Department of Internal Medicine, Section On Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Department of Biostatistics and Data Science, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Geroscience. 2022 Apr;44(2):983-995. doi: 10.1007/s11357-021-00509-9. Epub 2022 Jan 10.
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/m. Using mixed models, mean values of the biomarker index improved over 20 weeks with caloric restriction (- 0.82 [Formula: see text] 0.58 points, p = 0.05), but not with exercise (- 0.28 [Formula: see text] 0.59 points, p = [Formula: see text]), with no evidence of an interaction effect of CR [Formula: see text] EX [Formula: see text] 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 [Formula: see text] = between - 0.21 and - 0.24). A reduction in the biomarker index was also associated with increased 4-m usual walk speed ([Formula: see text] = - 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.
中间终点对于评估针对衰老生物学的干预措施在临床试验中的效果是必要的。一个工作组确定了五个基于血液的生物标志物，它们可以作为一个综合指数来达到这一目的。我们在一项针对射血分数保留的心力衰竭伴肥胖表型（HFpEF）患者的随机临床试验中评估了该面板对热量限制或有氧运动的反应，这些患者肥胖且主要为女性。肥胖型 HFpEF 在女性中非常普遍，是一种老年综合征，其疾病病理由非心脏因素和衰老的共同驱动因素驱动。我们在一项随机、对照、2×2 因子的热量限制和/或有氧运动试验中，在 88 名稳定的肥胖 HFpEF 老年参与者中测量了基线和 20 周后的血清白细胞介素 6、TNF-α 受体-I、生长分化因子 15、胱抑素 C 和 N 末端 pro-B 型利钠肽，我们计算了一个复合生物标志物指数，将每个生物标志物的基线五分位数得分相加，并分析了干预措施对指数和单个生物标志物的影响，以及它们与身体机能变化的关联。这项事后分析包括 88 名随机参与者（71 名女性[81%]）。参与者的平均年龄为 66.6±5.3 岁，体重指数（BMI）为 39.3±6.3kg/m2。使用混合模型，20 周时热量限制组的生物标志物指数平均值升高（-0.82±0.58 分，p=0.05），但运动组没有（-0.28±0.59 分，p=0.67），CR[Formula: see text]EX[Formula: see text]时间没有交互效应（p=0.80），调整了年龄、性别和 BMI。在基线时，生物标志物指数与 6 分钟步行距离、短体适能电池评分、跑步机试验峰值工作量和运动至力竭时间（所有[Formula: see text] = -0.21 到-0.24）呈负相关。生物标志物指数的降低也与 4 米常规步行速度的增加相关（[Formula: see text] = -0.31）。在患有慢性肥胖型 HFpEF 的老年患者中，热量限制改善了设计用于反映生物衰老的生物标志物指数。此外，该指数与身体机能和运动耐量相关。
