Study reveals how aging accelerates molecular changes in the brain, offering new hope for tackling cognitive decline and mental illness.
Resource: Transcriptional profiling of a human frontal cortex nucleus reveals convergent effects of aging and psychiatric disease. Image credit: Atthapon Rakshaput / Shutterstock
In a recent study published in the journal Nature Neuroscience, The researchers used next-generation single-stranded RNA sequencing (snRNA-seq) techniques to elucidate the age-related gene expression changes that occur in cells of the frontal cortex (OFC). They further investigated the transcriptional changes in different cell types that occur in OFC cells due to various common psychiatric disorders such as schizophrenia (SCZ) and Alzheimer’s disease (AD).
Their findings reveal that the biological mechanisms (specifically changes in gene expression) that underlie cognitive dysfunction and memory loss due to aging show a remarkable convergence with those seen in psychiatric patients, particularly those diagnosed with AD. They identified LAMP5+LHX6+ interneurons as cells showing the most significant degree of age-related alteration. Specifically, aging-related changes appear to be accelerated in patients with pre-existing psychiatric conditions.
These findings represent important advances in our understanding of cognitive aging and may form the basis for the development of new therapeutic interventions against age-related pathologies.
Background
Aging is a natural and complex process characterized by the deterioration of normal (physical and mental) functions necessary for life. Unfortunately, the mechanisms that underpin aging remain poorly understood, particularly those related to the brain. Extensive research in mice, nonhuman primates, and, in rare cases, human postmortem tissue has revealed that aging brains differ structurally and functionally from their younger counterparts.
The sharpest distinctions between young and old brains can be seen 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. In contrast, most psychiatric conditions are known to worsen with advancing age. Unfortunately, the molecular mechanisms and gene expression changes underpinning these observations remain unclear.
Medical advances ensure that human life expectancy continues to increase, resulting in a greater proportion of elderly people and thus age-related diseases than ever before. The concurrent increase in the incidence and prevalence of psychiatric disorders makes understanding the cellular-level biological changes that occur in both aging and neurodegenerative disorders a critical first step in the future development of therapeutic interventions against these often debilitating conditions.
About the study
The present study aimed to address current cognitive gaps through transcriptomic analysis of nuclei extracted from the orbitofrontal cortex (OFC) of postmortem human brains (both neurotypical and with psychiatric disorders) across all age groups (26–84 years), thereby elucidating the alterations of the gene expression is related to the two pathologies.
Samples for the study (n = 87) were obtained from the New South Wales Brain Resource Center with written consent from donors or their immediate families. People with a psychiatric diagnosis (bipolar disorder, major depressive disorder [MDD]schizophrenia [SCZ]) were classified as the psychiatric cohort (n = 54), while those without were included in the neurotypical cohort (n = 33). Dounce homogenization of samples immersed in nucleus extraction buffer was used to extract nuclei for downstream analysis.
The Chromium Single Cell 3′ Reagent Kit v3.1, coupled with the Illumina NovaSeq 6000 system, was used to prepare a single-stranded RNA-seq (snRNA-seq) library 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 tagged with known marker genes from the Allen Brain Atlas.
Age-related cell composition was calculated by comparing the proportions of observed cell types with the corresponding age of the donor at death. A similar approach using snRNA-seq data instead of absolute cell ratios was used to elucidate transcriptional differences (‘differential expression’ [DE]) across all age groups and to identify cells with the highest degree of age-related gene expression alterations.
Comparisons between DE results from neurotypical and psychiatric brains were used to elucidate signatures (common and unique) in the two pathologies (age and disease). To determine whether the observed transcriptional alterations could lead to cell type-specific contributions to cognitive decline and other neurodegenerative outcomes, an over-representation analysis was performed.
“To validate our cell type findings, we compared our identified DE genes in microglia and astrocytes (major cell type cluster) to datasets that have identified gene expression changes during aging in purified microglia and astrocytes from brain cortex, respectively.”
Study findings
Nuclei successfully extracted from donor OFCs totaled ~800,000. Demographic and neuropathological assessments between neurotypical and psychiatric patient brains revealed statistical similarities between ages, sex, postmortem interval (PMI) and RNA integrity number (RIN), validating biologically meaningful comparisons between these cohorts.
Analysis of cell composition revealed that the abundance of most cell types did not decrease with age. Oligodendrocyte progenitor cells (OPCs) were the only exception, showing significant age-related decreases in their relative proportions. Interestingly, while OPCs decreased, there was a trend towards an increase in oligodendrocytes, highlighting the complex nature of cellular changes with aging. In contrast, all cell types investigated showed significant age-related alterations (DE n = 3,299) in their transcriptional profiles. Excitatory neurons of the upper layer were more affected by advanced age.
It was observed that DE from both age-related pathologies and psychiatric overlap/convergence, particularly in oligodendrocytes and astrocytes. Specifically, psychiatric conditions were found to accelerate age-related AD, highlighting the cumulative effects of their molecular pathways.
“Analysis of differential gene expression within the 21 cell types identified showed that all cell types are affected by aging and that the majority of age-related transcriptional changes are cell type specific. However, one 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 the primate cortex and to be most similar to mouse hippocampal ivy cells.”
conclusions
This study highlights the overlap in differential cell type-specific gene expression that accompanies natural aging and psychiatric disease. It characterizes these changes, thoroughly 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 diseases by identifying their common molecular underpinnings.
Exciting new results from single-nuclear RNA sequencing of 800,000 nuclei from 90 postmortem brain samples showing convergent effects of aging and #Alzheimer disease and others #psychiatric disorders.��
— Max Planck Institute of Psychiatry (@mpi_psychiatry) September 3, 2024
