A previous report of DNA methylation dynamics across 17 hematopoietic cell types found that the distribution of DNA methylation levels was similar across all stem and progenitor cell types, while there was a shift toward lower methylation levels in differentiated cells of the myeloid lineage [38]

A previous report of DNA methylation dynamics across 17 hematopoietic cell types found that the distribution of DNA methylation levels was similar across all stem and progenitor cell types, while there was a shift toward lower methylation levels in differentiated cells of the myeloid lineage [38]. as covariates in the same model. 12864_2021_8009_MOESM5_ESM.docx (15K) GUID:?8468C319-5B6D-4E0C-9C45-4B234751C482 Additional file 6:?Supplemental Table 5. Output from logistic regression model of PD, with AccelEpiTOC and all covariates, stratified by Sex. All terms included as covariates in the same model. Model 2, includes other DNAm age markers. 12864_2021_8009_MOESM6_ESM.docx (16K) GUID:?9D16578A-4003-4D44-8890-738A5BF2811B Additional file 7: Supplemental Figure 1. Best fitting logistic model of PD. 12864_2021_8009_MOESM7_ESM.docx (22K) GUID:?84A541E5-98F0-4FDD-9A50-9A2DA58F60C4 Data Availability StatementThe datasets analyzed during the current study are available in the GEO repository, accession numbers “type”:”entrez-geo”,”attrs”:”text”:”GSE72774″,”term_id”:”72774″GSE72774 and “type”:”entrez-geo”,”attrs”:”text”:”GSE72776″,”term_id”:”72776″GSE72776 (PEG), and the purified blood cell DNAm data at “type”:”entrez-geo”,”attrs”:”text”:”GSE35069″,”term_id”:”35069″GSE35069. Abstract Background Aging and inflammation are important components of Parkinsons disease (PD) pathogenesis and both are associated with changes in hematopoiesis and Prohydrojasmon racemate blood cell composition. DNA methylation (DNAm) presents a mechanism to investigate inflammation, aging, and hematopoiesis in PD, using epigenetic mitotic Prohydrojasmon racemate aging and aging Prohydrojasmon racemate 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. Results We 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 Rabbit Polyclonal to Smad2 (phospho-Ser465) 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, and the presence of Lewy bodies, intraneuronal aggregates composed of misfolded -synuclein (Syn) [9, 10]. There is now ample research that shows that important, systemic immune signals originating outside the brain contribute to PD pathogenesis [11, 12]. Immunosenescence, defined as age-related changes in the immune system, and inflamm-aging, or chronic, low-level inflammatory states, have also been widely linked to neurodegenerative changes and PD, summarized in a number of meta-analyses and reviews [13C18]. Recent reports further indicate that inflamm-aging propagates from the periphery to the brain and vice versa [19]. Additionally, Syn is notably also widely expressed and abundant in hematopoietic cells as well as neurons [20]. While our understanding of the function of Syn both peripherally and within the central nervous system (CNS) is still developing, several studies have indicated that it may play an important role in the hematopoietic system related to exo- and endocytosis, apoptosis, autophagy, maturation, and differentiation of hematopoietic cells [20C23]. Thus, there is good rationale to study the intersection between inflammation, aging, and hematopoiesis in PD. Changes in DNA methylation (DNAm) patterns have been observed to track cell divisions and reflect the proliferative history of different tissues [24C26]. During cell division, DNAm changes occur that appear to accumulate in the stem cells of a tissue in line with and representing the stem cell division rate and chronologic age [24, 27]. These DNAm changes are the basis for the DNAm epigenetic mitotic clock, epiTOC (Epigenetic Timer of Cancer), a biomarker that uses methylation patterns to provide an estimate of the relative stem cell division rate of a tissue in an individual [24]. This epigenetic mitotic clock enumerates cellular proliferation of the tissue (i.e. the number of cell divisions) and records the acceleration of the mitotic tick rate, or measure of cell divisions, beyond what would be expected with aging based on controls [24]. The epiTOC epigenetic mitotic tick rate has been found to be universally accelerated in cancer tissues and pre-cancerous lesions [24]. Here we propose that the epigenetic mitotic tick rate, tracking the mitotic history of circulating leukocytes with whole-blood DNAm, may also have intriguing implications for Parkinsons and other diseases of aging with inflamm-aging and immune-related components. Furthermore, while the epigenetic mitotic clock represents the history of cell divisions of blood cells, epigenetic aging clocks (i.e. DNAm biomarkers of aging), are reflective of the biologic aging process of the tissue [28]. Our previous research indicates that PD patients show more advanced biologic aging markers (i.e. faster biologic than chronologic aging) than controls, with accelerated immune system aging showing the strongest associations of the blood-based measures [29C31]. Alterations in immune profiles in PD patients measured with blood epigenetics have since been replicated [32]. We will now further.