Age‐associated microRNA expression in human peripheral blood is associated with all‐cause mortality and age‐related traits

Abstract

SummaryRecent studies provide evidence of correlations of DNA methylation and expression of protein‐coding genes with human aging. The relations of microRNA expression with age and age‐related clinical outcomes have not been characterized thoroughly. We explored associations of age with whole‐blood microRNA expression in 5221 adults and identified 127 microRNAs that were differentially expressed by age at P < 3.3 × 10−4 (Bonferroni‐corrected). Most microRNAs were underexpressed in older individuals. Integrative analysis of microRNA and mRNA expression revealed changes in age‐associated mRNA expression possibly driven by age‐associated microRNAs in pathways that involve RNA processing, translation, and immune function. We fitted a linear model to predict ‘microRNA age’ that incorporated expression levels of 80 microRNAs. MicroRNA age correlated modestly with predicted age from DNA methylation (r = 0.3) and mRNA expression (r = 0.2), suggesting that microRNA age may complement mRNA and epigenetic age prediction models. We used the difference between microRNA age and chronological age as a biomarker of accelerated aging (Δage) and found that Δage was associated with all‐cause mortality (hazards ratio 1.1 per year difference, P = 4.2 × 10−5 adjusted for sex and chronological age). Additionally, Δage was associated with coronary heart disease, hypertension, blood pressure, and glucose levels. In conclusion, we constructed a microRNA age prediction model based on whole‐blood microRNA expression profiling. Age‐associated microRNAs and their targets have potential utility to detect accelerated aging and to predict risks for age‐related diseases.

Circulating small non-coding RNAs associated with age, sex, smoking, body mass and physical activity

“…In agreement with our results, ageing was reported to be more strongly associated with miRNA expression than sex 29 . miRNA-320b was found to be age-related in both our study and in a large study on whole blood 31 . We found that the age-associated pathways are mostly signalling pathways such as Ras, PI3K-Akt, MAPK and AMPK.…”

“…127 of 150 miRNAs analysed were shown to be affected by age in a study on wholeblood from 5221 individuals. A miRNA age prediction model was developed using this large dataset and the miRNA predicted age correlated with chronological age with an r=0.61 adjusted for cell type composition 31 . Transforming growth factor beta signalling has been suggested as one of the main pathways regulated by the differentially expressed circulating miRNAs 32 .…”

A functional variant in the miR‐142 promoter modulating its expression and conferring risk of Alzheimer disease

“…Moreover, Sorensen, Nygaard, and Christensen () performed miRNA expression profiles in CSF and blood of patients with AD and found a number of differentially expressed miRNAs, in which miR‐142 is one of the significantly upregulated miRNAs in patients with AD compared to controls. Two independent studies also revealed that the expression of miR‐142 is increased by age (Huan et al, ; Zhang, Azhar, & Wei, ). Here, our expression data confirmed that both mature miR‐142‐3p and ‐5p are expressed at relatively high levels in the brain; though, our RNA‐Seq analysis proposed miR‐142‐3p, which is the guide strand of miR‐142, to be more active in the regulation of its target genes in the brain.…”

“…Convergent evidence from multiple investigations also indicates the expression of miR-142 in the brain, suggesting that dysregulation or malfunction of miR-142 contribute to the pathogenesis of brain disorders. For instance, Junker et al (2009) reported miR-142 among the 10 miRNAs that are more abundant in active multiple sclerosis (MS) independent studies also revealed that the expression of miR-142 is increased by age (Huan et al, 2018;Zhang, Azhar, & Wei, 2012).…”

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

“…These mRNAs include IGF1R , INSR , IRS2 , HMGA2 , and IGFBP2 (Zhu et al., 2011) which are essential for energy metabolism, a key aspect of cellular senescence. A recent study analyzed a large number of blood samples from Framingham Heart Study (FHS) participants and investigated if miRNA expression is related to chronological age in FHS participants (Huan et al., 2017). They observed most miRNA were underexpressed in old individuals; however, let‐7 family members were not found as age‐associated miRNAs in their study, possibly due to a large sample size with a wide age range compared with our study.…”