Sex-specific differences in cognitive and brain aging

The world’s population is rapidly aging. Age-related cognitive decline is a major biomedical challenge with no effective medical treatments. However, aging affects men and women differently on average — most women live longer than men worldwide and in many populations appear to experience less cognitive decline and to lose less brain tissue over time. However, many women undergo dramatic loss of sex hormones compared to men, which may make their decline different from men’s. Sex chromosomes and sex hormones are likely involved, but the exact mechanisms that underlie these fundamental differences in brain aging and cognitive decline — both between the sexes and within each sex — remain largely unknown. Understanding what makes one sex more vulnerable or resilient to aging will reveal novel targets for treatment that could benefit everyone.

We will search for fundamental mechanisms of sex biology that contribute to cognitive aging by studying aging in different species, including worms, mice and humans. To find key genes and pathways involved in these processes, we will study unique mouse models of sex biology, including mice with varying doses of the X and Y chromosomes, mice that switch gonads from male to female and vice versa, and mice in which the expression of X chromosome genes can be precisely mapped in the brain as the animals age. We will also search for genetic variants in humans that govern sex biology and modify cognitive aging and measure how these variants alter gene expression. We will integrate and curate our findings from mice and humans, altering the expression of target genes in worms and mice and assessing whether this enhances or worsens age-related brain function. We expect to find networks that regulate sex hormones and sex-linked genes, to identify new targets in neurons and other cell types, and to validate those targets at the cellular and system levels. We will also map how the expression of both active and inactive X chromosome genes changes in the brain with age. We anticipate that by focusing on sex biology, these fundamental and landmark studies will identify biological factors that are important for cognitive aging across different species, setting the stage for future in-depth studies of their cellular and molecular pathways and paving the way for novel personalized therapeutics. If we are successful in our work on understanding the biological effects of sex hormones and sex chromosomes, we hope that individuals across the spectrum of sex and gender could ultimately benefit.