Frailty in lung transplant recipients is associated with anemia and telomere dysfunction but independent of epigenetic age

Frailty is a syndrome of vulnerability to stressors linked to worse outcomes before and after lung transplantation. However, the biological basis of this association is unknown. Biological correlates of aging include epigenetic reprograming, chronic inflammation, telomere dysfunction, and anemia. We hypothesized that these aging-associated biological processes would be associated with frailty in lung transplant recipients. In a nested case-control study, we compared 43 lung transplant recipients who were frail pretransplant and posttransplant with 43 nonfrail matched controls. We quantified peripheral blood leukocyte epigenetic aging (Horvath) and longevity (GrimAge) clocks, telomere length, cytokine profiles, and hemoglobin before transplant. Epigenetic clocks were correlated with age but not frailty. However, we observed hypermethylation of multiple gene pathways, including hedgehog signaling and angiogenesis, and associated decreased levels of plasma cytokines in frail recipients. Frailty was also associated with telomere dysfunction and anemia. Overall, telomere dysfunction and anemia of chronic disease were most linked to frailty in this cohort, whereas epigenetic aging and chronic inflammation were not. Understanding the heterogeneity of aging syndromes may help target interventions in frail lung transplant recipients.