Temporal changes in the gene expression heterogeneity during brain development and aging

Abstract

cells in largely non-mitotic tissues such as the brain are prone to stochastic (epi-)genetic alterations that may cause increased variability between cells and individuals over time. Although increased interindividual heterogeneity in gene expression was previously reported, whether this process starts during development or if it is restricted to the aging period has not yet been studied. the regulatory dynamics and functional significance of putative aging-related heterogeneity are also unknown. Here we address these by a meta-analysis of 19 transcriptome datasets from three independent studies, covering diverse human brain regions. We observed a significant increase in inter-individual heterogeneity during aging (20 + years) compared to postnatal development (0 to 20 years). Increased heterogeneity during aging was consistent among different brain regions at the gene level and associated with lifespan regulation and neuronal functions. overall, our results show that increased expression heterogeneity is a characteristic of aging human brain, and may influence aging-related changes in brain functions. Aging is a complex process characterized by a gradual decline in maintenance and repair mechanisms, accompanied by an increase in genetic and epigenetic mutations, and oxidative damage to nucleic acids, protein and lipids 1,2. The human brain experiences dramatic structural and functional changes in the course of aging. These include decline in gray matter and white matter volumes 3 , increase in axonal bouton dynamics 4 and reduced synaptic plasticity, all processes that may be associated with decline in cognitive functions 5. Changes during brain aging are suggested to be a result of stochastic processes, unlike changes associated with postnatal neuronal development that are known to be primarily controlled by adaptive regulatory processes 6-8. The molecular mechanisms underlying age-related alteration of regulatory processes and eventually leading to aging-related phenotypes, however, are little understood. Over the past decade, a number of transcriptome studies focusing on age-related changes in human brain gene expression profiles were published 2,9-12. These studies report aging-related differential expression patterns in many functions, including synaptic functions, energy metabolism, inflammation, stress response, and DNA repair. By analyzing age-related change in gene expression profiles in diverse brain regions, we previously showed that for many genes, gene expression changes occur in opposite directions during postnatal development (pre-20 years of age) and aging (post-20 years of age), which may be associated with aging-related phenotypes in healthy brain aging 13. While different brain regions are associated with specific, and often independent, gene expression profiles 9,10,12 , these studies also show that age-related alteration of gene expression profiles during aging is a widespread effect across different brain regions. One of the suggested effects of aging is increased variability between indivi...

Asynchronous, contagious and digital aging

“…In Drosophila, gut and skeletal muscle dysfunction appear to be primary drivers of aging and mortality [39][40][41][42] . As mentioned above, transcriptomic studies strongly agree that tissues, organs and even subregions within an organ such as the brain age at different rates 32,33 . This is consistent with findings from studies in rats of organ-specific changes in the transcriptome and proteome with age 43 .…”

“…Transcriptional changes in 17 organs across ten ages from neonatal to 30-month-old mice showed very different trajectories of aging with varied onset and amplitudes of changes 32 . In humans, a meta-analysis of >300 brains and 17 brain regions showed broad nonlinear changes in gene expression that varied across brain regions with age 33 . Similarly, DNA methylation, which shows a remarkable correlation with aging across species, was reported to be 24 times faster during the first…”

Universal DNA methylation age across mammalian tissues

“…Consistent with increased methylation, expression of both LHFPL4 and LHFPL3 declines with increasing age in numerous, albeit not all, human and mouse tissues ( Supplementary Tables 4.1-4.4 ). In particular, their reduced expression is consistently observed in the brain 3,4 . Importantly, age-related methylation changes in young animals concur strongly with those observed in middle-aged or old animals, excluding the likelihood that the changes are those involved purely in the process of organismal development ( Extended Data Figs.…”

Genome-wide transcript and protein analysis reveals distinct features of aging in the mouse heart

“…These findings indicate that post-transcriptional regulation may play a substantial role in aging. In addition, there are reports in literature describing the increase of transcript expression variability with age in mammalian tissues, including the heart (12,13). The agerelated dysregulation of some functional modules at the transcript level is accompanied by selective translation, therefore, the post-transcriptional machinery becomes crucial for achieving cellular homeostasis (14).…”