Objective:

To identify specific aging-related programmed cell death (PCD) signatures in heart failure (HF) and explore their potential as biomarkers.

Key Findings:

• Ferroptosis, autophagy, and necroptosis were strongly correlated with aging in HF.
• Eighteen differentially expressed aging-related PCD genes were identified.
• The LASSO model demonstrated the best diagnostic performance.
• Significant differences in the immune microenvironment were observed between high and low aging-PCD index groups.
• A regulatory network of 15 key genes and 19 transcription factors was constructed.
• STEAP3 may participate in ferroptosis-related injury in cardiomyocytes through glutathione metabolism and iron homeostasis.

Interpretation:

The study identifies aging-related PCD signatures in HF, suggesting potential biomarkers for clinical validation.

Limitations:

• The study was limited to a small sample size of 22 participants, which may affect the generalizability of the findings.
• The training and validation datasets were analyzed independently without batch effect correction.

Conclusion:

Aging-related PCD signatures in HF may provide candidate biomarkers for further clinical validation.