Girls' extra X helps aging?

or is it from their fetal cell microchimerism?

In typical aging, women have a brain that looks younger, with fewer cognitive deficits compared to men. The silent X in females seems to reawaken as they age, helping to slow their cognitive decline.

After an egg is fertilized by sperm, if there are two X chromosomes - a girl baby - only one chromosome per cell is ‘allowed’ to be active. The other one is ‘silenced’ and gene expression from it is suppressed (the female-specific mechanism for dosage compensation).

Recently researchers discovered that as female mice reached the equivalent of about 65 human years, their own 'silent' second X started expressing genes enhancing brain connections, helping cognitive functions.

Women live longer than men and exhibit less cognitive aging. The X chromosome contributes to sex differences, as females harbor an inactive X (Xi) and active X (Xa), in contrast to males with only an Xa. Thus, reactivation of silent Xi genes may contribute to sex differences. We use allele-­specific, single-­nucleus RNA sequencing to show that aging remodels transcription of the Xi and Xa across hippocampal cell types. Aging preferentially changed gene expression on the X’s relative to autosomes. Select genes on the Xi underwent activation, with new escape across cells including in the dentate gyrus, critical to learning and memory. Expression of the Xi escapee Plp1, a myelin component, was increased in the aging hippocampus of female mice and parahippocampus of women. AAV-­mediated Plp1 elevation in the dentate gyrus of aging male and female mice improved cognition. - M Gadek, et al.

Allele-specific, single-nucleus sequencing of cell types in the young and aging XX hippocampus. (A) Genetic model for allele-specific investigation of the X. M. musculus XX mice with an Xist deletion were crossed with XY M. castaneus mice. XX progeny without an Xist deletion (left) underwent random XCI. XX progeny with an Xist deletion (right) harbor an Xa chromosome strictly from the M. musculus strain and an Xi chromosome from the M. castaneus. Differences in SNPs between the strains enable a direct measure of expression from each X, the Xa and the Xi. Image credit: D. Velasco. (B) Diagram of the experimental workflow of allele-specific, single-nucleus sequencing. Young (n = 4 mice, age = 3 months) and old (n = 4 mice, age = 22 months) hippocampi from the strain-specific X-detection mice were dissected. Nuclei were dissociated and sequenced with 10x RNA sequencing on the Illumina NovaSeq 6000. Reads were aligned to the combined M. musculus and M. castaneus genome and analyzed by origin from Xa or Xi, cell type, and age. Hippocampi, cells, and NovaSeq were acquired with a ShutterStock Enhanced License. (C) Hippocampal cell types sequenced. Dimension reduction analysis using UMAP revealed 11 distinct cell type populations sequenced plus a mixed category. Clusters are the following: endothelial cells (Endo), astrocytes (Astro), vascular leptomeningial cells (VLMC), microglia (MG), DG neurons, CA1 neurons, glutamatergic undefined neurons (Glut_Undef), CA3 neurons, GABAergic neurons (GABA), oligodendrocyte progenitor cells (OPCs), and oligodendrocytes (Oligo). (D) Matrix plot showing expression relating cell type marker genes (columns), cell clusters (rows), and corresponding genes. (E) Heatmap of cell markers across UMAP clusters. Color intensity reflects extent of gene expression.

They report that aging preferentially modulates differential gene expression on the X compared to autosomes, with a near-global up-regulation of genes from both the Xa and Xi, in a cell type–specific manner.

Fetal cell carryover

The bidirectional fetomaternal trafficking of cells across the placenta

Did you know that females carry many generations of foreign fetal DNA? Mothers accumulate their own children's cells, but also their own mother's cells and all the cells from the siblings born before her, and maybe even from the maternal grandmother. These fetal cells last life long and show up everywhere in the body, including the brain.

During pregnancy, some baby cells migrate into the mother's bloodstream and then return to the child. It's called "mother-fetal microchimerism". For 41 weeks, the cells mix and circulate back and forth, and after the birth of the baby, many of these cells remain in the mother's body, leaving a permanent imprint on the tissues, bones, brain and skin of the baby to mother, and they often stay there for decades. Every other child a mother will have will leave a similar imprint on her body. Even if a pregnancy doesn’t end, or if you have an abortion, these cells still migrate into the blood flow.

If a mother’s heart is injured, fetal cells will rush to the site of the injury, and turn into different types of cells specialized in heart repair. The child helps the mother repair, while the mother builds the child. The mother's body protects the baby at all costs, and the baby protects and rebuilds the mother in return, so they can safely develop and survive.

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REFERENCES

M Gadek, et al. Aging activates escape of the silent X chromosome in the female mouse hippocampus. Science Advances (2025). DOI: 10.1126/sciadv.ads8169

S Shrivastava et al. Microchimerism: A new concept https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714269/

U Mahmood, K O'Donoghue. Microchimeric fetal cells play a role in maternal wound healing after pregnancy. Chimerism. 2014;5:40–52. doi: 10.4161/chim.28746