Revisiting the X-Chromosome Inactivation and Its Impact on Female Longevity

Abstract

X-chromosome inactivation is the genetic mechanism by which X-linked gene expression is equalized between the male and female genders of all placental mammal species. Given that the probability of mutant X-linked allele expression decreases as a result of the inactivation, it has been proposed that females have biological advantages relative to males. These advantages have grabbed the attention of the scientific community in recent years and have focused it on this topic and its clinical implications. To shed some new light on this intriguing phenomenon, this article reviews the most relevant molecular events involved in this process. These events include the role of Xist, the selection mechanism for future X-chromosome inactivation, the age-related inactivation skewing, and the relationship between inactivation and the emergence of X-linked diseases, possible treatments, and longevity.

Sex‐specific aging in animals: Perspective and future directions

“…Misregulation of dosage compensation in males could explain shorter lifespan of Drosophila males. In comparison, in humans, where one copy of the X chromosome is inactivated in XX females (with some important exceptions, Tukiainen et al, 2017 ), biased (non‐random) inactivation of one copy of the X over the other is associated with shorter lifespan (Chuaire‐Noack et al, 2014 ; Gentilini et al, 2012 ; Ostan et al, 2016 ). However, as this process occurs in females, it does not explain the shorter male lifespan.…”

Sex gap in aging and longevity: can sex chromosomes play a role?

“…Of course, the unguarded X effect depends on how well functional diploidy is restored in females in species with XCI. In humans, a skewed XCI is associated with faster aging and a shorter lifespan, and centenarian females tend to have a balanced XCI [ 15 , 96 , 97 ]. Why some individuals exhibit skewed XCI and not others remains to be understood.…”

Telomere length as a potential biomarker of coronary artery disease

“…This has led to speculation that sex-specific telomere shortening is one cause of sex-specific mortality. Survival advantage could be the result of variation in telomere maintenance alleles on the X-chromosome 45 .…”