Clonal Hematopoiesis and Epigenetic Age Acceleration in Elderly Danish Twins

Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) is common in the elderly and has been reported to associate with accelerated epigenetic age (AgeAccel), especially intrinsic (ie, cell-type independent) AgeAccel and to a lesser degree extrinsic AgeAccel, which reflects the immune-cell composition of the peripheral blood. We investigated the association between CHIP occurrence and AgeAccel in 154 Danish twin pairs aged 73-90 years (mean 79), using both individual-level and intrapair analyses, the latter to control for shared genetic and environmental factors. Of 308 individuals, 116 carried a CHIP mutation. CHIP carriers had non-significantly increased AgeAccel compared with non-carriers; the strongest association was for the Intrinsic Epigenetic Age Acceleration (IEAA) estimator (CHIP carriers 1.4 years older, P = 0.052). In intrapair analyses, the extrinsic Hannum age estimator showed the strongest association (1.6 years older, P = 0.027). In mutation-specific analyses, TET2 mutations were associated with the extrinsic Hannum age estimator in both individual-level (3.0 years older, P = 0.003) and intrapair analyses (2.8 years older, P = 0.05). DNMT3A mutations were associated with IEAA in individual-level (1.9 years older, P = 0.034) but not intrapair analysis (0.9 years, P = 0.41). Analyses of logit-transformed variant allele frequency were generally consistent with these results. Together, these observations indicate that different factors may be driving the expansion of DNMT3A and TET2 clones, respectively. Finally, CHIP carriers accelerated in both the Hannum and the GrimAge age estimators did not have an increased mortality risk in our cohort followed for 22 years (HR = 1.02, P = 0.93), hence not replicating the stratification model proposed by Nachun et al.

Figure 1.

Kaplan-Meier mortality estimates according to combined CHIP and AgeAccelHG status. CHIP± indicates the presence or absence of clonal hematopoiesis of indeterminate potential. AgeAccelHG± indicates whether individuals had positive age acceleration in both Hannum and GrimAge estimators (+) or in only one or neither estimators (−). The plot is based on a Cox proportional hazards model with delayed entry (origin date in the individuals’ birth date and entry date at date of blood sampling), hence the x-axis shown in the plot starts at blood sampling. One twin pair of the present study population died very soon after blood sampling; this twin pair was removed for the plot, as a gap in analysis time, would otherwise have distorted the dimensions of the plot. The estimates obtained for all individuals (N = 224) and leaving out the twin pair (N = 222) were identical (data not shown). AgeAccelHG = age acceleration defined by both the Hannum and GrimAge estimators; CHIP = clonal hematopoiesis of indeterminate potential.