Shengming Kexue · Jun 2026
Recent advances in brain aging and epigenetics
By LIU HD, ZHANG J, LIU Q
<?A3B2 tlsb=.01w?>The global increase in the aging population presents a significant public health challenge, with brain aging at its core. Brain aging is a complex process of physiological decline characterized by structural degeneration (e.g., atrophy, white matter deterioration), functional cognitive loss, and increased susceptibility to neurodegenerative diseases like Alzheimer′s disease (AD). Epigenetic dysregulation has emerged as a fundamental driver of this process. This review synthesizes recent advances in understanding how three primary epigenetic mechanisms—DNA methylation, histone modifications, and non-coding RNAs—orchestrate the molecular landscape of the aging brain. DNA methylation patterns undergo profound, cell-type-specific changes with age. The construction of ″epigenetic clocks″ based on DNA methylation has provided a powerful tool to estimate biological age and predict healthspan. In the brain, excitatory neurons are particularly vulnerable, exhibiting age-related hypermethylation and transcriptional repression of genes critical for synaptic function. Conversely, microglia show hypomethylation at pro-inflammatory gene promoters, contributing to a chronic neuroinflammatory state that characterizes the aging brain. These alterations are not uniform, with distinct brain regions like the hypothalamus displaying unique age-related methylation dynamics that may act as early drivers of systemic aging. Histone modifications also play a pivotal role in remodeling the chromatin landscape during aging. A notable example is the cell-type-specific loss of heterochromatin marker H3K9me3 <?A3B2 pi129?>in excitatory neurons, leading to genomic instability. In neural stem cells, diminished H3K4me3 <?A3B2 pi129?>at key developmental genes impairs neurogenesis. In Alzheimer′s disease, a widespread gain of H3K27ac and H3K9ac at genes related to transcription and immunity suggests an epigenetic reprogramming that exacerbates pathology. Furthermore, metabolic pathways intersect with epigenetics, as reduced levels of the enzyme ACSS2 <?A3B2 pi129?>in AD models lead to decreased histone acetylation and subsequent downregulation of synaptic genes. Non-coding RNAs (ncRNAs) add another layer of regulatory complexity. MicroRNAs (miRNAs) exhibit brain-region-specific and sex-specific expression changes with age, targeting pathways involved in synaptic plasticity, inflammation, and neurodegeneration. For instance, a trio of miRNAs (miR-181a-5p, miR-148a-3p, miR-146a-5p) has been directly linked to cognitive decline, and their inhibition can restore function in aged mice. Novel classes of ncRNAs, such as tRNA-derived fragments (tsRNAs), are also implicated; one fragment, Glu-5′tsRNA-CTC, accumulates in aged mitochondria, impairing glutamate synthesis and memory. Long non-coding RNAs (lncRNAs) like Meg3 <?A3B2 pi129?>and NEAT1 <?A3B2 pi129?>are emerging as key regulators in neurodegeneration, with Meg3 <?A3B2 pi129?>specifically triggering a human-specific form of neuronal death. In conclusion, epigenetic regulation in brain aging is characterized by cell-type specificity, intricate crosstalk between different modification systems, and a direct link to pathological states. Future research leveraging single-cell technologies will be crucial to deconvolve this complexity further. The reversible nature of epigenetic marks offers promising avenues for developing novel biomarkers for early diagnosis and targeted therapies to mitigate cognitive decline and promote healthy brain aging.