Epigenetic ageing of the prefrontal cortex and cerebellum in humans and chimpanzees

ABSTRACT Epigenetic age has emerged as an important biomarker of biological ageing. It has revealed that some tissues age faster than others, which is vital to understanding the complex phenomenon of ageing and developing effective interventions. Previous studies have demonstrated that humans exhibit heterogeneity in pace of epigenetic ageing among brain structures that are consistent with differences in structural and microanatomical deterioration. Here, we add comparative data on epigenetic brain ageing for chimpanzees, humans’ closest relatives. Such comparisons can further our understanding of which aspects of human ageing are evolutionarily conserved or specific to our species, especially given that humans are distinguished by a long lifespan, large brain, and, potentially, more severe neurodegeneration with age. Specifically, we investigated epigenetic ageing of the dorsolateral prefrontal cortex and cerebellum, of humans and chimpanzees by generating genome-wide CpG methylation data and applying established epigenetic clock algorithms to produce estimates of biological age for these tissues. We found that both species exhibit relatively slow epigenetic ageing in the brain relative to blood. Between brain structures, humans show a faster rate of epigenetic ageing in the dorsolateral prefrontal cortex compared to the cerebellum, which is consistent with previous findings. Chimpanzees, in contrast, show comparable rates of epigenetic ageing in the two brain structures. Greater epigenetic change in the human dorsolateral prefrontal cortex compared to the cerebellum may reflect both the protracted development of this structure in humans and its greater age-related vulnerability to neurodegenerative pathology.

摘要 表观遗传年龄已成为生物衰老的一个重要生物标志物。它表明某些组织比其他组织衰老得更快，这对于理解衰老这一复杂现象以及制定有效的干预措施至关重要。先前的研究已经证明，人类大脑结构之间的表观遗传衰老速度存在异质性，这与结构和微观解剖学退化的差异是一致的。在此，我们增加了黑猩猩（人类的近亲）大脑表观遗传衰老的对比数据。这种比较可以进一步加深我们对人类衰老的哪些方面在进化上是保守的，或者是我们人类所特有的理解，特别是考虑到人类以长寿、大脑大以及可能随着年龄增长更严重的神经退行性变为特征。具体而言，我们通过生成全基因组CpG甲基化数据，并应用已建立的表观遗传时钟算法来估算这些组织的生物年龄，从而研究了人类和黑猩猩的背外侧前额叶皮质和小脑的表观遗传衰老。我们发现，相对于血液，两个物种的大脑都表现出相对较慢的表观遗传衰老。在大脑结构之间，与小脑相比，人类背外侧前额叶皮质的表观遗传衰老速度更快，这与先前的研究结果一致。相比之下，黑猩猩在这两种大脑结构中的表观遗传衰老速度相当。与小脑相比，人类背外侧前额叶皮质更大的表观遗传变化可能既反映了该结构在人类中的长期发育，也反映了它在年龄相关的神经退行性病变方面具有更大的易感性。