Abstract
Telomere length (TL) reflects the replicative potential of a cell and is a useful parameter to assess chronological age of an organism. Aplastic anemia (AA) and dyskeratosis congenita (DKC) are bone marrow failure syndromes (BMFS) characterized by shortened telomeres compared to age-matched healthy individuals in peripheral blood leukocytes. Human aging is associated with DNA methylation (DNAm) changes at specific sites in the genome. The aim of this study was to analyze whether aging specific epigenetic modifications can be used to track donor age and reflect premature aging in patients with AA and DKC.
A large set of publically available DNAm profiles were used to identify an Epigenetic-Aging-Signature. The DNAm level of three corresponding CpG sites was then analyzed by pyrosequencing after bisulfite conversion. The results were used for linear regression models for age predictions. This method was applied with peripheral blood leukocytes of a training as well as a validation set. Furthermore, TL analysis by flow-FISH of peripheral blood leukocytes of 106 healthy donors was used to generate age-adapted reference values. Pyrosequencing and telomere length analysis were carried out in 16 AA and 6 DKC patients
Our analysis revealed that DNAm levels at three AR-CpGs – located in the genes ITGA2B, ASPA and PDE4C – were best suited for age predictions. The mean absolute deviation from chronological age in the validation set of 69 donors was less than 5 years. Age-adapted telomere length analysis revealed significant telomere attrition in AA (- 1.1 kb) and DKC patients (-3.7 kb, all below the 1% percentile). In analogy, the epigenetic changes revealed premature aging in AA patients – particularly in those which revealed extensive telomere attrition.
Our results indicate that patients with AA and DKC undergo massive premature aging on the epigenetic level comparable to the observed telomere shortening in these diseases. Determination of this newly defined Epigenetic-Aging-Signature in combination with telomere length measurement may be used to further refine diagnosis of AA and DKC in the clinical setting.
No relevant conflicts of interest to declare.
Author notes
Asterisk with author names denotes non-ASH members.
