Characterizing the Risk of Chemotherapy Side Effects Based on Epigenetic Age and Modification by Resistance Training Intervention

有强有力的证据表明，癌症治疗有助于增加共同发病率，功能性 衰退，加速了生物衰老。阻力训练(RT)干预可能有助于 通过增加瘦身质量和力量，将这种机能下降降至最低。被诊断为 结肠癌尤其可能受益于RT干预，因为结肠癌的高患病率 确诊时骨骼肌团块不由自主地减少(肌质疏松症)，这与 化疗相关毒副作用，预后差。老年评估，它衡量了 功能老化方面，可以提高对化疗毒性风险的预测以指导治疗 决定。然而，此工具的应用经常受到以下方面所需资源的限制 评估。表观遗传时钟，根据特定的基因预测年龄段或表型年龄 DNA甲基化模式(DNaM)是很容易检测的，也是生物老化的有效标志。 表观遗传年龄加速(AgeAccel；dNaM-根据年代年龄调整的估计年龄) 与肌肉质量和功能下降的指标有关。我们假设 AgeAccel升高的结肠癌患者将面临更大的化疗毒性风险， AgeAccel在结肠癌化疗期间增加的剂量减少和延迟，以及 RT干预可以降低表观遗传衰老的速度。我们计划在科学上解决这个问题 配合耐药训练降低结肠癌化疗毒性的前提 (强制)临床试验。这项针对II期和III期结肠癌患者的RT临床试验包括 在开始和结束时收集的DNA和身体成分的多模式测量 化疗。我们的首要目标是评估以下几个指标之间的关系 基线年龄加速和3级和4级化疗毒性、剂量减少和延迟的发生率 在部队参与者中。我们预计，增加的基准年龄将与 随着这些结果的发生率增加，RT可以降低这些结果的强度 联想。我们的第二个主要目标是评估治疗过程中表观遗传老化的速度， 以及此速率是否被RT修改。我们预计AgeAccel在年末将更高 化疗相对于开始，表观遗传衰老的速度将在 RT组。综上所述，这些分析将为我们提供新的视角来了解 年龄预测癌症治疗的耐受性，并告知评估AgeAccel是否可以 作为指导治疗决定的有用工具。

There is strong evidence that cancer treatment contributes to increased co-morbidity, functional decline, and accelerated biologic aging. Resistance training (RT) interventions may help to minimize this functional decline by increasing lean mass and strength. Patients diagnosed with colon cancer are particularly likely to benefit from RT interventions given the high prevalence of involuntary loss of skeletal muscle mass (sarcopenia) at diagnosis, which is associated with chemotherapy-associated toxicities, and poor prognosis. Geriatric assessment, which measures facets of functional aging, can improve the prediction of chemotoxicity risk to guide treatment decisions. However, application of this tool is frequently limited by the resources required for assessment. Epigenetic clocks, which predict chronologic or phenotypic age based on specific patterns of DNA methylation (DNAm), are easy to assay, well-validated markers of biologic aging. Epigenetic age acceleration (AgeAccel; DNAm-estimated age adjusting for chronologic age) has been associated with indicators of decreased muscle mass and function. We hypothesize that colon cancer patients with increased AgeAccel will be at greater risk for chemotherapy toxicities, dose reductions, and delays, that AgeAccel will increase during colon cancer chemotherapy, and that a RT intervention can reduce the rate of epigenetic aging. We plan to address this scientific premise in collaboration with the Resistance Training to Reduce Chemotoxicity in Colon Cancer (FORCE) clinical trial. This clinical trial of RT in stage II and III colon cancer patients includes DNA and multi-modal measures of body composition collected at the beginning and end of chemotherapy. Our first primary aim will evaluate the relationship between several measures of AgeAccel at baseline and incidence of grade 3 and 4 chemotoxicities, dose reductions, and delays among FORCE participants. We anticipate that increased baseline AgeAccel will be associated with an increased incidence of these outcomes, and that RT can reduce the strength of these associations. Our second primary aim will assess the rate of epigenetic aging during treatment, and whether this rate is modified by RT. We expect that AgeAccel will be higher at the end of chemotherapy relative to the beginning, and that the rate of epigenetic aging will be attenuated in the RT group. Together, these analyses will provide novel insight into the biologic processes of aging that predict tolerance of cancer treatment, and inform appraisal of whether AgeAccel may serve as a useful tool to guide treatment decisions.