Institute of Neuroscience and State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China.
University of Chinese Academy of Sciences, Beijing, China.
Nature. 2020 Mar;579(7797):118-122. doi: 10.1038/s41586-020-2037-y. Epub 2020 Feb 26.
It has long been assumed that lifespan and healthspan correlate strongly, yet the two can be clearly dissociated. Although there has been a global increase in human life expectancy, increasing longevity is rarely accompanied by an extended healthspan. Thus, understanding the origin of healthy behaviours in old people remains an important and challenging task. Here we report a conserved epigenetic mechanism underlying healthy ageing. Through genome-wide RNA-interference-based screening of genes that regulate behavioural deterioration in ageing Caenorhabditis elegans, we identify 59 genes as potential modulators of the rate of age-related behavioural deterioration. Among these modulators, we found that a neuronal epigenetic reader, BAZ-2, and a neuronal histone 3 lysine 9 methyltransferase, SET-6, accelerate behavioural deterioration in C. elegans by reducing mitochondrial function, repressing the expression of nuclear-encoded mitochondrial proteins. This mechanism is conserved in cultured mouse neurons and human cells. Examination of human databases shows that expression of the human orthologues of these C. elegans regulators, BAZ2B and EHMT1, in the frontal cortex increases with age and correlates positively with the progression of Alzheimer's disease. Furthermore, ablation of Baz2b, the mouse orthologue of BAZ-2, attenuates age-dependent body-weight gain and prevents cognitive decline in ageing mice. Thus our genome-wide RNA-interference screen in C. elegans has unravelled conserved epigenetic negative regulators of ageing, suggesting possible ways to achieve healthy ageing.
长期以来，人们一直认为寿命和健康寿命密切相关，但实际上两者可以明确区分开来。尽管人类的预期寿命在全球范围内有所增加，但长寿的增加很少伴随着健康寿命的延长。因此，了解老年人健康行为的起源仍然是一个重要且具有挑战性的任务。在这里，我们报告了一个保守的表观遗传机制，它是健康衰老的基础。通过基于全基因组 RNA 干扰的筛选，研究了调节衰老过程中秀丽隐杆线虫行为恶化的基因，我们鉴定出 59 个基因作为潜在的与年龄相关行为恶化相关的调节剂。在这些调节剂中，我们发现神经元表观遗传阅读器 BAZ-2 和神经元组蛋白 3 赖氨酸 9 甲基转移酶 SET-6 通过降低线粒体功能、抑制核编码线粒体蛋白的表达，加速了秀丽隐杆线虫的行为恶化。这种机制在培养的小鼠神经元和人类细胞中是保守的。对人类数据库的检查表明，这些秀丽隐杆线虫调节剂的人类同源物 BAZ2B 和 EHMT1 的表达在前额皮层中随年龄增加而增加，并与阿尔茨海默病的进展呈正相关。此外，Baz2b（BAZ-2 的小鼠同源物）的缺失会减轻衰老小鼠体重随年龄增长的增加，并防止认知能力下降。因此，我们在秀丽隐杆线虫中的全基因组 RNA 干扰筛选揭示了衰老的保守表观遗传负调节剂，这为实现健康衰老提供了可能的途径。
