Aging Is Linked to More Activity in Short Genes Than in Long Genes

Our DNA is made up of genes that vary greatly in size. In humans, genes range from as short as a few hundred molecules known as bases to as long as two million bases. These genes carry the instructions to build proteins and other information important to keep your body moving. Now, new research suggests that longer genes become less active than shorter genes as we age. It may become clear how.

Luis Amaral, a professor of chemistry and bioengineering at Northwestern University, says he and his colleagues didn’t set out to examine gene length first. Some of Amaral’s collaborators at Northwestern University have attempted to identify changes in gene expression as mice age…but they have struggled to identify consistent changes. rice field. “Almost everything seemed random,” says Amaral.

Then, at the suggestion of Thomas Stoger, a postdoctoral fellow in Amaral’s lab, the team decided to look at changes in gene length. Previous studies have suggested that there may be such large-scale changes in gene activity with age. For example, it has been shown that the amount of RNA decreases over time and transcription (the process by which copies of RNA or transcripts are transcribed) is disrupted. formed from a DNA template) can have a greater effect on long genes than on short ones.

Stoeger, Amaral, and their team used machine learning algorithms to identify the features that best explain changes in RNA. From 17 different tissues including heart, brain and kidney of 4-, 9-, 12-, 18-, and 24-month-old male mice. (The mouse strains used in this study are considered ‘very old’ at 24 months.) This analysis revealed a clear and consistent pattern across tissues. Longer transcripts were fewer than shorter ones in older animals. This imbalance in expression of long and short genes provided a possible explanation for why we were unable to find a specific set of genes with altered expression. The specific genes expressed varied from experiment to experiment, Amaral said, but overall, the shorter genes appeared to be more active than the longer ones as the animals aged. “You can always find hundreds of genes that look like they’re changing, but in terms of this linear trend, it all makes sense,” he says. Transcriptional changes are the most likely explanation for his and his colleagues’ findings, but say other processes, such as RNA degradation, may also be at work.)

The team repeated the experiment using data collected from different types of post-mortem human tissue and tissue extracted at specific ages from other animals. They found that this age-related imbalance in gene length-related expression was consistent across organisms. The human discovery was particularly exciting because, unlike mice that were genetically identical and raised in the same laboratory conditions, humans lived differently and died from different causes at different times, Amaral says. “The fact that we find the same patterns despite this diversity shows that this is a robust one,” he says. “This result dramatically increases my confidence that this is a true and significant pattern.”

When Amaral and his colleagues examined the longest and shortest transcripts, the top 5% of genes with the shortest transcripts included genes associated with shorter lifespans, such as those involved in maintaining telomere length. (terminal DNA sequences). functions of chromosomes that become shorter with age) and immune functions. They found that the top 5% of genes with the longest transcripts included genes associated with lifespan, such as neuronal activity and transcriptional regulation. They also examined the effects of 12 anti-aging interventions on the balance of short and long gene activity by reassessing data from previously published animal studies. Seven of these interventions, including six anti-aging drugs, resulted in relative increases in long gene transcripts, suggesting that this aging-associated imbalance may be reversible. The findings he announced in December. natural aging.

The study is consistent with previous research, according to Maria Ermolaeva, a group leader at the Leibniz Institute on Aging in Germany, who was not involved in the study. We show that the accumulation of DNA damage has a strong effect on longer genes. The longer the gene, she says, the more likely it is to have problems that can’t be repaired. lead to a decrease in “The authors of the new study may have observed global consequences of this previously described molecular phenomenon,” Ermolaeva says.

The age-related transcriptome imbalance the authors observe has “interesting relevance”, but whether this process drives aging remains to be seen, says the Department of Molecular Biology Gerontology at the University of Birmingham, UK. Professor João Pedro de Magalhães says: in this study. “I wouldn’t dismiss it as a possibility, but I think it would require some pretty strong evidence that we don’t have yet,” he says. It may simply reflect other processes associated with aging, such as increased system activity. Small genes are often associated with immune function, and immune processes such as inflammation tend to become more active as we age, adds de Magalhães. “So it makes some sense to see a pattern in terms of gene length, because it reflects processes that change with age.”

Amaral speculates that transcriptional imbalance may be caused by the accumulation of deleterious exposures (e.g., viral infections) over a lifetime that gradually alter the cellular machinery required to successfully transcribe longer genes. I’m here. “Aging may be a measure of this imbalance. The greater the imbalance, the more aging the tissue ages,” he adds. We would like to examine how it affects the transcriptome imbalance of .

Amaral says there are many open questions to address, such as how the transcription machinery changes with age. I hope it excites people, especially.”

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