Maximum lifespan of a species is the oldest that individuals can survive, reflecting the genetic limit of longevity in an ideal environment. Here we report methylation-based models that accurately predict maximum lifespan (r=0.89), gestational time (r=0.96), and age at sexual maturity (r=0.87), using cytosine methylation patterns collected from over 12,000 samples derived from 192 mammalian species. Our epigenetic maximum lifespan predictor corroborated the extended lifespan in growth hormone receptor knockout mice and rapamycin treated mice. Across dog breeds, epigenetic maximum lifespan correlates positively with breed lifespan but negatively with breed size. Lifespan-related cytosines are located in transcriptional regulatory regions, such as bivalent chromatin promoters and polycomb-repressed regions, which were hypomethylated in long-lived species. The epigenetic estimators of maximum lifespan and other life history traits will be useful for characterizing understudied species and for identifying interventions that extend lifespan.

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.

SummaryBackgroundSerum small dense LDL-cholesterol (sdLDL-C) value is suggested to bean important risk factor for atherosclerosis. Since sdLDL-C changes may be related to PCSK9 and SREBP-2 functions, the aim of this study was to investigate correlations between sdLDL-C, circulating PCSK9, SREBP-2 expression and some lipid parameters in serum and butty coat fraction of healthy subjects.MethodsOne hundred and twenty-four subjects were randomly included in the study. The lipid profile was measured using routine laboratory methods. The serum sdLDL-C level was calculated by a heparin-related precipitation technique. The cellular LDL-C/protein and cholesterol/protein values were measured after lysing of cells with methanol/chloroform binary solvent. The circulating PCSK9 level was measured using ELISA technique. The SREBP-2 expression level was estimated using theRT-qPCR technique.ResultsData showed significant correlations between LDL-C, TG and sdLDL-C levels (r=0.34, p=0.001; r=0.2, p=0.04). The circulating PCSK9 level was correlated to LDL-C (r=0.29, p=0.04), but not to sdLDL-C (r=-0.08, p=0.57). Also, cellular LDL-C value was not related to serum LDL-C level (r=-0.12, p=0.39). Furthermore, there was an inverse correlation between cellular LDL-C/protein value and estimated de novo cholesterol/protein value (r= -0.5, p=0.001). Similar results were observed for cellular LDL-C/protein value and SREBP-2 expression level (r= -0.52, p=0.004).ConclusionsWe concluded that the serum sdLDL-C value is not related to circulating PCSK9. Furthermore, SREBP-2 regulatory system was able to elevate the cellular cholesterol level after reducing LDL influx. We suggest to investigate the cellular sdLDL fate and lipid synthesis pathways in PCSK9-targeting studies.

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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. 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. 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. 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.