Sex-Specific Links Between Organ Aging and Heart Failure Severity and Differential Impact of Diabetes and TyG-BMI

Background Biological aging varies across individuals and tissues, influencing chronic diseases, including heart failure (HF). Emerging proteomic techniques enable quantification of organ-specific aging acceleration (OAA), but whether OAA affects HF severity and differs by sex remains unclear. We aim to assess the sex-specific association between OAA of heart, artery and kidneys and HF severity, and to investigate relevant clinical factors of organ aging. Methods In 556 participants from the HELPFul cohort, we estimated predicted biological age for heart, artery, and kidneys using plasma proteomics and calculated OAA as the deviation from chronological age. Associations between OAA and HF stage, echocardiographic parameters, and cardiometabolic risk factors were evaluated using regression models. Composite indices, including TyG-BMI, CTI and TG/HDL were assessed for associations with advanced OAA. Results Mean age was 63±9 years; 65% were women. Patients were classified as HF stage A (35%), B (29%) and C/D (36%). Heart OAA was significantly associated with advanced HF (Stage C/D) in both sexes (OR = 1.12, 95% CI: 1.03 to 1.23 in women; OR = 1.18, 95% CI: 1.05 to 1.32 in men), while arterial OAA was linked to HF only in women (OR = 1.10, 95% CI: 1.01 to 1.18). Multi-organ aging (≥2 organs with advanced OAA) conferred over three-fold higher odds of being in Stage C/D. Heart OAA correlated with impaired cardiac structure and function, particularly reduced ejection fraction in men and increased left ventricular mass index in both sexes. Diabetes emerged as the most relevant factor of arterial and kidney aging, with effects more pronounced in women. TyG-BMI was significantly associated with advanced kidney OAA, only in women (z-scored OR = 1.88, 95% CI: 1.45 to 2.45). Conclusions Proteomic-derived organ biological aging correlates with HF severity, diabetes and TyG-BMI, with sex-specific patterns. These findings underscore the organ aging beyond chronological age as an important indicator and inform future practice into tailored and sex-specific strategies for HF management.