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.

Chemotherapy toxicity during colon cancer treatment creates an acute and long-term health burden for patients, and it is extremely common. Our study will inform novel appraisal of whether epigenetic age can be used to identify colon cancer patients at high risk for chemotherapy toxicity, dose reductions, and delays, and whether a resistance training intervention can reduce the rate of epigenetic aging, to mitigate that risk. We contend epigenetic age has the capacity to inform more personalized approaches to treating colon cancer patients to improve long-term outcomes.