Abstract
BackgroundAging and inflammation are important components of Parkinson’s disease (PD) pathogenesis and both are associated with changes in hematopoiesis and blood cell composition. DNA methylation (DNAm) presents a mechanism to investigate inflammation, aging, and hematopoiesis in PD, using epigenetic mitotic aging and aging clocks. Here, we aimed to define the influence of blood cell lineage on epigenetic mitotic age and then investigate mitotic age acceleration with PD, while considering epigenetic age acceleration biomarkers.ResultsWe estimated epigenetic mitotic age using the “epiTOC” epigenetic mitotic clock in 10 different blood cell populations and in a population-based study of PD with whole-blood. Within subject analysis of the flow-sorted purified blood cell types DNAm showed a clear separation of epigenetic mitotic age by cell lineage, with the mitotic age significantly lower in myeloid versus lymphoid cells (p = 2.1e-11). PD status was strongly associated with accelerated epigenetic mitotic aging (AccelEpiTOC) after controlling for cell composition (OR = 2.11, 95 % CI = 1.56, 2.86, p = 1.6e-6). AccelEpiTOC was also positively correlated with extrinsic epigenetic age acceleration, a DNAm aging biomarker related to immune system aging (with cell composition adjustment: R = 0.27, p = 6.5e-14), and both were independently associated with PD. Among PD patients, AccelEpiTOC measured at baseline was also associated with longitudinal motor and cognitive symptom decline.ConclusionsThe current study presents a first look at epigenetic mitotic aging in PD and our findings suggest accelerated hematopoietic cell mitosis, possibly reflecting immune pathway imbalances, in early PD that may also be related to motor and cognitive progression.
Highlights
The human blood-system performs numerous vital functions, including the circulation of oxygen and nutrients, temperature homeostasis, and constant immune surveillance of the entire body [1]
Several key concepts are directly relevant to this analysis (Fig. 1B): (1) Aging and inflammation are both associated with a myeloid-bias in hematopoiesis leading to increased numbers of progenitor and mature myeloid cells [3]. (2) The hematopoietic expansion of cell populations is achieved mainly through vast, daily proliferation of progenitor cells at different stages of development, while adult hematopoietic stem cells (HSC) replicate relatively slowly, to minimize accumulation of mutations in these parent cells [33, 34]
Our aims are two-fold, first, define the influence of blood cell lineage and composition on the epiTOC estimated mitotic age using DNA methylation (DNAm) from purified blood cells, and with whole-blood DNAm, associate epigenetic mitotic aging with Parkinson’s disease (PD) considering the impact of cell composition
Summary
The human blood-system performs numerous vital functions, including the circulation of oxygen and nutrients, temperature homeostasis, and constant immune surveillance of the entire body [1]. Aging and inflammation are important components of Parkinson’s disease (PD) pathogenesis and both are associated with changes in hematopoiesis and blood cell composition. We aimed to define the influence of blood cell lineage on epigenetic mitotic age and investigate mitotic age acceleration with PD, while considering epigenetic age acceleration biomarkers. PD patients exhibit an accelerated hematopoietic mitotic tick rate relative to controls independent of age, which is reflective of chronic, low-level systemic immune activation, inflammation, and PDspecific pathogenesis. We aimed to investigate whether the epigenetic mitotic tick rate, as an indicator of the proliferative history of blood and hematopoiesis, is associated with early PD and longitudinal PD symptom development among patients. Given differences in cell turnover rate, the number of cells required daily for homeostasis, and lineage-dependent daily proliferation, different cell types within a whole-blood sample likely have different proliferative histories. (3) DNAm heterogeneity exists between blood cell types and cellular composition may explain substantial variability observed in whole-blood DNAm [35].
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