Inflammaging, a state of chronic low-grade inflammation, is a key contributor to biological aging and diabetes. Traditional inflammatory indices within the interplay between inflammation and epigenetic aging have remains insufficiently explored. In addition, novel platelet-based inflammatory indices based on platelets may perform better than traditional inflammatory indices. This study was a cross-sectional study with survival analysis and analyzed data from 2494 participants in the National Health and Nutrition Examination Survey (NHANES) 1999-2002. In addition to four traditional inflammatory indices (Neutrophil-to-Lymphocyte Ratio [NLR], Systemic Inflammation Response Index [SIRI], Systemic Immune-Inflammation Index [SII], and Pan-Immune-Inflammation Value [PIV]). Three novel platelet-based inflammatory indices, including Neutrophil-to-Platelet Ratio (NPR), Monocyte-to-Platelet Ratio (MPR), and Monocyte-Neutrophil-to-Platelet Ratio (MNPR) were used. Biological aging indicators were quantified using seven indicators: six DNA methylation clocks (HorvathAge, HannumAge, SkinBloodAge, PhenoAge, GrimAge2Mort, and DunedinPACE) and one clinical biomarker-based measure (Klemera-Doubal BioAge). For age-based metrics, epigenetic age deviation (EAD) was defined as the residual from regression on chronological age. Multivariate linear regression and restricted cubic spline (RCS) models were used to assess the associations between inflammatory indices and biological aging indicators. Cox proportional hazards models were further applied to evaluate diabetes-specific mortality risk using linked mortality follow-up data through December 31, 2019, with a median follow-up duration of 206.00 months, and mediation analysis was performed to explore the role of metabolic indicators. Traditional inflammatory indices exhibited significant associations with accelerated biological aging across multiple biological aging indicators (all P < 0.05). Compared with traditional inflammatory indices, platelet-based indices showed that the placement of platelets, particularly in the denominator versus the numerator, was associated with differences in aging-related outcomes, suggesting an important role of platelets in inflammation. Further analysis results indicate that the inflammatory indicators with platelets in the denominator perform better in risk stratification prediction. Survival analysis revealed that patients with the "High NPR + Accelerated Aging" phenotype faced the highest risk of diabetes-specific mortality, particularly within the GrimAge2Mort model. Mediation analysis identified the triglyceride-glucose (TyG) index as a critical mediator in the pathway linking epigenetic aging to diabetes-related mortality. Among the evaluated indices, the novel inflammatory index, especially NPR, showed stronger associations with epigenetic aging than traditional inflammatory indices. This study not only elucidates the role of platelets in inflammaging and diabetes, but also offers a novel perspective for prognostic assessment in diabetes management.
