Normal aging of the pulmonary system associates with a multitude of physiologic, anatomic and molecular changes in the lung. Epigenetic marks, non-sequence based variations in the human genome, have been identified as important molecular hallmark of normal aging, with investigations mainly focused on DNA, not RNA, methylation. Epitranscriptomics refers to studies of modifications of RNA. N6-methyl-adenosine (m6A) is the most studied of these RNA modifications, but aging-related global RNA methylation in lung tissue has not been explored. We hypothesize that differential RNA methylation in lung tissue may represent a new research direction for advancing understanding of normal lung biology and genomics changes with aging. Given the growing evidence that normal aging has a cumulative molecular impact, considering age-related changes to the epitranscriptome may advance insights into age-related resilience in the lung. We will investigate global RNA methylation through the following Specific Aims : 1) Quantification of global N6-methyl-adenosine in lung tissue from 400 individuals with normal spirometry from the Lung Tissue Research Consortium, exploring variability of RNA methylation with age, with additional consideration of sex and race associated variability; 2) Identification of genetic variation that associates with RNA methylation; 3)Evaluation of RNA methylation as a predictor of gene expression and a contributor to gene regulatory network signatures in lung tissue. There are no published studies of RNA methylation and aging in the normal lung. This project will address whether RNA methylation captures normal aging in the lung and will support more in-depth evaluations of the epitranscriptome as a marker of lung health. This proposal is responsive to PA-19-049 (New Research Directions to Advance the NHBLI Strategic Vision Normal Biology) by modeling aging associated non-sequence variation of RNA in lung tissue from individuals with normal lung function.
Aging associates with changes in molecular features in the lung and understanding the normal ranges of age- related variability may inform insights into normal lung biology and resilience. Investigating global RNA methylation in lung tissue may uncover new mechanisms underlying differences for age-related disparities in lung health, especially differences by sex and race. Modeling RNA methylation together with genetic variation and gene expression may highlight targetable new pathways to consider for maintaining respiratory health in the later decades of life.