New Theorizing on Teleomere Length and Gene Regulation

Telomeres are caps of repeated DNA sequences at the ends of chromosomes. They shorten with each cell division, one part of a limiting mechanism for the number of times that somatic cells can replicate. Average telomere length in tissues is a function of pace of cell division, activity of the telomere-lengthening enzyme telomerase, and the pace at which stem cells deliver fresh new long-telomere replacement cells. All of this varies widely by tissue type and other factors, and average telomere length in easily measured tissues tends to decrease with ill health and age, most likely as a result of declining stem cell activity.

All of this tends to suggest that telomere length is a measure of secondary and later consequences of aging, and is not in and of itself a primary cause of aging. The counterargument to that is provided by studies in which enhanced telomerase activity lengthened life span in mice, but it isn't clear at this point whether lengthening telomeres is the reason for that outcome, versus other functions of telomerase or cellular reactions to altered levels of that enzyme. Continuing this theme, these researchers suggest a mechanism by which changing telomere length could alter the regulation of gene expression, and thus cellular behavior, for a wider range of genes than previously suspected:

[Researchers] found that the length of the endcaps of DNA, called telomeres, form loops that determine whether certain genes are turned off when young and become activated later in life, thereby contributing to aging and disease. "Our results suggest a potential novel mechanism for how the length of telomeres may silence genes early in life and then contribute to their activation later in life when telomeres are progressively shortened. This is a new way of gene regulation that is controlled by telomere length."

Even before the telomeres shorten to the critical length that damages the DNA, the slow erosion in length has an effect on the cell's regulation of genes that potentially contributes to aging and the onset of disease. The [findings] required the researchers to develop new methods for mapping interactions that occur near the endcaps and to use an extensive array of methodologies to verify the impact. Specifically, the team showed that when a telomere is long, the endcap can form a loop with the chromosome that brings the telomere close to genes previously considered too far away to be regulated by telomere length. Once the telomere and the distant genes on the same chromosome are close to each other, the telomere can generally switch those genes off.

Conversely, when telomeres are short, the chromosome does not form a loop and the telomere can no longer influence whether target genes are switched on or off. The researchers were able to identify three genes whose expression patterns are altered by telomere length but believe this number is the just the tip of the iceberg. "We have developed the concept that telomere shortening could be used as a timing mechanism to respond to physiological changes in very long-lived organisms, such as humans, to optimize fitness in an age-appropriate fashion."

Link: http://www.utsouthwestern.edu/newsroom/news-releases/year-2014/nov/telomere-length.html

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