The Second X Chromosome Slows Cognitive Aging
In mammals, females have two X chromosomes while males have one X chromosome and one Y chromosome. Other, lower species can and do have other differences in chromosomal DNA between the sexes. It is known that mammalian females typically live longer than males, but are the various aspects of this slowed aging driven by the presence of female gonads and hormonal signaling or by the presence of the additional X chromosome? There has been some discussion as to whether having only one X chromosome magnifies the effects of stochastic mutational damage, for example. To gain insight into this sort of question, researchers have engineered mice that mix and match male and female chromosomes versus male and female gonads. The research here is an example of what one can do given these animal models.
True sex differences exist in aging. Women live longer than men around the world; they also show resilience to cognitive decline and higher baseline function in typical aging in many populations, when dementia and its subsequent development are carefully excluded. Since cognition is a key manifestation of brain function eroded by aging, understanding sex differences and their causes are high value areas of investigation.
Whether female mice show better cognition in typical aging - and whether sex chromosomes or gonads influence sex difference in cognitive aging - remain largely unknown. To examine this, we utilized genetic mouse models of sex biology. The Four Core Genotype (FCG) model tests whether gonads or sex chromosomes contribute to a sex difference. The XY* model tests whether the X or Y chromosome contributes. We tested for cognitive aging and any accompanying sex differences in young and aged mice using the two-trial Y maze paradigm which measures spatial and working memory, a target of aging. As expected, aging decreased cognition in both sexes. While no sex differences were observed in young mice, female sex attenuated age-induced cognitive decline.