MicroRNA Differences Across the Course of Aging Correlate with Life Span
A cell might be considered a state machine whose state and state transitions are determined by the amounts of various proteins present. The process of gene expression by which genetic blueprints are converted into proteins is enormously complex, and a large fraction of the various types of molecule assembled inside a cell have much more to do with manipulating the steps involved in gene expression than with other cellular activities. Every facet of gene expression, from the pace at which proteins are produced to which protein is produced when there are multiple options for a given stretch of DNA, is subject to a constant, ever-changing set of interactions, feedback loops between production and influence over production. Researchers are these days putting a great deal of effort into mapping the classes of protein machinery involved in regulation of gene expression, such as microRNAs (miRNA), and some of that work is focused on aging:
Biomarkers of aging are biological parameters that change in a predictable direction with aging in most individuals and, when assessed early in life, may predict subsequent longevity better than chronological age alone. Beyond their prognostic utility, the discovery of biomarkers of aging is attractive because they may shed light into the intrinsic mechanism of aging as a biological process. Identifying biomarkers of aging may also provide insight into the biological mechanisms that accelerate or decelerate aging. miRNAs have emerged as important regulators of biological mechanisms that are relevant for aging. miRNAs are short non-coding RNAs that regulate gene expression. With over 1800 human miRNAs reported, miRNAs influence a wide range of biological functions, such as stem cell self-renewal, cell proliferation, apoptosis, and metabolism.
Profiles of miRNAs found in plasma and serum have been linked to numerous cancers, cognitive impairment, Alzheimer's disease and other neurodegenerative disorders, and other pathologies, indicating that miRNAs are a new class of biomarkers of human diseases present in blood. Because of the close relationship between these diseases and longevity, miRNAs may also serve as biomarkers of human aging. Our prior work has shown that miRNAs can serve as genetic biomarkers of aging in the nematode C. elegans. Because miRNAs and aging genetic pathways are conserved from nematodes to humans, an increasing number of human miRNA studies have been carried out over the past several years. These studies have shown differential abundance of multiple miRNAs in peripheral blood mononuclear cells (PBMCs) or serum/plasma when comparing younger and older adults. We used miRNA PCR arrays to measure miRNA levels in serum samples obtained longitudinally at ages 50, 55, and 60 from 16 participants of the Baltimore Longitudinal Study of Aging (BLSA) who had documented lifespans. We compared miRNA expression changes not only across (i.e., between older and younger participants) but also within participants (using the three samples taken at different ages from each individual). In accordance with recent research that found a strong association between circulating miRNAs and human aging, our study suggests that circulating miRNAs are biomarkers of longevity.
Many interesting expression profiles were observed between study participants with different lifespans. For example, when comparing samples analyzed at age 50 between the long-lived and short-lived subgroups, we identified the 10 most differentially higher and lower expressed miRNAs. The most upregulated miRNA in long-lived participants, miR-373-5p, is part of the miR-373 family, which functions as a tumor suppressor in breast cancer. The most downregulated miRNA in long-lived participants, miR-15b-5p, has been found to be upregulated in oral cancer cells. Because lifespan is a complex trait characterized by escaping, delaying, or surviving fatal age-related diseases, including cancers, further scrutiny of the potential roles of the identified miRNAs in human aging is of great importance and interest. Six of the nine miRNAs (miR-211-5p, 374a-5p, 340-3p, 376c-3p, 5095, 1225-3p) may serve as useful biomarkers, as each of the six miRNAs were correlated with lifespan and were significantly up- or downregulated. Future studies can identify how examining expression of multiple miRNAs simultaneously versus one or a few miRNAs individually would affect these correlations. While some miRNA biomarker or disease-association studies have found significant correlations only by analyzing a profile of expression of multiple miRNAs, our study did identify miRNAs that individually correlate with lifespan. Further, it is striking that miRNA expression at ages 50, 55, and 60 correlates with the eventual, quite varied lifespans of the 16 participants in our pilot study.