Epigenetic Aging and Hematopoietic Cell Transplantation in Patients With Severe Aplastic Anemia

Cellular aging in hematopoietic cell transplantation (HCT) is important in the context of immune reconstitution and age-related complications. Recently, several DNA-methylation (DNAm)-based biomarkers of aging known as "epigenetic clocks" have been introduced as novel tools to predict cellular age. Here, we used Cox proportional hazards models to assess the possible associations of donor pre-HCT DNAm age, and its post-HCT changes, using the recently published lifespan-associated epigenetic clock known as "DNAm-GrimAge," with outcomes among patients with severe aplastic anemia (SAA). The study included 732 SAA patients from the Transplant Outcomes in Aplastic Anemia project, who underwent unrelated donor HCT and for whom a donor pre-HCT blood DNA sample was available; 41 also had a post-HCT sample collected at day 100. In multivariable analyses, we found similar associations for donor chronological age and pre-HCT DNAm-GrimAge with post-HCT survival (hazard ratio [HR] per decade = 1.13; 95% confidence interval [CI], 0.99-1.28; P = .07 and HR = 1.14; 95% CI, 0.99-1.28; P = .06, respectively). In donors with 10+ years of GrimAge acceleration (ie, deviation from expected DNAm age for chronological age), elevated risks of chronic graft versus host disease (HR = 2.4; 95% CI, 1.21-4.65; P = .01) and possibly post-HCT mortality (HR = 1.79; 95% CI, 0.96-3.33; P = .07) were observed. In the subset with post-HCT samples, we observed a significant increase in DNAm-GrimAge in the first 100 days after HCT (median change 12.5 years, range 1.4 to 26.4). Higher DNAm-GrimAge after HCT was associated with inferior survival (HR per year = 1.11; 95% CI, 1.02-1.21; P = .01), predominantly within the first year after HCT. This study highlights the possible role cellular aging may play in HCT outcomes.