《生命科学》 2026, 38(6): 1114-1123
脑衰老与表观遗传学的研究进展
摘 要：
全球老龄化趋势日益加剧，脑衰老作为老龄化进程中核心的生理功能衰退过程，具体表现为大脑结构、功能及细胞层面的多方面退化，是阿尔茨海默病、帕金森病等神经退行性疾病的重要危险因素。表观遗传调控作为基因表达的关键调控机制，其失调已被证实是驱动衰老的核心因素之一，在脑衰老进程中发挥至关重要的作用。本文综述了脑衰老相关的表观遗传调控机制及研究进展，重点介绍了DNA甲基化、组蛋白修饰及非编码RNA三大核心表观遗传修饰的作用模式。
通讯作者：张 娟 , Email:zj2014@ustc.edu.cn 刘 强 , Email:liuq2012@ustc.edu.cn
Abstract:
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 in excitatory neurons, leading to genomic instability. In neural stem cells, diminished H3K4me3 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 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 and NEAT1 are emerging as key regulators in neurodegeneration, with Meg3 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.
Communication Author：ZHANG Juan , Email:zj2014@ustc.edu.cn LIU Qiang , Email:liuq2012@ustc.edu.cn
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