Mapping the Aging Brain: A Single-Cell View of Transcriptomic Changes

By Dr. Chinta SidharthanReviewed by Lily Ramsey, LLMJan 9 2025

Aging is a natural process involving gradual changes in cellular and molecular systems that affect organismal function and health. In the brain, aging impacts diverse cell types, potentially altering their functions in distinct ways.

In a recent study published in Nature, a team of scientists from the Allen Institute for Brain Science in the United States explored how healthy aging influences gene expression across brain cell types in mice.

Using advanced single-cell ribonucleic acid (RNA) sequencing, the researchers analyzed over 1.2 million transcriptomes from young and aged mice to identify cell-specific and region-specific gene expression patterns.

​​​​​​​Study: Brain-wide cell-type-specific transcriptomic signatures of healthy ageing in mice. Image Credit: Josh Namdar/Shutterstock.com

Background

Aging disrupts the balance of molecular and cellular processes, including those in the brain, affecting a wide variety of specialized cell types. Research has identified broad hallmarks of aging, such as inflammation, neuronal dysfunction, and cellular senescence, which are conserved across organisms.

Recent studies using transcriptomics have also uncovered age-associated changes in specific brain regions and cell types, revealing complex variations in aging responses.

However, the understanding of aging at the cell-type level across the brain remains incomplete. Furthermore, although earlier studies have demonstrated gene expression shifts in targeted brain regions, whole-brain analyses have hitherto been limited by technical constraints.

Advances in single-cell technologies have now made it possible to capture a comprehensive view of how diverse neuronal and non-neuronal cells age. Despite these advances, significant gaps remain in understanding how these changes affect brain function and interact with systemic aging.

The Current Study

The present study employed single-cell RNA sequencing to investigate how aging affects gene expression across diverse brain cell types. The researchers collected brain tissue from young, 2-month-old mice and aged male and female mice that were 18 months old, covering regions from the forebrain, midbrain, and hindbrain.

Using advanced sequencing technologies and fluorescence-activated cell sorting, they generated a dataset comprising over 1.2 million high-quality cell transcriptomes. The dataset included neurons and non-neuronal cells, which allowed them to draw detailed comparisons across cell classes.

The team categorized the cells into 172 transcriptomic subclasses, which spanned 25 cell classes. They identified age-associated genes using computational models and statistical approaches, such as the MAST method and pseudo-bulk analysis. These methods accounted for factors such as gene detection rates and biological variability.

The study also employed spatial transcriptomics to validate findings, focusing on regions with significant age-related changes.

Additionally, high-resolution clustering was also conducted to examine cell-type-specific and region-specific aging patterns. Cell types associated with energy regulation and immune responses, including tanycytes and ependymal cells, were examined for aging signatures.

Additionally, the study analyzed changes in less abundant cell types, such as immature neurons and major subclasses of oligodendrocytes. The comprehensive analysis included gene ontology assessments to identify biological processes affected by aging, such as neuronal structure maintenance, immune activity, and inflammation.

Results

The researchers observed that aging significantly alters gene expression across brain cell types, with both unique and shared patterns. Neurons exhibited reduced expression of genes associated with signaling and structural functions, particularly in the hypothalamus, while non-neuronal cells showed increased expression of immune-related and inflammatory genes.

One of the most important findings was the discovery of cell-type-specific aging effects in glial cells, vascular cells, and neurons.

Tanycytes, which are specialized glial cells found in the hypothalamus, and ependymal cells near the hypothalamus exhibited marked age-related gene expression changes, with increased immune response and reduced neurogenic potential.

This suggested that cells that were critical for energy balance and cerebrospinal fluid circulation may be particularly vulnerable to aging.

The analysis revealed a decrease in the abundance and function of immature neurons in neurogenic regions, consistent with declining neurogenesis during aging.

Oligodendrocytes also showed altered gene expression, including changes related to myelin maintenance and lipid metabolism, which could compromise white matter integrity.

Additionally, vascular cells exhibited diverse responses, with endothelial cells showing increased expression of protective and inflammatory genes, while pericytes were significantly reduced. Microglia also displayed pro-inflammatory changes, with specific clusters enriched in aging brains, suggesting region-specific immune activation.

Aging was also linked to significant transcriptomic shifts in hypothalamic neurons, including those regulating energy homeostasis. These neurons showed concurrent declines in structural gene expression and increases in immune-related genes, indicating dual impacts of aging on neuronal integrity and immune function.

The results revealed that the hypothalamus was a critical hub of aging in the brain, with extensive changes in neuronal and non-neuronal cell types in the region.

Conclusions

Overall, the study systematically mapped how aging affects gene expression in brain cells and uncovered cell-type-specific and region-specific aging signatures in murine models.

It identified the hypothalamus as a major hub of aging, with pronounced changes in neurons and glial cells involved in energy regulation and immune responses.

These findings also provided a foundation for exploring therapeutic strategies to address age-related functional declines and promote healthy aging.