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合并症，功能性 衰老，加速生物衰老。阻力训练（RT）干预可能有助于 通过增加瘦体重和力量来最大限度地减少这种功能下降。确诊患者 结肠癌特别可能受益于RT干预，因为高患病率 诊断时骨骼肌质量的不自主损失（肌肉减少症），这与 化疗相关毒性和不良预后。老年评估，衡量 功能性衰老的各个方面，可以提高对化疗毒性风险的预测，以指导治疗 决策然而，这一工具的应用往往受到以下方面所需资源的限制： 考核表观遗传时钟，它根据特定的生物学特征来预测年龄或表型年龄。 DNA甲基化模式（DNAm）是易于分析的生物老化的有效标志物。 表观遗传年龄加速（DNAm Accel;根据年代年龄调整的DNA估计年龄） 与肌肉质量和功能下降的指标有关。我们假设 结肠癌患者具有增加的结肠癌加速度将具有更大的化疗毒性风险， 剂量减少和延迟，结肠癌化疗期间， RT干预可以降低表观遗传衰老的速度。我们计划解决这个科学问题 前提与阻力训练合作，以减少结肠癌的化学毒性 （FORCE）临床试验。这项在II期和III期结肠癌患者中进行的RT临床试验包括 DNA和身体组成的多模态措施收集在开始和结束的 化疗我们的第一个主要目标将评估几个测量值之间的关系， 基线加速和3级和4级化疗毒性、剂量减少和延迟的发生率 参与者中。我们预计，基线加速率的增加将与 这些结果的发生率增加，RT可以降低这些结果的强度， 协会.我们的第二个主要目标是评估治疗过程中表观遗传衰老的速度， 以及这一速率是否被RT修改。我们预计， 化疗相对于开始，表观遗传衰老的速度将在 RT集团。总之，这些分析将提供新的见解的生物过程， 老化，预测癌症治疗的耐受性，并告知评估是否可使用 作为指导治疗决策的有用工具。

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.