Single-cell transcriptomic and epigenomic analysis reveals X-linked sex differences in aging mouse hypothalamus

Sex disparities influence brain aging, neurodegenerative diseases, and the overall aging process across species. The hypothalamus, crucial for physiological homeostasis and healthy aging, exhibits complex cell and molecular variations between male and female counterparts throughout life. To dissect this, we performed a single-nucleus multi-omics examination of the hypothalamus in male and female mice at various ages: young, middle-aged, and aged.

We pinpointed key hypothalamic cell types and assessed their sex and age-specific transcriptional and chromatin accessibility patterns. A crucial observation was the female-specific alterations on the X chromosome (chrX) that stood out during aging. These changes encompassed the X inactivation center and a general uptick in chrX gene expression and accessibility, especially in immune cells and neurons.

Analyzing immune cells through a pseudotime framework unveiled an aging path distinct to each sex, marked by heightened inflammation in females as compared to males. Further into the epigenetic facets driving these sexual differences, we discovered that H3K27me3, the repressive histone mark prevalent on the inactive X in females, became more abundant and exhibited significant genome-wide redistribution with aging. This shift was particularly pronounced on the inactive chrX in females.

In summary, these results underscore unique cell-type-specific aging trajectories in the male and female hypothalamus, identify female aging signatures linked to X-linked epigenetic regulatory mechanisms, and offer a thorough resource for comprehending the molecular underpinnings of sex disparities in brain aging.