Discussion
toxicities, myeloid malignancies, cancer, various myeloid malignancies
CANCER, BREAST CANCER
In this single-arm pilot study, we demonstrated that it was feasible to evaluate DNAm ages using blood samples collected as part of a mHealth exercise trial among older adults with myeloid malignancies. We evaluated the relationship between accelerated DNAm age and physical, psychological, and cognitive functions in older adults with myeloid malignancies. Examination of correlations between accelerated DNAm ages and clinical measures at baseline revealed that DunedinPACE was inversely correlated with grip strength. We showed that after a mhealth exercise intervention (over two cycles of treatment or approximately 8–12 weeks), DNAm age measured via GrimAge and PhenoAge were stable from baseline to post-intervention. Nevertheless, from baseline to post-intervention, decreases in accelerated GrimAge, accelerated PhenoAge, DunedinPACE, were correlated with increase in both distance walked on 6MWT and in grip strength.Older adults with myeloid malignancies are vulnerable to treatment-related toxicities which can lead to declines in physical, psychological, and cognitive functions, thereby increasing morbidity and mortality. Identifying those at risk using a biomarker such as accelerated DNAm age allows healthcare professionals to warn of declines in functions. Accelerated DNAm age is associated with functional decline in the general population.Behavioral interventions, such as the mHealth exercise intervention evaluated here, may ameliorate treatment-related toxicities and slow the rate of accelerated aging. After an 8-week exercise intervention in older patients with myeloid malignancies, we found that DNAm age was generally unchanged. While we do not have a control arm for comparison, a previous study demonstrated among patients with breast cancer, radiation and chemotherapy lead to accelerated DNAm age from pre- to post-treatment by 6.2–25.6 years [We demonstrated decreases in accelerated aging were correlated with increases in both distance walked on 6MWT and grip strength. However, the mechanisms by which epigenetic clocks are changed in response to behavioral interventions such as exercise are unclear. DNAm ages are generated from a set of CpG sites, and the methylation levels are a reflection of biological age. These CpG sites reside across the genome, but depending on the platform used to measure methylation, are biased towards promoter regions and may therefore influence expression of certain genes. Previous studies have demonstrated that exercise can lead to hypomethylation and hypermethylation of specific CpG sites, as well as global hypomethylation and hypermethylation [Our study has strengths. First, we included older adults with myeloid malignancies, a population not typically studied in clinical trials. Second, we were able to measure DNAm ages prospectively in a clinical trial. Several limitations also should be noted. For example, our sample includes patients with various myeloid malignancies and at different stages and types of treatment (e.g., hypomethylating agents alone or in combination). Therefore, it is difficult to differentiate the effects of the cancer, treatment, and exercise on DNAm ages. Given the small sample size, we were unable to perform subgroup analyses and it may have also limited our ability to detect other associations. Given the evolving treatment landscape for myeloid malignancies and the increasing difficulty in recruiting a homogeneous population, future larger multicenter trials are needed to recruit this population in order to understand the influence of aging, cancer, treatment, and exercise on DNAm ages.In conclusion, DunedinPACE is inversely correlated with grip strength at baseline. We demonstrated that GrimAge and PhenoAge on average are stable after a mHealth exercise intervention in older adults with myeloid malignancies receiving chemotherapy. Decreases in accelerated PhenoAge and GrimAge as well as decreases in DunedinPACE over 8–12 weeks of exercise are correlated with increased physical performance. Our findings will inform an ongoing pilot randomized controlled trial (clinicaltrials.gov identifier: NCT04981821) testing the effect of the mHealth exercise intervention in older adults with myeloid malignancies, in which we will evaluate the change in DNAm age, comparing the intervention and control arms. Our study supports the use of GrimAge, PhenoAge, and DunedinPACE when measuring accelerated aging as part of an exercise clinical trial.