Two conserved epigenetic regulators prevent healthy ageing
Two conserved epigenetic regulators prevent healthy ageing
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DOI：
10.1038/s41586-020-2037-y
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发表时间：
2020-02
期刊：
影响因子：
64.8
通讯作者：
Jie Yuan;Si-yuan Chang;Shirley Yin;Zhi-Yang Liu;Xiu Cheng;Xi-Juan Liu;Qiang Jiang;Ge Gao;De-Ying Lin;Xin-Lei Kang;Shiyun Ye;Zheng Chen;Jiang-An Yin;Pei Hao;Lubing Jiang;Shi-Qing Cai
中科院分区：
文献类型：
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作者：
Jie Yuan;Si-yuan Chang;Shirley Yin;Zhi-Yang Liu;Xiu Cheng;Xi-Juan Liu;Qiang Jiang;Ge Gao;De-Ying Lin;Xin-Lei Kang;Shiyun Ye;Zheng Chen;Jiang-An Yin;Pei Hao;Lubing Jiang;Shi-Qing Cai
长期以来，人们一直认为寿命和健康寿命密切相关，但两者可以明显分离。虽然人类的预期寿命在全球范围内有所增加，但寿命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项重要而具有挑战性的任务。在这里，我们报告了一个保守的表观遗传机制的健康老龄化。通过全基因组RNA干扰为基础的筛选基因，调节行为恶化的agingCaelorhabditis秀丽隐杆线虫，我们确定了59个基因作为潜在的调制器的速度与年龄相关的行为恶化。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加速了C中的行为恶化。elegans通过降低线粒体功能，抑制核编码的线粒体蛋白的表达。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显示，这些C.额叶皮层中的elegans调节因子BAZ 2B和EHMT 1随着年龄的增长而增加，并与阿尔茨海默病的进展呈正相关。此外，BAZ-2的小鼠直向同源物Baz 2b的消融减弱了年龄依赖性体重增加，并防止了衰老小鼠的认知能力下降。因此，我们的全基因组RNA干扰筛选在C。eleganshas揭示了衰老的保守表观遗传负调节因子，提出了实现健康衰老的可能途径。
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 ageingCaenorhabditis 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 inC. elegansby 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 theseC. elegansregulators, 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 inC. eleganshas unravelled conserved epigenetic negative regulators of ageing, suggesting possible ways to achieve healthy ageing.