Scientists have found an extremely subtle twist in the genetics of aging cells, one that seems to make them increasingly less functional as time goes on. Researchers from Northwestern University have revealed animals like mice, rats, killifish, and even humans show a gradual imbalance of long and short genes in virtually every cell in their body as they age. The discovery suggests there aren't specific genes that control the aging process. Instead, old age seems to be governed by systems-level changes with complex effects. And this can impact thousands of different genes and their respective proteins. For an individual gene, however, the changes are so tiny as to be insignificant. That's probably why they've slipped past our notice until now. "We have been primarily focusing on a small number of genes, thinking that a few genes would explain disease," says Northwestern University data scientist Luís Amaral. "So, maybe we were not focused on the right thing before. Now that we have this new understanding, it's like having a new instrument. It's like Galileo with a telescope, looking at space. Looking at gene activity through this new lens will enable us to see biological phenomena differently." Normally, in an individual cell or a group of cells, a code represented in DNA is translated into RNA, becoming a collection of free-floating instructions known as a transcriptome. This mobile library of genetic recipes is what the cell uses to create its parts and carry out its various functions. Its contents also seem to change with age. In a healthy, young animal, the activity of short and long genes is balanced across a transcriptome, and this balance is carefully monitored and maintained. But as an individual grows older, short genes become more of a dominant trend. In several different types of animals, in fact, shorter transcriptomes were found to proliferate with age. "The changes in the activity of genes are very, very small, and these small changes involve thousands of genes," explains developmental biologist Thomas Stoeger. "We found this change was consistent across different tissues and in different animals. We found it almost everywhere. I find it very elegant that a single, relatively concise principle seems to account for nearly all of the changes in activity of genes that happen in animals as they age." Like the process of aging itself, the transition to smaller transcriptomes starts early and is gradual. In rats, tissue samples taken at 4 months of age had a relatively longer median length of genes than those taken at 9 months of age. The transcriptome changes found in killifish from the age of 5 weeks to 39 weeks were similar. To test the pattern in humans, researchers turned to data from the Genotype-Tissue Expression (GTEx) project, which publicly provides genetic information collected from almost 1,000 deceased individuals. Among humans, transcriptome length was once again found to be predictive of older age, becoming significant in the 50 to 69 age group. Compared to the younger age group of 30 to 49, the older group showed longer transcripts that were less likely to 'fold' or become functionally active compared to shorter ones. "The result for humans is very strong because we have more samples for humans than for other animals," says Amaral. "It was also interesting because all the mice we studied are genetically identical, the same gender, and raised in the same laboratory conditions, but the humans are all different. They all died from different causes and at different ages. We analyzed samples from men and women separately and found the same pattern." Not yet satisfied with their results, researchers at Northwestern next investigated the effect of several anti-aging interventions on the length of transcriptomes. The majority of interventions favored long transcripts, despite their differing impacts on the body. The authors conclude that aging cannot be boiled down to a single origin of transcriptome imbalance. Instead, they argue that "multiple environmental and internal conditions" probably lead to short genes becoming more active in the body. "Spurred by our findings on anti-aging interventions, we believe that understanding the direction of causality between other age-dependent cellular and transcriptomic changes and length-associated transcriptome imbalance could open novel research directions for anti-aging interventions," the authors conclude. Source
