Identifying epigenetic aging moderators using the epigenetic pacemaker

Epigenetic clocks are DNA methylation-based chronological age prediction models that are commonly employed to study age-related biology. The difference between the predicted and observed age is often interpreted as a form of biological age acceleration, and many studies have measured the impact of environmental and disease-associated factors on epigenetic age. Most epigenetic clocks are fit using approaches that minimize the error between the predicted and observed chronological age, and as a result, they may not accurately model the impact of factors that moderate the relationship between the actual and epigenetic age. Here, we compare epigenetic clocks that are constructed using penalized regression methods to an evolutionary framework of epigenetic aging with the epigenetic pacemaker (EPM), which directly models DNA methylation as a function of a time-dependent epigenetic state. In simulations, we show that the value of the epigenetic state is impacted by factors such as age, sex, and cell-type composition. Next, in a dataset aggregated from previous studies, we show that the epigenetic state is also moderated by sex and the cell type. Finally, we demonstrate that the epigenetic state is also moderated by toxins in a study on polybrominated biphenyl exposure. Thus, we find that the pacemaker provides a robust framework for the study of factors that impact epigenetic age acceleration and that the effect of these factors may be obscured in traditional clocks based on linear regression models

Is Evolution of Blind Mole Rats Determined by Climate Oscillations?

The concept of climate variability facilitating adaptive radiation supported by the ‘‘Court Jester’’ hypothesis is disputed by the ‘‘Red Queen’’ one, but the prevalence of one or the other might be scale-dependent. We report on a detailed, comprehensive phylo-geographic study on the ,4 kb mtDNA sequence in underground blind mole rats of the family Spalacidae (or subfamily Spalacinae) from the East Mediterranean steppes. Our study aimed at testing the presence of periodicities in branching patterns on a constructed phylogenetic tree and at searching for congruence between branching events, tectonic history and paleoclimates. In contrast to the strong support for the majority of the branching events on the tree, the absence of support in a few instances indicates that network-like evolution could exist in spalacids. In our tree, robust support was given, in concordance with paleontological data, for the separation of spalacids from muroid rodents during the first half of the Miocene when open, grass-dominated habitats were established. Marine barriers formed between Anatolia and the Balkans could have facilitated the separation of the lineage ‘‘Spalax’’ from the lineage ‘‘Nannospalax’’ and of the clade ‘‘leucodon’’ from the clade ‘‘xanthodon’’. The separation of the clade ‘‘ehrenbergi’’ occurred during the late stages of the tectonically induced uplift of the Anatolian high plateaus and mountains, whereas the separation of the clade ‘‘vasvarii’’ took place when the rapidly uplifting Taurus mountain range prevented the Mediterranean rainfalls from reaching the Central Anatolian Plateau. The separation of Spalax antiquus and S. graecus occurred when the southeastern Carpathians were uplifted. Despite the role played by tectonic events, branching events that show periodicity corresponding to 400-kyr and 100-kyr eccentricity bands illuminate the important role of orbital fluctuations on adaptive radiation in spalacids. At the given scale, our results supports the ‘‘Court Jester’’ hypothesis over the ‘‘Red Queen’’ one