The Underlying Biology of Health Disparities

National Institute On Aging

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Abstract

We have continued our work examining the biology of health disparities because it is through biological mechanisms that social determinates of health result in disparate health outcomes. Notable results from this year include studies involving extracellular RNA. The recent discovery of circulating cell-free RNA (extracellular RNA; exRNA) in human body fluids has sparked interest in whether these molecules are functional or can be used as markers of disease. In a recent publication in Aging Cell (Dluzen DF, Noren Hooten N, Supriyo D et al 2018), we focused on establishing an exRNA profile of human aging using serum. To do so, we developed a sequencing pipeline that enables us to simultaneously sequence all RNAs (small and long) in one sequencing reaction. Cataloging the normal distribution of exRNA in young and old individuals and identifying age-dependent differences will aid in establishing important references for the study of age-related disease. The Ensembl database classifies RNA into various categories, termed biotypes. Circulating extracellular RNAs (exRNAs) are potential biomarkers of disease. We thus hypothesized that age-related changes in exRNAs can identify age-related processes. We profiled both large and small RNAs in human serum to investigate changes associated with normal aging. exRNA was sequenced in 13 young (30-32 yrs.) and 10 old (80-85 yrs.) African American women to identify all RNA transcripts present in serum. We found that most RNA biotypes were similar in distribution between young and old, but several biotypes, including mitochondrial tRNAs, mitochondrial ribosomal RNAs, and unprocessed pseudogenes, were significantly higher in older individuals. Pathway analysis revealed that RNAs related to mitochondria, response to oxidative stress, and chromatin remodeling were all enriched in the circulation of older individuals, providing potential clues as to what pathways may be dysregulated as humans age. We also further validated our sequencing results in a larger cohort of individuals and found age-related changes in a messenger RNA, a small nucleolar RNA, a pseudogene transcript, a small nuclear pseudogene transcript, and several microRNAs. We also identified many circular RNAs (circRNAs) in serum, which we have named ex-circRNAs. Recent attention has been focused on circRNAs, as this class of ncRNAs may be important modulators of gene expression. CircRNAs have long half-lives (i.e. are stable) compared to mRNAs, making them an attractive new serum biomarker. Our identification of changes in circulating exRNAs establishes baseline references for how these biomarkers change with human age. As the risk for many diseases including cancer, cardiovascular disease, and neurological diseases increase with age, it is important to consider age when examining these factors in relation to a specific disease. Establishing these profiles with normal aging will hopefully help to identify circulating biomarkers that can distinguish individuals with faster biological aging that may result in shortened health span and lifespan. Our study is particularly relevant to health disparities since African American (AA) women have higher incidence, morbidity, and mortality from many age-associated diseases. Here, we have focused on profiling serum extracellular RNA from young and old AA women in contrast to previous studies that have focused primarily on exRNA from white individuals. Our findings provide important insight into disease processes that disproportionally affect AA women as we identified Systemic Lupus Erythematosus Signaling as a prominent canonical pathway in our pathway analysis of exRNA from old individuals. Furthermore, our establishment of an age-associated profile of exRNA in AA women will aid in the development of reference libraries of exRNA and will help in identifying whether exRNAs are suitable candidates for future diagnostics or therapeutics.