Older molecular brain age in severe mental illness

Abstract

Psychiatric disorders are associated with accelerated aging and enhanced risk for neurodegenerative disorders. Brain aging is associated with molecular, cellular and structural changes that are robust on the group-level, yet show substantial inter-individual variability. Here we assessed deviations in gene expression from normal age-dependent trajectories, and tested their validity as predictors of risk for major mental illnesses and neurodegenerative disorders. We performed large-scale gene expression and genotype analyses in postmortem samples of two frontal cortical brain regions from 214 control subjects aged 20–90 years. Individual estimates of “molecular age” were derived from age-dependent genes, identified by robust regression analysis. Deviation from chronological age was defined as “delta age”. Genetic variants associated with deviations from normal gene expression patterns were identified by expression quantitative trait loci (cis-eQTL) of age-dependent genes or genome-wide association study (GWAS) on delta age, combined into distinct polygenic risk scores (PRS cis-eQTL and PRS GWAS ), and tested for predicting brain disorders or pathology in independent postmortem expression datasets and clinical cohorts. In these validation datasets, molecular ages, defined by 68 and 76 age-related genes for two brain regions respectively, were positively correlated with chronological ages (r=0.88/0.91), elevated in bipolar disorder (BP) and schizophrenia (SCZ), and unchanged in major depressive disorder (MDD). Exploratory analyses in independent clinical datasets show that PRSs were associated with SCZ and MDD diagnostics, and with cognition in SCZ and pathology in Alzheimer’s disease (AD). These results suggest that older molecular brain aging is a common feature of severe mental illnesses and neurodegeneration.

COVID-19-Related Mortality Risk in People With Severe Mental Illness: A Systematic and Critical Review

“…One study found that molecular brain age (i.e., biological age of the brain) was 2–6 years higher than the chronological age in individuals with SZ, and 4.7–7.5 years higher in subjects with BD. No increase in brain aging was noted in subjects with MDD ( 67 ).…”

Depression, aging, and immunity: implications for COVID-19 vaccine immunogenicity

“…However, again this factor is unlikely to fully explain the away the findings as population-based studies that did not limit participants to those treated in hospitals, were the focus of at least one meta-analysis [ 141 ]. Fourth, biological aging has been hypothesized to be accelerated in multiple psychiatric disorders [ 110 , 158 , 159 ] and older age is a risk factor for adverse outcomes after SARS-CoV-2 infection [ 160 , 161 ]. Fifth, psychiatric medications have been proposed as potential moderators of COVID-19 disease severity [ 143 ], although teasing apart the effects of psychiatric disorders from comorbid medical conditions, and the direct pharmacological effect of various classes of anti-depressants, mood-stabilizers, and anti-psychotic medications, is challenging.…”

Network modules linking expression and methylation in prefrontal cortex of schizophrenia

“…Previous studies have investigated different biological ageing biomarkers (e.g., neuroimaging, epigenetics, and proteins) to estimate the biological age against chronological age and reported accelerated ageing process in psychiatric disorders, although how the ageing process interacts with psychiatric diseases is still unclear [87][88][89]. A recent work on gene expression of postmortem brain tissues estimated the 'molecular age' from the age-related genes and found older molecular brain ageing in severe mental illnesses including SZ and BIP [90]. Genetic variants related to the molecular age deviation were also associated with SZ and major depressive disorder diagnostics, suggesting the pleiotropic genetic effect for the ageing process and the diseases [91], which is in line with what we observed here.…”