SIRT2 induces the checkpoint kinase BubR1 to increase lifespan
SIRT2 induces the checkpoint kinase BubR1 to increase lifespan
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DOI：
10.15252/embj.201386907
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发表时间：
2014-07-01
期刊：
影响因子：
11.4
通讯作者：
Sinclair, David A.
中科院分区：
文献类型：
--
作者：
North, Brian J.;Rosenberg, Michael A.;Sinclair, David A.
过表达有丝分裂检查点激酶基因BubR 1的小鼠寿命更长，而BubR 1（H/H）的小鼠寿命更短，并显示出加速衰老的迹象。随着野生型小鼠年龄的增长，许多组织中的BubR 1水平下降，这一过程被认为是正常衰老和年龄相关疾病的基础。因此，了解为什么BubR 1随着年龄的增长而下降以及如何减缓这一过程具有相当大的意义。sirtuins（SIRT 1 -7）是NAD（+）依赖性去乙酰化酶家族，可以延缓年龄相关疾病。在这里，我们表明BubR 1水平随着年龄的增长而下降是由于NAD（+）下降和SIRT 2维持BubR 1赖氨酸-668处于脱乙酰状态的能力，这被乙酰转移酶CBP抵消。SIRT 2的过表达或用NAD+前体烟酰胺单核苷酸（NMN）处理小鼠增加体内BubR 1丰度。在BubR 1（H/H）动物中SIRT 2的过表达增加了中位寿命，在雄性小鼠中效果更大。总之，这些数据表明，有必要进一步探索SIRT 2和NAD（+）延缓哺乳动物衰老疾病的潜力。
Mice overexpressing the mitotic checkpoint kinase gene BubR1 live longer, whereas mice hypomorphic for BubR1 (BubR1(H/H)) live shorter and show signs of accelerated aging. As wild-type mice age, BubR1 levels decline in many tissues, a process that is proposed to underlie normal aging and age-related diseases. Understanding why BubR1 declines with age and how to slow this process is therefore of considerable interest. The sirtuins (SIRT1-7) are a family of NAD(+)-dependent deacetylases that can delay age-related diseases. Here, we show that the loss of BubR1 levels with age is due to a decline in NAD(+) and the ability of SIRT2 to maintain lysine-668 of BubR1 in a deacetylated state, which is counteracted by the acetyltransferase CBP. Overexpression of SIRT2 or treatment of mice with the NAD+ precursor nicotinamide mononucleotide (NMN) increases BubR1 abundance in vivo. Overexpression of SIRT2 in BubR1(H/H) animals increases median lifespan, with a greater effect in male mice. Together, these data indicate that further exploration of the potential of SIRT2 and NAD(+) to delay diseases of aging in mammals is warranted.