Changes in the Regulation of the Unfolded Protein Response During Aging in Peromyscus

Endoplasmic reticulum (ER) stress has been linked to various metabolic pathologies, neurodegeneration, and aging. Although various mechanistic aspects of the resulting unfolded protein response (UPR) have been elucidated, its regulation in genetically diverse populations remains elusive. In the present study we evaluated the expression of chaperones BiP/GRP78, GRP94 and calnexin (CANX) in the lungs, liver, and brain of 7 months old and 2–3 years old outbred deer mice P. maniculatus and P. leucopus. Chaperones’ _expression was highly variable between species, tissues and ages suggesting that levels of expression of individual chaperones do not change consistently during aging. Despite this variation, a high degree of coordination was maintained between chaperones’ _expression indicating the tight regulation of the UPR which is consistent with its adaptive activity to maintain homeostasis. In the brain though of older P. maniculatus, at which neurodegenerative changes were detected, loss of coordination was revealed, especially between BiP and either of GRP94 or calnexin which indicates that de-coordination rather than aberrant expression is linked to deregulation of the UPR in aging. These findings underscore the involvement of UPR in the onset of aging-related pathologies and suggest that beyond levels of expression, concerted activation may be of significance to attain homeostasis. These findings emphasize the value of genetically diverse models and suggest that beyond levels of expression of individual targets the coordination of transcriptional networks should be considered when links to pathology are explored. Genes that belong to the same network are frequently co-expressed, but collectively, how the coordination of the whole transcriptome is perturbed during aging remains unclear. To explore this, we calculated the correlation of each gene in the transcriptome with every other, in the brain of young and older outbred deer mice (P. leucopus and P. maniculatus) and also, we evaluated the coordination of chaperons expression during aging with whole trascriptome. In about 25 % of the genes, coordination was inversed during aging. Gene Ontology analysis in both species, for the genes that exhibited inverse transcriptomic coordination during aging pointed to alterations in the perception of smell, a known impairment occurring during aging. In P. leucopus, alterations in genes related to cholesterol metabolism were also identified. Among the genes that exhibited the most pronounced inversion in their coordination profiles during aging was THBS4, that encodes for thrombospondin 4, a protein that was recently identified as rejuvenation factor in mice. Relatively to its breadth, abolishment of coordination was more prominent in the long-living P. leucopus than in P. maniculatus but in the latter, the intensity of de-coordination was higher. The results suggest that aging is associated with more stringent retention of expression profiles for some genes and more abrupt changes in others, while more subtle but widespread changes in gene expression appear protective. Our findings shed light in the mode of the transcriptional changes occurring in the brain during aging and suggest that strategies aiming to broader but more modest changes in gene expression may be preferrable to correct aging-associated deregulation in gene expression

Methylation studies in Peromyscus: aging, altitude adaptation, and monogamy.

DNA methylation-based biomarkers of aging have been developed for humans and many other mammals and could be used to assess how stress factors impact aging. Deer mice (Peromyscus) are long-living rodents that have emerged as an informative model to study aging, adaptation to extreme environments, and monogamous behavior. In the present study, we have undertaken an exhaustive, genome-wide analysis of DNA methylation in Peromyscus, spanning different species, stocks, sexes, tissues, and age cohorts. We describe DNA methylation-based estimators of age for different species of deer mice based on novel DNA methylation data generated on highly conserved mammalian CpGs measured with a custom array. The multi-tissue epigenetic clock for deer mice was trained on 3 tissues (tail, liver, and brain). Two human-Peromyscus clocks accurately measure age and relative age, respectively. We present CpGs and enriched pathways that relate to different conditions such as chronological age, high altitude, and monogamous behavior. Overall, this study provides a first step towards studying the epigenetic correlates of monogamous behavior and adaptation to high altitude in Peromyscus. The human-Peromyscus epigenetic clocks are expected to provide a significant boost to the attractiveness of Peromyscus as a biological model

Correlation of PCSK9 and Serum sdLDL Levels and Other Demographic and Laboratory Indicators in Healthy Individuals

Background and Objectives: Atherosclerosis is a type of cardiovascular disease (CVD), which is known as the most important cause of death in the world. In atherosclerosis, arteries get thicker due to the entry of lipids and become inflamed. Epidemiological studies have shown that in addition to demographic and laboratory factors (age, sex, cholesterol, smoking, hypertension, obesity, and diabetes), genetic factors are also associated with progression of atherosclerosis. LDL-C is one of the most important risk factors for cardiovascular disease. In this study, the relationship of PCSK9 levels with serum sdLDL-C levels and other variables, was investigated. &nbsp; Methods: In this cross-sectional study, a total of 126 individuals (68 Men and 58 women), were studied. Serum PCSK9 concentration, was measured using quantitative sandwich ELISA; serum sdLDL-C levels were measured using precipitation method; and other laboratory parameters were measured by routine methods. Data were analyzed by statistical tests of Kolmogorov-Smirnov, Pearson linear regression, and t- tests. The significance level was considered p<0.05. &nbsp; Results: PCSK9 levels had a significant correlation with total cholesterol (r=0.3, p=0.001) and LDL-C (r=0.3, p=0.001). In addition, there was a significant correlation between sdLDL-C/LDL-C and sdLDL-C (r=0.875, p<0.001); however, PCSK9 did not correlate with sdLDL-C and other parameters. &nbsp; Conclusion: The results of this study showed that PCSK9 variations are associated with lipid profile, but although sdLDL-C level is associated with lipid profile, it is not affected by PCSK9. &nbsp; &nbsp

DNA methylation networks underlying mammalian traits

Using DNA methylation profiles ( n = 15,456) from 348 mammalian species, we constructed phyloepigenetic trees that bear marked similarities to traditional phylogenetic ones. Using unsupervised clustering across all samples, we identified 55 distinct cytosine modules, of which 30 are related to traits such as maximum life span, adult weight, age, sex, and human mortality risk. Maximum life span is associated with methylation levels in HOXL subclass homeobox genes and developmental processes and is potentially regulated by pluripotency transcription factors. The methylation state of some modules responds to perturbations such as caloric restriction, ablation of growth hormone receptors, consumption of high-fat diets, and expression of Yamanaka factors. This study reveals an intertwined evolution of the genome and epigenome that mediates the biological characteristics and traits of different mammalian species

DNA methylation networks underlying mammalian traits

Using DNA methylation profiles ( = 15,456) from 348 mammalian species, we constructed phyloepigenetic trees that bear marked similarities to traditional phylogenetic ones. Using unsupervised clustering across all samples, we identified 55 distinct cytosine modules, of which 30 are related to traits such as maximum life span, adult weight, age, sex, and human mortality risk. Maximum life span is associated with methylation levels in subclass homeobox genes and developmental processes and is potentially regulated by pluripotency transcription factors. The methylation state of some modules responds to perturbations such as caloric restriction, ablation of growth hormone receptors, consumption of high-fat diets, and expression of Yamanaka factors. This study reveals an intertwined evolution of the genome and epigenome that mediates the biological characteristics and traits of different mammalian species