The review explores the link between gene length and aging, summarizing recent findings linking reduced long gene expression to age-related decline and potential antiaging strategies.
Review: Gene length could be a critical factor in genome aging. Image credit: JabaWeba / Shutterstock
Recent article published in the journal Proceedings of the National Academy of Sciences discussed recent research on the correlation between gene length and genomic aging. Expression of longer genes occurs less frequently with age than expression of shorter genes. This phenomenon has been termed “gene length-dependent transcriptional knockdown” (GLTD).
Long gene expression
Understanding the genetic underpinnings of aging has long been a major focus of biological scientific research. Numerous studies aim to identify the genes that play a central role in aging. However, identifying the genetic basis of aging has been a challenge.
One of the theories consistently proposed by various groups of researchers is that with age, the expression of longer genes becomes less frequent than that of shorter genes. A group of researchers called this theory gene length-dependent transcriptional decline, where aging is linked to physical properties of genes, such as their length, rather than their function. This approach contrasts with the traditional focus on gene function, suggesting that the physical structure of the genome plays a critical role in aging.
Numerous independent studies involving humans and other animal models, such as fruit flies and mice, have already established a pattern of reduced gene expression in larger genes. The author believes that while this theory has been criticized, the findings may also have important implications for the development of important biomarkers and treatments for aging. However, some researchers caution that gene length is only one factor that contributes to aging.
Insights into aging from data revisited
Early efforts by stem cell biologist Ander Izeta from the Biogipuzkoa Research Institute in Spain failed to reveal patterns of gene expression in aging. However, his research got a new lease of life when he came across data from a 2016 study by a molecular geneticist named Jan Hoeijmakers from Erasmus University in the Netherlands. The Hoeijmakers had found a decrease in long gene expression in aging livers, which, at the time, had not been confirmed to be a widespread pattern. Hoeijmakers’ previous work on rare genetic diseases such as Xeroderma pigmentosum and Cockayne syndrome revealed that defective DNA repair mechanisms lead to age-like symptoms. This laid the foundation for his later discoveries linking gene length and aging.
Izeta extended this research by exploring a mouse database called the Tabula Muris Senis, which had gene expression data spanning the lifespan of mice from more than 300,000 cells. This research found patterns similar to those in Hoeijmakers’ study, but in various other organs, including the brain, heart, pancreas, lungs, kidneys, thymus, spleen, and even muscle and skin. Furthermore, the pattern was shown to be consistent across many species, including humans.
Thomas Stoeger, a computational biologist at Northwestern University in the United States, reached a similar conclusion, albeit from a different direction, when he studied the overlooked genes in aging. He identified a new aging-related gene known as the proline- and glutamine-rich splicing factor or Sfpqwhich is involved in the transcription of ribonucleic acid (RNA) of long genes.
Later, Stoeger and colleagues reported that the use of antiaging treatments such as resveratrol, senolytics, and rapamycin increased the expression of long genes in aging mice. This finding further confirmed the malleable nature of long gene expression, suggesting that antiaging therapies could potentially reverse age-related transcriptional decline. This malleable quality of long gene expression associated with aging also underscored its importance as a biomarker and utility in testing antiaging therapies.
Importance of gene length
The expression of long genes is unevenly distributed in the body. Nervous system cells are known to express some of the largest known genes, such as the 2.3 million base pair human dystrophin gene, which is transcribed into RNA in 16 hours. Long transcription times also increase the chance of transcription errors. These errors are especially prominent in long genes, making them more prone to damage over time.
The Hoeijmakers, who first established a link between aging and reduced expression of a long gene, also found that rare diseases such as Xeroderma pigmentosum and Cockayne syndrome, associated with defective deoxyribonucleic acid (DNA) repair mechanisms, caused symptoms similar to aging, such as hearing loss, blindness and weakness. Mouse models of these diseases showed symptoms of accelerated aging, further supporting the link between impaired DNA repair and reduced long-term gene expression. His observations of accelerated aging in mice with defective DNA repair mechanisms further supported the link between transcriptional errors in long genes and aging.
More recent studies have also confirmed the reduction of transcription of long genes in aging mouse models. Furthermore, DNA damage due to UV radiation was found to affect long genes more than short ones. This suggests that DNA repair mechanisms could play a key role in slowing the aging process by protecting long-lived genes from damage.
Criticism and skepticism
The role of long genes in aging remains under debate. Harvard researcher Vadim Gladyshev believes that aging causes multidimensional changes in the transcriptome, epigenome and metabolism. He therefore cautions against overinvesting in the role of long genes in aging. He argues that no single factor, including gene length, can be solely responsible for the complex process of aging, as it involves multiple biological systems that change over time.
However, Izeta believes the case offers new avenues for exploring aging biomarkers and potential anti-aging treatments. This focus on gene length and structure rather than function challenges conventional thinking in the field and could lead to breakthroughs in understanding aging at the molecular level. This line of research also works against the inherent bias where gene expression is always examined in terms of function rather than form or physical properties. Therefore, studying the relationship between long genes and aging as a “pure physics” phenomenon offers a new approach to aging research.
