Scientists uncover shared gene expression patterns in aging and psychiatric disorders

Research shows how aging accelerates molecular changes in the brain, offering new hope for tackling cognitive decline and mental illness.

Source: Single-nucleus transcriptomic profiling of the human orbitofrontal cortex reveals convergent effects of aging and psychiatric diseases. Image credits: Atthapon Raksthaput / Shutterstock

This is evident from a recent study published in the journal Nature Neuroscience, researchers used next-generation single-nucleus RNA sequencing (snRNA-seq) techniques to elucidate age-related gene expression changes that occur in orbitofrontal cortex (OFC) cells. They further examined transcriptomic changes in different cell types that occur in OFC cells due to several common psychiatric disorders such as schizophrenia (SCZ) and Alzheimer’s disease (AD).

Their findings reveal that the biological mechanisms (particularly the changes in gene expression) underlying cognitive dysfunction and memory loss due to aging show a remarkable convergence with those observed in psychiatric patients, especially those diagnosed with AD. They identified themselves LAMP5⁺LHX6⁺ interneurons are the cells that experience the most significant degree of age-related change. Notably, aging-associated changes appear to be accelerated in patients with pre-existing psychiatric conditions.

These findings represent a substantial advance in our understanding of cognitive aging and may provide the basis for the development of novel therapeutic interventions against age-related pathologies.

Background

Aging is a natural and complex process characterized by the deterioration of physiological (physical and mental) functions necessary for life. Unfortunately, the mechanisms underlying aging remain poorly understood, especially those related to the brain. Extensive research in mice, non-human primates and, rarely, human postmortem tissue has shown that aging brains are structurally and functionally different from their younger counterparts.

The sharpest distinction between young and old brains can be observed in the 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. Conversely, most psychiatric conditions are known to worsen with age. Unfortunately, the molecular mechanisms and gene expression changes that support these observations remain elusive.

Medical advances ensure that human life expectancy continues to increase, resulting in a greater proportion of elderly people and therefore age-related diseases than ever before. A concurrent increase in the incidence and prevalence of psychiatric 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 debilitating conditions.

About the study

The present study aimed to address current knowledge gaps through transcriptomic analysis of nuclei extracted from the orbitofrontal cortex (OFC) of postmortem human brains (both neurotypical and with psychiatric disorders) in age groups (26–84 years), allowing the changes in gene expression are elucidated. associated with the two pathologies.

Samples for the study (n = 87) were obtained from the New South Wales Brain Tissue Resource Center with written consent from donors or their immediate families. Persons with a psychiatric diagnosis (bipolar disorder, depressive disorder [MDD]schizophrenia [SCZ]) were classified as the psychiatric cohort (n = 54), while those without a cohort were included in the neurotypical cohort (n = 33). Dounce homogenization of samples immersed in nuclear extraction buffer was used to extract nuclei for downstream analysis.

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

The age-related cellular composition was estimated by comparing the proportions of the observed cell types with the corresponding donor age at death. A similar approach using snRNA-seq data instead of absolute cell proportions was used to elucidate transcriptomic differences (‘differential expression’ [DE]) across age groups and to identify cells with the highest degree of age-related gene expression changes.

Comparisons between DE results from neurotypical and psychiatric brains were used to elucidate features (shared and unique) of the two pathologies (age and disease). To identify whether observed transcriptomic changes could result in cell type-specific contributions to cognitive decline and other neurodegenerative outcomes, an overrepresentation analysis was performed.

“To validate our cell type-specific findings, we compared our identified DE genes in microglia and astrocytes (main cell type cluster) to datasets that identified gene expression changes over the course of aging in purified microglia and astrocytes from the cerebral cortex respectively.”

Findings of the study

The number of successfully extracted nuclei from donor OFCs totaled ~800,000. Demographic and neuropathological evaluations between neurotypical and psychiatric patient brains revealed statistical similarities between their age, sex, postmortem interval (PMI), and RNA integrity number (RIN), validating biologically meaningful comparisons between these cohorts.

Cell composition analysis revealed that the abundance of most cell types did not decrease with age. Oligodendrocyte progenitor cells (OPCs) were the only exception and showed significant age-related decreases in their relative proportions. Interestingly, although OPCs decreased, there was a trend of increasing oligodendrocytes, highlighting the complex nature of cellular changes in aging. In contrast, all cell types examined showed substantial changes (DE n = 3,299) in their age-related transcriptome profiles. Excitatory neurons in the upper layer were most affected by aging.

DE from both age- and psychiatric-associated pathologies were observed to overlap/converge, especially in oligodendrocytes and astrocytes. Notably, psychiatric disorders were found to accelerate age-related DE, highlighting the additive effects of their molecular pathways.

“Differential gene expression analysis within the identified 21 cell types indicated that all cell types are affected by aging and that the majority of age-related transcriptional changes are cell type specific. A specific cell type (inhibitory LAMP5)⁺LHX6⁺ neurons (In_LAMP5_2)) appear to be most affected by aging. Interestingly, this LAMP5⁺LHX6⁺ The subtype has been reported to increase in abundance in primate cortex and most closely resemble ivy cells of the mouse hippocampus.”

Conclusions

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

Exciting new results from single-core RNA sequencing of 800,000 nuclei from 90 postmortem brain samples that reveal converging effects of aging and #Alzheimer’s illness and others #psychiatric disorders.��https://t.co/NriayHyzLj

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