Review explores the connection between gene length and aging, summarizing recent findings that link reduced long-gene expression to age-related decline and potential anti-aging strategies.
Review: Gene length could be a critical factor in the aging of the genome. Image Credit: JabaWeba / Shutterstock
A recent article published in the journal Proceedings of the National Academy of Sciences discussed recent research on the association between gene length and genome aging. The expression of longer genes occurs less frequently with age than the expression of shorter genes. This phenomenon has been termed "gene length-dependent transcription decline" (GLTD).
Long-gene expression
Understanding the genetic underpinnings of aging has long been one of the major focal points of biological science 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. One team of researchers called this theory the gene length-dependent transcription decline, where aging is linked to the physical properties of the 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 longer genes. The author believes that while this theory has invoked criticism, the findings might also have significant implications for the development of important aging biomarkers and therapies. However, some researchers caution that gene length is just one factor contributing to aging.
Insights on aging from revisited data
Early attempts by stem cell biologist Ander Izeta from the Biogipuzkoa Research Institute in Spain failed to uncover any gene expression patterns in aging. However, his research found a new lease of life when he encountered data from a 2016 study by a molecular geneticist called Jan Hoeijmakers from Erasmus University in the Netherlands. Hoeijmakers had found a decline in long-gene expression in aging livers, which, at the time, was not confirmed to be a widespread pattern. Hoeijmakers’ earlier work on rare genetic diseases, such as Xeroderma pigmentosum and Cockayne syndrome, revealed that defective DNA repair mechanisms lead to symptoms resembling aging. This laid the foundation for his later discoveries linking gene length and aging.
Izeta expanded this research by exploring a murine database called Tabula Muris Senis, which had gene expression data spanning the lifespan of mice from over 300,000 cells. This research identified patterns similar to those from Hoeijmakers’s study but in various other organs, including the brain, heart, pancreas, lungs, kidneys, thymus, spleen, and even muscles and skin. Furthermore, the pattern was established to be consistent in multiple species, including humans.
Thomas Stoeger, a computational biologist at Northwestern University in the United States, arrived at a similar conclusion, albeit from a different direction, when he studied overlooked genes in aging. He identified a new aging-associated gene known as Splicing factor proline—and glutamine-rich or Sfpq, which is involved in the ribonucleic acid (RNA) transcription of long genes.
Later, Stoeger and colleagues reported that the use of anti-aging 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 anti-aging therapies could potentially reverse age-related transcriptional decline. This malleable quality of long-gene expression linked to aging also highlighted its importance as a biomarker and utility in testing anti-aging therapies.
Importance of gene length
The expression of long genes is unevenly distributed in the body. The cells of the nervous system are known to express some of the longest known genes, such as the 2.3 million base pair long human dystrophin gene, which is transcribed into RNA in 16 hours. Long transcription times also increase the probability of transcriptional errors. These errors are particularly prominent in long genes, making them more susceptible to damage over time.
Hoeijmakers, who first established a connection between aging and reduced long-gene expression, also found that rare diseases such as Xeroderma pigmentosum and Cockayne syndrome, which are associated with defective deoxyribonucleic acid (DNA) repair mechanisms, caused symptoms similar to aging, such as hearing loss, blindness, and frailty. His mouse models of these diseases exhibited accelerated aging symptoms, further supporting the link between impaired DNA repair and long-gene expression decline. 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 in the transcription of long genes in aging murine models. Furthermore, DNA damage due to ultraviolet light was found to impact 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 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 metabolome. Therefore, he cautions against over-investing 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 changing over time.
However, Izeta believes that the hypothesis offers new avenues for exploring aging biomarkers and potential anti-aging therapies. 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 a molecular level. This line of research also works against the inherent bias where gene expression is always examined in terms of function and not form or physical properties. Therefore, studying the link between long genes and aging as a “pure physics” phenomenon offers a fresh approach to the research on aging.
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