Intermediate endpoints are needed to evaluate the effect of interventions targeting the biology of aging in clinical trials. A working group identified five blood-based biomarkers that may serve such a purpose as an integrated index. We evaluated the responsiveness of the panel to caloric restriction or aerobic exercise in the context of a randomized clinical trial conducted in patients with heart failure with preserved ejection fraction (HFpEF) with obese phenotype who were predominantly female. Obese HFpEF is highly prevalent in women, and is a geriatric syndrome whose disease pathology is driven by non-cardiac factors and shared drivers of aging. We measured serum Interleukin-6, TNF-α-receptor-I, growth differentiating factor-15, cystatin C, and N-terminal pro-b-type natriuretic peptide at baseline and after 20 weeks in older participants with stable obese HFpEF participating in a randomized, controlled, 2 × 2 factorial trial of caloric restriction and/or aerobic exercise. We calculated a composite biomarker index, summing baseline quintile scores for each biomarker, and analyzed the effect of the interventions on the index and individual biomarkers and their associations with changes in physical performance. This post hoc analysis included 88 randomized participants (71 women [81%]). The mean ± SD age was 66.6 ± 5.3 years, and body mass index (BMI) was 39.3 ± 6.3 kg/m2. Using mixed models, mean values of the biomarker index improved over 20 weeks with caloric restriction (− 0.82 ±\documentclass[12pt]{minimal}
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\begin{document}$$\pm$$\end{document} 0.58 points, p = 0.05), but not with exercise (− 0.28 ±\documentclass[12pt]{minimal}
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\begin{document}$$\pm$$\end{document} 0.59 points, p = 0.50\documentclass[12pt]{minimal}
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\begin{document}$$0.50$$\end{document}), with no evidence of an interaction effect of CR ×\documentclass[12pt]{minimal}
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\begin{document}$$\times$$\end{document} EX ×\documentclass[12pt]{minimal}
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\begin{document}$$\times$$\end{document} time (p = 0.80) with adjustment for age, gender, and BMI. At baseline, the biomarker index was inversely correlated with 6-min walk distance, scores on the short physical performance battery, treadmill test peak workload and exercise time to exhaustion (all ρ\documentclass[12pt]{minimal}
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\begin{document}$$\rho$$\end{document}s = between − 0.21 and − 0.24). A reduction in the biomarker index was also associated with increased 4-m usual walk speed (ρ\documentclass[12pt]{minimal}
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\begin{document}$$\rho$$\end{document}s = − 0.31). Among older patients with chronic obese HFpEF, caloric restriction improved a biomarker index designed to reflect biological aging. Moreover, the index was associated with physical performance and exercise tolerance.
