The Association of Visceral and Subcutaneous Fat Areas with Phenotypic Age in Non-elderly Adults, Mediated by HOMA-IR and HDL-C

Backgroud: Aging results in diminished adaptability, as well as declines in physiological and psychological functions and resilience. An epigenetic clock known as "PhenoAge" captures the concept of "pre-clinical aging." When phenotypic age surpasses chronological age, this condition is termed phenotypic age acceleration (PhenoAgeAccel). Subcutaneous adipose tissue, visceral adipose tissue, HOMA-IR, and HDL-C have all been shown to correlate with aging; however, the connections between these factors and PhenoAge are still insufficiently investigated. Methods: Data for this study were sourced from the National Health and Nutrition Examination Survey (2015-2018), including a total of 2580 participants. Complex survey designs were taken into consideration. Logistic regression was used to assess the association between body fat area and PhenoAgeAccel, while subgroup analysis helped identify variations in population characteristics. A dose-response relationship between body fat area and PhenoAgeAccel was observed using restricted cubic spline (RCS) analysis. Mediation and interaction analyses were further employed to investigate the roles of HOMA-IR and HDL-C in this association. Clinical predictive metrics such as Area Under the Curve (AUC), Net Reclassification Improvement (NRI), and Integrated Discrimination Improvement (IDI) were utilized to determine the diagnostic value. Results: In non-elderly adults, the association between body fat area and PhenoAgeAccel differs from chronological age. For subcutaneous fat area (SFA), this relationship was non-linear in individuals aged 18-44 years and 45-59 years, with thresholds of 2.969 m² and 3.394 m², respectively. In contrast, visceral fat area (VFA) exhibited a non-linear relationship with PhenoAgeAccel in individuals aged 18-44 years, but a linear relationship in those aged 45-59 years, with thresholds of 0.769 m²and 1.220 m², respectively. Mediation effect analysis revealed that HOMA-IR had a more pronounced effect in individuals aged 18-44 years, with a mediation proportion of 13.4% in the relationship between VFA and PhenoAgeAccel, and 6.9% in the relationship between SFA and PhenoAgeAccel. Conversely, HDL-C shows greater significance in individuals aged 45-59 years, with a mediation proportion of 21.7% in the relationship between VFA and PhenoAgeAccel, and 11.6% in the relationship between SFA and PhenoAgeAccel. HOMA-IR ≥2.73 or VFA >0.925 m², as well as HOMA-IR ≥2.73 or SFA >3.137 m² accelerate PhenoAge; whereas HDL-C levels >1.60 and ≤3.90 mmol/L combined with SFA ≤3.137 m² or VFA ≤0.925 m² decelerate PhenoAge. Conclusion: Our main findings are as follows: 1) both subcutaneous and visceral fat area significantly influence PhenoAge. 2) HOMA-IR and HDL-C serve as partial mediators in the relationship between body fat area and PhenoAge. 3) higher levels of body fat area or insulin resistance accelerate aging, whereas lower levels of body fat area combined with higher levels of HDL-C decelerate aging.