A Loss of Transcriptional Coordination Observed in Cells from Older Individuals
Existing evidence suggests that transcription of genetic blueprints into RNA becomes less coordinated with age, producing greater variance between cells. It is a question mark as to how greatly this contributes to age-related disease, and also a question mark as to exactly how it is linked to the underlying molecular damage at the root of aging. Expanding this area of research, scientists here show that within individual cells the coordination of transcription between genes also becomes dysregulated. The more age-related damage there is in tissues, the worse the dysregulation of transcription. A potential next step might be to assess this effect before and after the application of a rejuvenation therapy, such as clearance of senescent cells, in order to clearly demonstrate whether or not disruption of transcriptional coordination is a reaction to cell and tissue damage of aging.
How is it that random, disorganized damage, which accumulates differently among different humans, and moreover, among different cells of the same individual eventually leads to the same outcomes? Several theories try to address this paradox, and they have great implications for our ability to affect the aging process, making elderly life better and longer. The potential to develop treatments for aging depends on understanding the fundamental process of growing old.
A common approach holds that most cells in the human body are barely damaged during aging, while just a few "rotten apples" - a small fraction of non-functioning cells - are significantly damaged. Accordingly, a potential treatment for aging could involve removing these few highly-damaged cells. Researchers have also suggested that the proper function of biological tissues may decline during aging because many cells lose their ability to tightly regulate their genes. According to this theory, there are no single non-functioning cells - or rotten apples - on the one hand, but none of the apples is "fresh" on the other.
Using a novel approach from physics, researchers developed a computational method that quantifies the coordination level between different genes. With this approach, they measured the transcriptional activity of individual cells and compared cells from old and young subjects, discovering phenomena never before observed: old cells lost significant coordination levels compared to young cells. To test the consistency of this phenomenon, they analyzed data collected from more than twenty experiments from six different labs. In all cases they found reduced levels of coordination during aging among different organisms: human, mice, and fruit flies, and among different cell types: brain cells, hematopoietic stem cells, pancreatic cells, and more.
The researchers also observed coordination reduction in tissues with an increased level of damage, suggesting a direct link between increased damage level and coordination breakdown. The findings support the theory that during aging, accumulated random damage affects regulation mechanisms and disrupts the ability of genes to coordinate, resulting in a general decrease in tissue function. This study conclusively demonstrates the long-speculated relationship between aging, gene regulation, and somatic damage. The results open up new avenues of research with practical implications. If the same level of coordination reduction between genes is indeed a leading cause for aging phenomena, there may be a need to change course in current efforts to develop aging treatments.
Link: https://www1.biu.ac.il/indexE.php?id=33&pt=20&pid=117&level=2&cPath=33&type=1&news=3576