Epigenetic age acceleration, telomere length, and neurocognitive function in long-term survivors of childhood cancer

Abstract

Survivors of childhood cancer are prone to neurocognitive impairment and premature aging, raising concerns about early onset dementia. In this cross-sectional study, 1413 survivors of childhood cancer complete a neuropsychological battery. Mean leukocyte telomere length residual (mLTL) and epigenetic age acceleration (EAA) from five different epigenetic clocks, are derived from linear regression of mLTL or epigenetic age on chronological age. Among survivors treated with CNS-directed therapy, higher EAA, measured by PCGrimAge, or DunedinPACE is associated with worse performance on multiple measures of attention, processing speed, and executive functions (p's < 0.05). Among non-CNS-treated survivors, results are similar for PCGrimAge, however, DunedinPACE is specifically associated with attention variability (p < 0.05). mLTL is not associated with neurocognition. EAA is associated with worse neurocognitive function and may identify survivors at risk for accelerated cognitive aging or serve as an efficacy biomarker for neurocognitive interventions.

Fig. 1. Epigenetic age acceleration (EAA) in survivors of childhood cancer treated with (n = 750) and without (n = 633) central nervous system directed therapy compared with non-cancer controls (n = 282).

Marginal adjusted means and 95%CI (error bars) from linear regression models (t-test, two-sided, no adjustment for multiple comparisons) adjusted for sex, body mass index, smoking, and physical activity. Regardless of exposure to CNS-directed therapy, survivors experienced significantly higher EAA, faster DundedinPACE, and shorter mean leukocyte telomere length compared with non-cancer controls (all p < 0.001), full results can be found in Supplementary Table 2. Source data are provided as a Source data file.