bariatric surgery reduces genomic instability and may lower long-term cancer risk. The study is the first to evaluate DNA repair capacity after BS and to include OAGB patients, demonstrating similar benefits to RYGB. Limitations include the relatively small sample size (n=35), short follow-up (6 months), heterogeneous surgical procedures, and lack of a non-surgical control group. Longer-term studies are needed to confirm whether these improvements translate into reduced cancer incidence and mortality.