Further Considering the Altered Transcription of Longer Genes with Age

The machinery of gene expression changes with age. In recent years, it has been noted that the length of gene sequences correlates with the degree to which transcription of gene sequences into RNA molecules changes over the course of aging. Later work has started to examine the proximate causes of these changes, various fine detail mechanisms buried in the depths of transcription. The research community is not yet at the point of being able to conclusively demonstrate that altered transcription of longer genes produces meaningful downstream consequences in degenerative aging, as interventions specifically targeting just this process of transcriptional change have yet to be established. This is worth keeping an eye on, however.

Recent studies of aging organisms have identified a systematic phenomenon, characterized by a negative correlation between gene length and their expression in various cell types, species, and diseases. We term this phenomenon gene-length-dependent transcription decline (GLTD) and suggest that it may represent a bottleneck in the transcription machinery and thereby significantly contribute to aging as an etiological factor.

Currently, it is yet to be understood whether GLTD is only a marker of aging or whether it also actively plays a role in the aging process itself. We consider this to be the greatest outstanding question on GLTD. To measure the potential impact of GLTD on aging, it would be necessary to identify interventions or experimental schemes that only affect GLTD. However, no such intervention or experimental scheme is currently known.

To quantify the magnitude of impact of any such intervention, we may further need to first apply them to animal models. Even in such studies, it would remain challenging to attribute effects toward aging to GLTD rather than any single subsets of genes that change their transcription as part of GLTD. Nevertheless, we cautiously suspect a causal contribution.

Link: https://doi.org/10.1016/j.tig.2024.01.009