Regulation of gene expression is a matter of control over the structure of packaged nuclear DNA, determining which regions are accessible to transcription proteins. This control becomes dysfunctional with age. Evidently there will be sex differences in the outcomes of this dysfunction because males and females have different chromosomes. It remains an open question as to which of these classes of difference are important in male versus female life expectancy and outcomes in aging, and why. Here, researchers discuss the phenomenon of silent X chromosome activation in older females, and whether it might provide a significant contribution to sex differences in aging.
Unlike men, who carry one X chromosome and one Y chromosome, women have two X chromosomes in each cell. However, one of the two X chromosomes is effectively silenced. It folds into a compact structure known as the Barr body and can no longer be read. Without this mechanism, the genes on the X chromosome would be read twice as often in women as in men. Scientists have known for some time that some genes can escape inactivation in the Barr body, resulting in higher gene activity in women. These genes are suspected to influence disease.
Researchers examined the major organs of mice at different stages of life. In the older animals, the proportion of genes that had escaped was on average twice as high as in adult animals - six percent instead of three percent of the genes on the X chromosome. In some organs, the numbers were even higher: in the kidneys, for instance, nearly 9 percent. "With aging, epigenetic processes gradually loosen the tightly packed structure of the inactive X chromosome. This mainly happens at the ends of the chromosome, allowing for genes located in those regions to be read again."
Many of the genes that become active again with age are associated with disease. What effects the reactivated genes may have on disease development will need to be investigated in future studies. This doubled gene activity could have positive effects in some cases and negative effects in others. ACE2, for example - a gene that escapes in the lungs with age - can help limit pulmonary fibrosis. Increased activity of the gene TLR8 in old age, however, may play a role in autoimmune diseases such as late-onset lupus.
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