D-beta-hydroxybutyrate extends lifespan in C. elegans.
D-beta-hydroxybutyrate extends lifespan in C. elegans.
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DOI：
10.18632/aging.100683
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发表时间：
2014-08
期刊：
影响因子：
--
通讯作者：
Bradshaw PC
中科院分区：
文献类型：
--
作者：
Edwards C;Canfield J;Copes N;Rehan M;Lipps D;Bradshaw PC
酮体β -羟基丁酸（βHB）是一种组蛋白去乙酰化酶（HDAC）抑制剂，已在许多疾病模型中显示出保护作用，但其对衰老的影响尚未得到很好的研究。因此，我们确定了βHB补充对秀丽隐杆线虫寿命的影响。补充βHB可使平均寿命延长约20%。RNAi敲低hdac的hda-2或hda-3也能延长寿命，并进一步阻止β hb介导的寿命延长。β hb介导的寿命延长需要DAF-16/FOXO和SKN-1/Nrf寿命通路、sirtuin SIR-2.1和AMP激酶亚基AAK-2。在饮食限制的遗传模型中，βHB没有延长寿命，这表明βHB可能通过类似的机制起作用。添加βHB也上调了βHB脱氢酶的活性，增加了蠕虫的耗氧量。RNAi敲低短链脱氢酶和SKN-1靶基因F55E10.6，可抑制βHB添加诱导的βHB脱氢酶活性和寿命增加，提示F55E10.6具有诱导型βHB脱氢酶的功能。此外，补充βHB提高了线虫的耐热性，并部分阻止了葡萄糖毒性。它还能延缓阿尔茨海默病的淀粉样蛋白毒性，降低帕金森病的α -突触核蛋白聚集。结果表明，D-βHB通过抑制hdac和激活保守的应激反应途径延长寿命。
The ketone body beta-hydroxybutyrate (βHB) is a histone deacetylase (HDAC) inhibitor and has been shown to be protective in many disease models, but its effects on aging are not well studied. Therefore we determined the effect of βHB supplementation on the lifespan of C. elegans nematodes. βHB supplementation extended mean lifespan by approximately 20%. RNAi knockdown of HDACs hda-2 or hda-3 also increased lifespan and further prevented βHB-mediated lifespan extension. βHB-mediated lifespan extension required the DAF-16/FOXO and SKN-1/Nrf longevity pathways, the sirtuin SIR-2.1, and the AMP kinase subunit AAK-2. βHB did not extend lifespan in a genetic model of dietary restriction indicating that βHB is likely functioning through a similar mechanism. βHB addition also upregulated βHB dehydrogenase activity and increased oxygen consumption in the worms. RNAi knockdown of F55E10.6, a short chain dehydrogenase and SKN-1 target gene, prevented the increased lifespan and βHB dehydrogenase activity induced by βHB addition, suggesting that F55E10.6 functions as an inducible βHB dehydrogenase. Furthermore, βHB supplementation increased worm thermotolerance and partially prevented glucose toxicity. It also delayed Alzheimer's amyloid-beta toxicity and decreased Parkinson's alpha-synuclein aggregation. The results indicate that D-βHB extends lifespan through inhibiting HDACs and through the activation of conserved stress response pathways.
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影响因子：
3.7
作者：
Edwards CB;Copes N;Brito AG;Canfield J;Bradshaw PC
通讯作者：
Bradshaw PC
影响因子：
64.5
作者：
Budovskaya YV;Wu K;Southworth LK;Jiang M;Tedesco P;Johnson TE;Kim SK
通讯作者：
Kim SK
影响因子：
3.5
作者：
Ash, Peter E. A.;Zhang, Yong-Jie;Link, Christopher D.
通讯作者：
Link, Christopher D.
影响因子：
4.8
作者：
Devi, Latha;Raghavendran, Vijayendran;Anandatheerthavarada, Hindupur K.
通讯作者：
Anandatheerthavarada, Hindupur K.
影响因子：
29
作者：
Ahlqvist, Kati J.;Hamalainen, Riikka H.;Suomalainen, Anu
通讯作者：
Suomalainen, Anu