Study explores cell type-specific effects of aging and sex on human cortical neurons

It is well known that aging has profound effects on the human brain, causing changes in cellular composition and gene expression, while altering some aspects of the interaction between genes and environmental factors. While neuroscience studies have identified many molecular changes associated with aging, the age-related genetic factors that influence specific neuronal populations remain poorly understood.

Recent studies in flies, mice, primates, and human brain tissues, using single-cell or single-nuclear RNA sequencing and experimental genetic techniques, have shed new light on these cell-type-specific changes. For example, they have uncovered the effects of aging on glial cells in the mouse and human brain, the associations between cell-specific changes and altered chromatin proteins, and the influence of DNA methylation on aging in various tissues.

Researchers from the University of California (UC) San Diego and the Salk Institute recently conducted a study aimed at better understanding how age and sex impact human cortical neurons at the single-cell level. Their findings, published in Neuronprovide new insights into how aging affects cellular composition, gene expression, and DNA methylation in different human brain cell types, while uncovering differences between gene expression and DNA methylation in women and men.

“Altered transcriptional and epigenetic regulation of brain cell types may contribute to cognitive changes in advanced age,” Jo-Fan Chien, Hanqing Liu, and colleagues wrote in their paper. “Using multiomic mononuclear DNA methylation and transcriptome sequencing (snmCT-seq) in the frontal cortex of young adult and elderly donors, we found widespread age- and sex-related variation in specific neuron types.”

The researchers examined prefrontal cortex neurons in postmortem brain tissue from young adults (aged 23 to 30 years) and older adults (aged 70 to 74 years) of both sexes. They analyzed these neurons using a genetic technique known as single-nucleus DNA multi-omics transcriptome and methylome sequencing (snmCT-seq).

The team compiled a large dataset containing the profiles of more than 55,000 cells extracted from a total of 11 human donors. While some cellular processes were found to be stable across individuals, others appeared to vary depending on the person’s age and sex.

“The proportion of inhibitory neurons expressing somatostin (SST) and VIP (vasoactive intestinal polypeptide) was reduced in aged donors,” Chien, Liu, and colleagues wrote. “Excitatory neurons had more profound age-related changes in their gene expression and DNA methylation than inhibitory cells.”

“Hundreds of genes involved in synaptic activity, including EGR1, were less expressed in older adults. Genes located in subtelomeric regions increased their expression with age and were correlated with a reduction in telomere length.”

The researchers’ analyses revealed that the expression of genes involved in synaptic function (i.e., promoting communication between neurons via synapses) decreased with age. The downregulation of these genes was accompanied by an increase in DNA methylation, an epigenetic modification that involves the addition of a methyl group to human DNA.

The researchers also observed notable sex differences in gene expression and DNA methylation. While the frontal cortex of male and female donors contained the same cell types, they found that some genes were more expressed in males (e.g., PDIA2) and others were more expressed in females (e.g., RNA LINC01115).

Typically, women undergo a process called X chromosome inactivation, which involves the deactivation of one of the X chromosomes to align gene expression with that of men (who only have one X chromosome). However, some genes can escape this deactivation and be expressed by both of a woman’s X chromosomes.

The researchers were able to identify DNA methylation patterns that indicate X-associated genes that escape X-chromosome inactivation. One such gene is GEMIN8, which was found to be active in some cell types despite global X-chromosome inactivation.

“We mapped gene expression differences and X-chromosome inactivation escape genes across cell types,” Chien, Liu, and colleagues wrote.

Overall, this study provides additional insight into the age- and sex-specific effects of cell type on human cortical neurons. In the future, the experimental methods employed by these researchers could be used to analyze brain tissue extracted from a larger pool of male and female donors of different ages, as this could help validate their results and potentially lead to interesting new discoveries.

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