Genetic regulation of gene expression and splicing during a 10-year period of human aging

Abstract

Background Molecular and cellular changes are intrinsic to aging and age-related diseases. Prior cross-sectional studies have investigated the combined effects of age and genetics on gene expression and alternative splicing; however, there has been no long-term, longitudinal characterization of these molecular changes, especially in older age. Results We perform RNA sequencing in whole blood from the same individuals at ages 70 and 80 to quantify how gene expression, alternative splicing, and their genetic regulation are altered during this 10-year period of advanced aging at a population and individual level. We observe that individuals are more similar to their own expression profiles later in life than profiles of other individuals their own age. We identify 1291 and 294 genes differentially expressed and alternatively spliced with age, as well as 529 genes with outlying individual trajectories. Further, we observe a strong correlation of genetic effects on expression and splicing between the two ages, with a small subset of tested genes showing a reduction in genetic associations with expression and splicing in older age. Conclusions These findings demonstrate that, although the transcriptome and its genetic regulation is mostly stable late in life, a small subset of genes is dynamic and is characterized by a reduction in genetic regulation, most likely due to increasing environmental variance with age.

A Mouse Model for Studying the Development of Apical Periodontitis with Age

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“…Age- and lifestyle-related systematic trends form a second layer, which is further modulated by the actual health (or disease) status of the individuals, e.g., in the case of severe sepsis by the strong activation of inflammatory signatures (Hopp et al, 2018b ). Recent longitudinal studies revealed that individuals are more similar to their own expression profiles later in life than to profiles of other individuals of their own age (Alpert et al, 2019 ; Balliu et al, 2019 ; Ahadi et al, 2020 ). Individual aging patterns, so-called “ageotypes” can be defined on the basis of molecular pathways that changed over time in a given individual reflecting personal aging as a result of personal lifestyle and medical history (Ahadi et al, 2020 ).…”

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