Comprehensive transcriptional landscape of aging mouse liver

White, Ryan R.; Milholland, Brandon; MacRae, Sheila L.; Lin, Mingyan; Zheng, Deyou; Vijg, Jan

doi:10.1186/s12864-015-2061-8

Cited by 100 publications

(101 citation statements)

References 62 publications

(88 reference statements)

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“…Recent studies using high‐throughput RNA sequencing technology have revealed that the expression of mammalian mRNAs changes extensively during the aging process (Baumgart et al., 2016; White et al., 2015). The dynamic expression of mRNAs is mainly governed by transcription and decay via their interactions with trans‐regulatory factors (e.g., RNA‐binding proteins and noncoding RNAs) and cis‐regulatory elements (specific sequences on mRNAs for RNA‐binding protein interaction, miRNA targeting, RNA modification, etc.)…”

Section: Introductionmentioning

confidence: 99%

Profiling of m6A RNA modifications identified an age‐associated regulation of AGO2 mRNA stability

et al. 2018

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SummaryGene expression is dynamically regulated in a variety of mammalian physiologies. During mammalian aging, there are changes that occur in protein expression that are highly controlled by the regulatory steps in transcription, post‐transcription, and post‐translation. Although there are global profiles of human transcripts during the aging processes available, the mechanism(s) by which transcripts are differentially expressed between young and old cohorts remains unclear. Here, we report on N6‐methyladenosine (m6A) RNA modification profiles of human peripheral blood mononuclear cells (PBMCs) from young and old cohorts. An m6A RNA profile identified a decrease in overall RNA methylation during the aging process as well as the predominant modification on proteincoding mRNAs. The m6A‐modified transcripts tend to be more highly expressed than nonmodified ones. Among the many methylated mRNAs, those of DROSHA and AGO2 were heavily methylated in young PBMCs which coincided with a decreased steady‐state level of AGO2 mRNA in the old PBMC cohort. Similarly, downregulation of AGO2 in proliferating human diploid fibroblasts (HDFs) also correlated with a decrease in AGO2 mRNA modifications and steady‐state levels. In addition, the overexpression of RNA methyltransferases stabilized AGO2 mRNA but not DROSHA and DICER1 mRNA in HDFs. Moreover, the abundance of miRNAs also changed in the young and old PBMCs which are possibly due to a correlation with AGO2 expression as observed in AGO2‐depleted HDFs. Taken together, we uncovered the role of mRNA methylation on the abundance of AGO2 mRNA resulting in the repression of miRNA expression during the process of human aging.

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Section: Introductionmentioning

confidence: 99%

Profiling of m6A RNA modifications identified an age‐associated regulation of AGO2 mRNA stability

et al. 2018

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“…This has frequently been observed in microarray comparisons between young and old mouse tissues, which have revealed elevated expression of immune cell-derived proteins, such as Mrp8 and Mrp14 [29, 30, 37–40]. We hypothesized that elevated Mrp8/Mrp14 expression with aging drives accumulation of immune cells within aging tissues.…”

Section: Discussionmentioning

confidence: 88%

“…We chose liver as a model system to study inflammaging because (i) Mrp8 and Mrp14 mRNAs are robustly elevated in old versus young liver [3], (ii) stress-dependent differences in hepatic inflammation have been identified between WT and KO mice [18, 19], and (iii) hepatic inflammation is a robust feature of aging that has been well-characterized by previous work [27–29]. Our findings reveal unexpected gene expression differences between WT and KO mice at a young age (in the absence of physiological stress), and address the hypothesis that Mrp8 and Mrp14 accumulation promotes age-related inflammation.…”

Section: Introductionmentioning

confidence: 99%

Deficiency of myeloid-related proteins 8 and 14 (Mrp8/Mrp14) does not block inflammaging but prevents steatosis

et al. 2016

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The Mrp8 and Mrp14 proteins (calprotectin) accumulate within tissues during aging and may contribute to chronic inflammation. To address this possibility, we evaluated female calprotectin-deficient Mrp14-KO and wild-type (WT) mice at 5 and 24 months of age. However, there was no evidence that age-related inflammation is blunted in KO mice. Inflammation markers were in fact elevated in livers from old KO mice, and microarray analysis revealed more consistent elevation of genes specifically expressed by B-cells and T-cells. Adipose-specific genes, however, were less consistently elevated in aged KO mice, suggesting an anti-steatosis effect of Mrp8/14 deficiency. Consistent with this, genes decreased by the anti-steatosis agent SRT1720 were decreased in old KO compared to old WT mice. Expression of lipid metabolism genes was altered in KO mice at 5 months of age, along with genes associated with development, biosynthesis and immunity. These early-age effects of Mrp8/14 deficiency, in the absence of any external stressor, were unexpected. Taken together, our findings demonstrate a pro-steatosis rather than pro-inflammatory role of calprotectin within the aging liver. This appears to reflect a developmental-metabolic phenotype of Mrp14-KO mice that is manifest at a young age in the absence of pro-inflammatory stimuli.

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“…It has been known for quite some time that the fraction of the genome dedicated to regulation is much larger than the fraction that codes for amino acids, so it is time we gave the regulatory region its due. Indeed, it is now becoming apparent that not only does gene expression become increasingly disordered between cells with age (Bahar et al, 2006) but also that both natural aging and DNA damage-induced premature aging are accompanied by large-scale transcriptomic alterations, including increased variation in gene expression (White et al, 2015a, 2015b). …”

Section: The Somatic Mutation Catastrophe Theory Of Agingmentioning

confidence: 99%

Mutation and catastrophe in the aging genome

Milholland

Suh

Vijg

2017

Experimental Gerontology

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In the 1960s, Leslie Orgel proposed what is now known as the error catastrophe theory of aging, arguing that errors in protein translation that reduce the fidelity of the protein-translating enzymes would lead to a feedback loop of increasingly inaccurate protein synthesis, terminating in the death of the organism. This mechanism of aging would be consistent with the exponential increase of mortality observed in humans, but the error catastrophe theory of aging has been generally disregarded by researchers due to a lack of evidence for an age-related increase in protein errors. Another theory of aging, proposed at roughly the same time, is Leo Szilard’s two-hit model of somatic mutation accumulation, which assumed a linear increase in mutations over time but explained the nonlinear pattern of human mortality through a mechanism of genetic and cellular redundancy which kept mortality low until the redundancy was exhausted, at which point mortality rapidly rose. Here, we synthesize the two theories, along with the latest advances in genomics research. We propose a new catastrophe theory of aging, this time with somatic mutations as the primary agent of the feedback loop. Similar to protein errors affecting translation itself, somatic mutations in genes involved in DNA replication and repair would lead to a feedback loop of exponentially increasing mutation load. The difference from protein errors is that somatic mutations would mainly affect gene regulatory regions rather than the much smaller part of the genome encoding protein-coding information. Although the self-stimulating accumulation of somatic mutations is not mutually exclusive with the Szilard-based loss of redundancy, we present evidence that suggests that the accumulated mutations themselves could be numerous enough to cause mortality. Finally, we acknowledge the limits of our current knowledge and propose a course of research practices that will help to confirm or refute our model and advance the field of aging research as a whole.

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Comprehensive transcriptional landscape of aging mouse liver

Cited by 100 publications

References 62 publications

Profiling of m6A RNA modifications identified an age‐associated regulation of AGO2 mRNA stability

Profiling of m6A RNA modifications identified an age‐associated regulation of AGO2 mRNA stability

Deficiency of myeloid-related proteins 8 and 14 (Mrp8/Mrp14) does not block inflammaging but prevents steatosis

Mutation and catastrophe in the aging genome

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