Protein-coding genes in the human genome vary greatly in length, from a few hundred to millions of nitrogenous base pairs. Genes of various lengths are variably expressed in different cell types and organs. Genes that are very short or very long encode proteins involved in cellular processes that change with age, such as cellular energy generation, protein synthesis, and neural signal transmission. At the neuron level, the expression of some of the longest genes is reported.
Unlike other cellular macromolecules, DNA depends on repair systems to function throughout the cell’s lifetime, unlike other components such as RNA or proteins that are resynthesized based on the genetic information contained in DNA. Accumulation of DNA damage is associated with aging. At the level of replicating cells, DNA damage, such as cross-links, double-strand breaks and telomere shortening, causes the cell cycle to stop permanently.
Expression of long genes is particularly reduced in the context of deficiencies in DNA damage repair systems, being associated with premature aging in this context. The activity of RNA polymerase that carries out transcription can be blocked by DNA damage, resulting in reduced gene expression. Because long genes have multiple points where DNA damage can occur, they are highly susceptible to this phenomenon. Considering all these aspects, DNA damage appears to be causally related to GLTD, influencing aging in multiple ways.
Also, both reduction and increase of RNA polymerase transcription speed can determine GLTD. At the same time, once transcribed, long genes are more susceptible to premature cleavage and polyadenylation. As neurons express some of the longest genes, the magnitude of GLTD is highest in nervous tissue.
