Scientists discover common gene expression patterns in aging and mental disorders

Research reveals how aging accelerates molecular changes in the brain, offering recent hope for fighting cognitive decline and mental illness.

Rescue: Transcriptomic profiling of a single nucleus of the human orbitofrontal cortex reveals convergent effects of aging and mental illness. Photo Source: Atthapon Raksthaput / Shutterstock

In a recent study published in the journal Neurobiology of nature, The researchers used the next-generation single-nuclear RNA sequencing (snRNA-seq) technique to elucidate age-related gene expression changes that occur in cells of the orbitofrontal cortex (OFC). They further investigated the transcriptome changes in different cell types that occur in OFC cells due to various common mental disorders, such as schizophrenia (SCZ) and Alzheimer’s disease (AD).

Their findings reveal that the biological mechanisms (particularly changes in gene expression) underlying cognitive dysfunction and memory loss associated with aging show significant overlap with those observed in psychiatric patients, particularly those diagnosed with Alzheimer’s disease. They identified LAMP5⁺LHX6⁺ interneurons as the cells experiencing the most significant degree of age-related changes. Significantly, age-related changes appear to be accelerated in patients with pre-existing psychiatric conditions.

These results constitute a significant advance in our knowledge of cognitive aging and may become the basis for the development of recent therapeutic interventions against age-related pathologies.

Background

Aging is a natural and complicated process characterized by a decline in physiological (physical and mental) functions imperative to life. Unfortunately, the mechanisms underlying aging remain poorly understood, particularly those related to the brain. Extensive research in mice, nonhuman primates, and in infrequent cases, human postmortem tissue has shown that aging brains differ structurally and functionally from their younger counterparts.

The most pronounced differences between youthful and elderly brains can be observed in white matter tracts and the prefrontal cortex. Interestingly, neuroimaging studies of the brains of younger psychiatric patients reveal similar changes to those found in older neurotypical brains. On the other hand, it is known that most psychiatric conditions worsen with age. Unfortunately, the molecular mechanisms and gene expression changes underlying these observations remain elusive.

Advances in medicine ensure that human life expectancy continues to enhance, resulting in a greater proportion of older people, and therefore age-related diseases, than ever before. The concomitant enhance in the incidence and prevalence of mental disorders makes understanding the biological changes at the cellular level that occur in both aging and neurodegenerative disorders a crucial first step in the future development of therapeutic interventions against these often devastating conditions.

About the study

The aim of the present study was to fill the current knowledge gaps by transcriptome analysis of nuclei collected from the orbitofrontal cortex (OFC) of postmortem human brains (both neurotypical and with psychiatric disorders) in different age groups (26–84 years), which would allow to elucidate the changes in gene expression associated with these two pathologies.

Samples for the study (n = 87) were collected from the Up-to-date South Wales Brain Tissue Resource Centre with written consent from donors or their next of kin. Individuals with psychiatric diagnoses (bipolar disorder, major depression) [MDD]schizophrenia [SCZ]) were classified as the psychiatric cohort (n = 54), whereas those without this group were included in the neurotypical cohort (n = 33). Dounce homogenization of samples immersed in nuclei extraction buffer was used to extract nuclei for further analysis.

The Chromium Single Cell 3′ Reagents v3.1 kit in conjunction with the Illumina NovaSeq 6000 system was used to prepare a single-nucleotide RNA sequencing (snRNA-seq) library with a target recovery of 10,000 for each sample. The resulting sequences were then aligned and demultiplexed using Cell Ranger v6.0.1. These sequences were annotated with known marker genes from the Allen Brain Atlas.

Age-related cellular composition was estimated by comparing the proportions of observed cell types with the age of the corresponding donor at death. A similar approach using snRNA-seq data instead of absolute cell proportions was used to explain transcriptome differences (“differential expression” [DE]) in different age groups and identify cells with the highest degree of changes in age-related gene expression.

Comparisons of DE scores from neurotypical and psychiatric brains were used to elucidate signatures (common and unique) across both pathologies (age and disease). Overrepresentation analysis was performed to determine whether the observed transcriptomic changes could result in cell type-specific causes of cognitive decline and other neurodegenerative outcomes.

“To confirm our findings for specific cell types, we compared the identified DE genes in microglia and astrocytes (a major cell type cluster) with data sets that identified gene expression changes during aging in purified microglia and astrocytes from the cerebral cortex, respectively.”

Research results

The total number of successfully extracted nuclei from donor OFCs was approximately 800,000. Demographic and neuropathological assessments of the brains of neurotypical and psychiatric patients revealed statistical similarities between their age, gender, postmortem interval (PMI), and RNA integrity number (RIN), supporting biologically relevant comparisons between these cohorts.

Analysis of cellular composition revealed that most cell types did not decline in abundance with age. The only exception was oligodendrocyte precursor cells (OPCs), which showed significant age-related decreases in relative proportions. Interestingly, while OPC numbers decreased, there was a trend toward an enhance in oligodendrocyte numbers, emphasizing the complicated nature of cellular changes with age. In contrast, all cell types examined showed significant changes (DE n = 3299) in their age-related transcriptome profiles. The most affected by age were the excitatory neurons of the upper layer.

DE from age-related and psychiatric pathologies was observed to overlap/converge, particularly in oligodendrocytes and astrocytes. Significantly, psychiatric conditions were found to accelerate age-related DE, underlining the additive effects of their molecular pathways.

“Differential gene expression analysis across the 21 identified cell types revealed that aging affects all cell types, and most of the age-related transcriptional changes are cell type specific. However, a specific cell type (LAMP5-inhibiting⁺LHX6⁺ neurons (In_LAMP5_2)) seem to be most affected by aging. Interestingly, this LAMP5⁺LHX6⁺ “This subtype has been reported to be more common in the primate cerebral cortex and most closely resembles the ivy cells of the mouse hippocampus.”

Conclusions

This study highlights the overlap in cell type-specific differential gene expression accompanying natural aging and psychiatric diseases. It characterizes these changes, thereby comprehensively describing the biological pathways associated with loss of neuronal function and cognitive decline in the human OFC. Together, these data provide a crucial first step in discovering therapeutic interventions for both conditions by identifying their common molecular bases.

Thrilling recent single-nucleus RNA sequencing results from 800,000 nuclei from 90 postmortem brain samples show convergent effects of aging and #Alzheimer disease and others #psychiatric disorders.https://t.co/NriayHyzLj

— Max Planck Institute of Psychiatry (@mpi_psychiatry) September 3, 2024