Slight Tweak in the Genetics of Aging Cells

The older we get, the greater the risk of morbidity and mortality. In this context, changes in gene expression occur with increasing age. The transcripts of many genes change, but most of these changes are minor. In this context, getting older is probably accompanied by a global, subtle change in the transcriptome that affects gene expression. In addition, some studies have found that RNA formation decreases with age and that age-related DNA damage leads to a decrease in the expression of long genes. However, it is not clear which of these global or gene-centered processes contributes more to the age-dependent changes in gene expression.

To strengthen the molecular understanding of aging, researchers have analyzed age-resolved transcriptomic data from several studies.

The molecular basis of aging

We recognize that our study holds a far-reaching implication on how RNA-seq studies are analyzed and interpreted. Technical biases in RNA-seq studies, which affect gene-specific readouts according to their length, have been reported widely, and several tools have been subsequently deployed to computationally counter the effects of this length association. As demonstrated by our NanoString experiment, and by our reanalysis of published proteomics data, this data processing step may hide biologically driven associations between transcript length and relative fold change.

The study, published Dec. 9 in Nature magazine, analyzed age-resolved transcriptomic data from multiple studies to better understand the molecular basis of aging. The researchers found that transcript length alone explains most transcriptional changes observed with aging in animals and also in humans. They present three lines of evidence supporting the biological importance of the transcriptome imbalance that occurs during the course of life:

First, in vertebrates, there is a lower relative abundance of long transcripts in aging. Second, there are eight anti-aging interventions that can counter this length association. Third, in humans and also in mice, genes with the longest transcripts enrich for genes that have been reported to extend lifespan. In contrast, those with the shortest transcripts enrich for genes that have been reported to shorten lifespan. Overall, the study suggests that aging may be associated with a subtle change in the transcriptome that affects gene expression.

Spurred by our findings on antiaging interventions, we believe that understanding the direction of causality between other age-dependent cellular and transcriptomic changes and length-associated transcriptome imbalance could open novel research directions for antiaging interventions.
Stoeger et al., 2022