X CHROMOSOME-DERIVED MECHANISMS OF SEX DIFFERENCES IN LIFESPAN AND BRAIN AGING

Abstract

Abstract Women live longer than men worldwide – and also show cognitive resilience in many aging populations. One major source of biologic difference between the sexes is that females have two X chromosomes and males have one. This difference in sex chromosome complement causes unique X-derived mechanisms that are sex-specific. In mammalian development, one X randomly inactivates in XX cells. One X-derived sex difference is that females are mosaics with the active X chromosome in each cell being either maternally-derived (Xm) or paternally-derived (Xp), whereas males harbor only a maternally-derived X (Xm) in all cells. Interestingly, some females show considerable or complete skew toward Xm or Xp. We utilized several genetic models of sex biology to understand mechanisms of sex difference in aging. We found that the X chromosome contributes to longevity and better cognition in male and female mice. In aging, a genetic manipulation in females to express only the maternally-derived X (Xm), like males, accelerated cognitive decline and epigenetic brain aging. This suggests that Xm is harmful and that female mosaicism (Xm+Xp) provides a buffer to deleterious processes in aging. To assess if Xm alters transcription, we used mice with nuclear localized genetic reporters and sorted Xm from Xp neurons from young and aging XX hippocampi. We found that Xm imprinted several genes within aging hippocampal neurons, suggesting silenced cognitive loci. Our data suggests that Xm – the maternal X – accelerates brain aging and causes cognitive deficits. Understanding how Xm impairs brain function could increase understanding of female heterogeneity and of sex differences in cognitive heath – and unlock new X-derived pathways against cognitive deficits and brain aging of males, females, or both.