Scientists have discovered an extremely subtle twist in the genetics of aging cells that appears to make them less and less functional over time.
RResearchers from Northwestern University revealed animals like mice, rats, killifish, and even humans show a progressive imbalance of long and short genes in virtually every cell in their bodies as they age.
The discovery suggests that there are no specific genes that control the aging process. Instead, old age seems to be governed by systemic changes with complex effects. And it can impact thousands of different genes and their respective proteins.
For an individual gene, however, the changes are so small that they are insignificant. This is probably why they have escaped our notice until now.
“We mainly focused on a small number of genes, thinking that a few genes would explain the disease,” explains Northwestern University data scientist Luís Amaral.
“So maybe we weren’t 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 out into space. Looking at gene activity through this new lens will allow us to see biological phenomena differently.”
Normally, in an individual cell or group of cells, a code represented in DNA is translated into RNA, becoming a collection of floating instructions known as the transcriptome.
This mobile library of genetic recipes is what the cell uses to create its parts and perform its various functions. Its content also seems to change with age.
In a healthy young animal, the activity of short and long genes is balanced in a transcriptome, and this balance is carefully monitored and maintained. But as an individual ages, short genes are increasingly becoming a mainstream trend.
In fact, in several different types of animals, shorter transcriptomes have been shown to proliferate with age.
“Changes in gene activity are very, very small, and those small changes involve thousands of genes,” says developmental biologist Thomas Stoeger.
“We found this change to be consistent in different tissues and in different animals. We found it almost everywhere. I find it very elegant that a single, relatively concise principle seems to explain almost all changes in gene activity that occur. occur in animals as they age.”
Like the aging process itself, the transition to smaller transcriptomes begins early and is gradual.
In rats, tissue samples taken at 4 months of age had a relatively longer median gene length than those taken at 9 months of age.
The transcriptome changes found in the Killifish from 5 weeks to 39 weeks of age were similar.
To test the model in humans, the researchers turned to data from the Genotype-Tissue Expression Project (GTEx), which publicly provides genetic information gathered from nearly 1,000 deceased people.
In humans, transcriptome length was again found to be predictive of advanced age, becoming significant in the 50-69 age group.
Compared to the younger age group of 30–49, the older group showed longer transcripts that were less likely to “fold up” or become functionally active compared to the 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, of the same sex and raised in the same laboratory conditions, but humans are all different. They all died of different causes and at different ages. We analyzed samples from males and females separately and found the same pattern.”
Not yet satisfied with their results, the Northwestern researchers then studied the effect of several anti-aging interventions on transcriptome length. The majority of interventions favored long transcripts, despite their different impacts on the body.
The authors conclude that aging cannot be reduced to a single source of transcriptome imbalance.
Instead, they argue that “multiple environmental and internal conditions” likely lead to short genes becoming more active in the body.
“Stimulated by our findings on anti-aging interventions, we believe that understanding the direction of causation between other age-dependent cellular and transcriptomic changes and length-associated transcriptome imbalance could open up new directions. research for anti-aging interventions,” the authors conclude.
The study was published in natural aging.
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