Magnesium Depletion Score and Risk of Skin Cancer and Mortality: Evidence from NHANES 1999–2018 with Mediation by PhenoAge

• Higher MDS predicted increased risks of NMSC, cancer-specific, and all-cause mortality. • No significant association was observed between MDS and MSC. • PhenoAge partially mediated MDS–outcome associations, especially for mortality risks. To investigate the associations between the Magnesium Depletion Score (MDS) and risks of skin cancer and mortality, and to evaluate the mediating role of biological aging measured by PhenoAge. We analyzed data from 39,823 participants aged ≥20 years in NHANES 1999–2018. MDS was constructed based on diuretic use, proton pump inhibitor (PPI) use, estimated glomerular filtration rate (eGFR), and heavy alcohol intake. Outcomes included non-melanoma skin cancer (NMSC), melanoma skin cancer (MSC), cancer-specific mortality, and all-cause mortality. Weighted logistic regression and Cox proportional hazards models estimated associations, restricted cubic splines assessed dose–response relationships, and causal mediation analysis quantified the mediating effect of PhenoAge. In fully adjusted models, higher MDS was significantly associated with higher odds of NMSC (OR = 1.13, 95% CI: 1.04–1.23, P = 0.006), cancer-specific mortality (HR = 1.19, 95% CI: 1.10–1.28, P < 0.001), and all-cause mortality (HR = 1.32, 95% CI: 1.28–1.37, P < 0.001), with clear dose–response trends. Participants with MDS ≥3 showed higher odds of NMSC (OR = 1.57, 95% CI: 1.15–2.14, P = 0.004), cancer-specific mortality (HR = 1.73, 95% CI: 1.34–2.22, P < 0.001), and all-cause mortality (HR = 2.47, 95% CI: 2.18–2.79, P < 0.001) compared with those with MDS = 0. Associations with MSC were weaker and not statistically significant. Mediation analysis suggested that PhenoAge partially mediated the associations of MDS with study outcomes, accounting for 16.20% of the effect on NMSC, 82.27% on cancer-specific mortality, and 54.69% on all-cause mortality. Higher MDS was associated with increased risks of NMSC, cancer-specific mortality, and all-cause mortality, partly mediated by PhenoAge.