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NIH Team Finds miRNAs that Differentiate Young and Old with Dx Potential for Age-related Diseases

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A team of researchers from the National Institutes of Health has identified three circulating microRNAs that were differentially expressed in the serum of older versus younger individuals in a small sequencing study.

Based on pathway analysis, the group showed that the three molecules — which were downregulated in older subjects compared to younger subjects — are likely involved in inflammation and may be a biological marker of the aging process.

Further research should help better determine the mechanism of the miRNAs' downregulation during aging, as well as how they might be used as potential diagnostic or therapeutic tools for aging and age-related diseases, the authors wrote in the study, which appeared in the October issue of the journal Aging.

The study authors were unavailble to comment on the findings due to the US Government shutdown, but they wrote in their report that although they and others have previously identified age-dependant miRNAs in peripheral blood mononuclear cells, little has been known prior to this new study about the role of circulating, or cell-free, miRNAs in aging.

According to the authors, because miRNAs are key regulators of gene expression, which has been shown to play a definitive role in regulating lifespan in emerging data, there has been great interest in discovering stable miRNA biomarkers in serum that could potentially be used as a noninvasive diagnostic or prognostic tool for age-related disease or normal aging.

In the study, the team performed Illumina small-RNA next-generation sequencing on serum samples from 11 younger subjects with an average age of 30 and 11 older subjects with an average age of 64 from a cohort from the Healthy Aging in Neighborhoods of Diversity across the Lifespan study, a community-based longitudinal epidemiologic study examining the influences of race and socioeconomic status on the development of age-related health disparities among socioeconomically diverse African Americans and whites in Baltimore.

The researchers followed this genome-wide assessment with real-time PCR in a slightly larger cohort of 20 older and 20 younger individuals, focusing on the five miRNAs with the highest number of sequencing reads from their initial sequencing analysis.

Based on the PCR results, the group identified three serum miRNAs that were significantly decreased in older individuals compare to younger individuals: miR151a-3p, miR-181a-5p, and miR-1248. Two others, miR-3607-3p and miR-3607-5p, were also decreased in the older arm of the validation cohort, however, the difference was not statistically significant.

According to the study authors, a recent study by an Italian group found another miRNA, miR-21, to be upregulated in the serum of individuals over 66 compared to those under 66. To test this, the NIH team also examined the expression of miR-21, but did not find any significant differences between the younger and older cohorts in its study.

To gain a sense of the biological role of the three differentially expressed miRNAs they identified, the researchers used pathway analysis tools to predict potential targets of the molecules.

According to the authors, all three miRNAs were predicted to be important for survival and development, and also appeared likely to be involved in inflammatory processes, through pathways involving NFkB, TNFa, and TNF/IL-1/INF-a.

In addition, "cancer and neurological disease overlapped among all three miRNAs, consistent with the fact that age is a significant risk factor for these two diseases," the authors wrote.

Interestingly, the group also was able to show that the same miRNAs that they found expressed in human serum were also present in the serum of Rhesus monkeys, and that miR-151-5p and miR-1248 also significantly decreased with advancing monkey age.

According to the authors, the finding has potential to yield new tools for diagnosing and treating age-related disease, and for better understanding the physiological process of natural aging.

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