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Abstract
A growing body of research shows that epigenetic mechanisms are critically involved in normal and pathological aging. The Senescence-Accelerated Mouse Prone 8 (SAMP8) can be considered a useful tool to better understand the dynamics of the global epigenetic landscape during the aging process since its phenotype is not fully explained by genetic factors. Here we investigated dysfunctional age-related transcriptional profiles and epigenetic programming enzymes in the hippocampus of 2- and 9-month-old SAMP8 female mice using the Senescent-Accelerated Resistant 1 (SAMR1) mouse strain as control. SAMP8 mice presented 1,062 genes dysregulated at 2 months of age, and 1,033 genes at 9 months, with 92 genes concurrently dysregulated at both ages compared to age-matched SAMR1. SAMP8 mice showed a significant decrease in global DNA methylation (5-mC) at 2 months while hydroxymethylation (5-hmC) levels were increased in SAMP8 mice at 2 and 9 months of age compared to SAMR1. These changes were accompanied by changes in the expression of several enzymes that regulate 5-mC and methylcytosine oxidation. Acetylated H3 and H4 histone levels were significantly diminished in SAMP8 mice at 2-month-old compared to SAMR1 and altered Histone DeACetylase (HDACs) profiles were detected in both young and old SAMP8 mice. We analyzed 84 different mouse miRNAs known to be altered in neurological diseases or involved in neuronal development. Compared with SAMR1, SAMP8 mice showed 28 and 17 miRNAs differentially expressed at 2 and 9 months of age, respectively; 6 of these miRNAs overlapped at both ages. We used several bioinformatic approaches to integrate our data in mRNA:miRNA regulatory networks and functional predictions for young and aged animals. In sum, our study reveals interplay between epigenetic mechanisms and gene networks that seems to be relevant for the progression toward a pathological aging and provides several potential markers and therapeutic candidates for Alzheimer's Disease (AD) and age-related cognitive impairment.
Highlights
With the dramatic rise in life expectancy, the prevention or delay of age-related cognitive decline is becoming a critical issue to improve human health-span (Prince et al, 2013, 2015)
Several genes were altered in SAMP8 mice compared to SAMR1 mice
Genes differentially expressed in SAMP8 and SAMR1 mice at 2 and 9 months of age were integrated into a Venn diagram
Summary
With the dramatic rise in life expectancy, the prevention or delay of age-related cognitive decline is becoming a critical issue to improve human health-span (Prince et al, 2013, 2015). Aging is a multifaceted process in the continuous, progressive, and inevitable cycle of life; it is responsible for various depletive alterations in the physiological function of organisms and is molecularly associated with an increase in transcriptional noise (López-Otín et al, 2013). Research on age-related disorders has recently focused in epigenetic mechanisms since they are known to regulate gene expression in a stable and potentially reversible way and allow for the integration of long-lasting non-genetic inputs in the genome. A growing number of investigations have revealed that epigenetic mechanisms can modify the gene expression of processes involved in the etiopathological processes of Alzheimer’s Disease (AD): Oxidative Stress (OS); mitochondrial and immune function; neuroinflammation and neurotoxicity (Wang et al, 2008; Gräff et al, 2012; Hendrickx et al, 2014; Iwata et al, 2014; Gjoneska et al, 2015; Yu et al, 2015; Grossi et al, 2016; Smith et al, 2016). The etiology of the disease remains unclear, studies in both humans and rodents have shown that gene expression dysregulation is present in the development and progression of the emerging pathology (Heerboth et al, 2014; Mufson et al, 2016; Block and El-Osta, 2017)
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