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Evaluation of a blood-based geroscience biomarker index in a randomized trial of caloric restriction and exercise in older adults with heart failure with preserved ejection fraction

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Abstract

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 \(\pm\) 0.58 points, p = 0.05), but not with exercise (− 0.28 \(\pm\) 0.59 points, p = \(0.50\)), with no evidence of an interaction effect of CR \(\times\) EX \(\times\) 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 \(\rho\) s = between − 0.21 and − 0.24). A reduction in the biomarker index was also associated with increased 4-m usual walk speed (\(\rho\) 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.

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Acknowledgements

We thank the men and women who volunteered for this study as well as the research staff who conducted recruitment and assessments. We also give special thanks to Ben Nelson, John Stone, Heather Gregory at WFSM for assistance with data and biospecimen retrieval, and members of the Northwest Lipid Research Laboratory (University of Washington) for performing biochemical assays.

Funding

This work was supported by the National Institutes of Health (NIH) program grant to Wake Forest Claude D. Pepper Older Americans Independence Center (P30 AG21332, Dr. Kritchevsky PI, Dr Justice Pepper Pilot Award PI), Coordinating Center of the Claude D. Pepper Older Americans Independence Centers (U24AG059624, Dr. Kitzman), career development grant: K01 AG059837 (Dr. Justice), and research grants: R01 HL093713 and R01 AG020583 (Dr. Nicklas), and R01 AG18915, R01 AG045551 and (Dr. Kitzman). Also, supported in part by the Kermit Glenn Phillips II Chair in Cardiovascular Medicine at Wake Forest School of Medicine (Dr. Kitzman), additional support was provided through a grant from the Glenn Foundation for Medical Research (Drs. Espeland, Kritchevsky).

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Authors and Affiliations

  1. Department of Internal Medicine, Section On Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA

    Jamie N. Justice, Mark A. Espeland, Denise K. Houston, Barbara J. Nicklas & Stephen B. Kritchevsky

  2. Department of Biostatistics and Data Science, Wake Forest School of Medicine, Winston-Salem, NC, USA

    Nicholas M. Pajewski

  3. Department of Health and Exercise Science at Wake, Forest University in Winston-Salem, NC, USA

    Peter Brubaker

  4. Medpace Reference Laboratories, Cincinnati, OH, USA

    Santica Marcovina

  5. Department of Internal Medicine, Section On Cardiology, Wake Forest School of Medicine, Winston-Salem, NC, USA

    Dalane W. Kitzman

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The SECRET trial was conducted at Wake Forest School of Medicine from February 2009 through November 2014, which was approved by the Institutional Review Board, and registered (NCT00959660).

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NYHA HF Class: New York Heart Association Heart Failure class. Fat mass as total percent body fat from DEXA. IL-6: interleukin-6 (pg/mL). TNFaR1: tumor necrosis factor-receptor 1 (pg/mL). GDF-15: growth differentiating factor-15 (pg/mL). Cystatin C (mg/L). NT-proBNP: N-terminal-pro-natriuretic peptide (pM).

IL-6, interleukin-6 (pgmL). TNFaR1, tumor necrosis factor-receptor 1 (pgmL). GDF-15, growth differentiating factor-15 (pgmL). Cystatin C (mgL). NT-proBNP, N-terminal-pro-natriuretic peptide (pM).

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Justice, J.N., Pajewski, N.M., Espeland, M.A. et al. Evaluation of a blood-based geroscience biomarker index in a randomized trial of caloric restriction and exercise in older adults with heart failure with preserved ejection fraction. GeroScience 44, 983–995 (2022). https://doi.org/10.1007/s11357-021-00509-9

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