Altered proteome turnover and remodeling by short-term caloric restriction or rapamycin rejuvenate the aging heart.
Altered proteome turnover and remodeling by short-term caloric restriction or rapamycin rejuvenate the aging heart.
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DOI：
10.1111/acel.12203
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发表时间：
2014-06
期刊：
影响因子：
7.8
通讯作者：
Rabinovitch PS
中科院分区：
文献类型：
--
作者：
Dai DF;Karunadharma PP;Chiao YA;Basisty N;Crispin D;Hsieh EJ;Chen T;Gu H;Djukovic D;Raftery D;Beyer RP;MacCoss MJ;Rabinovitch PS
慢性热量限制（CR）和雷帕霉素抑制雷帕霉素（mTOR）信号传导的机制靶点，从而调节代谢并抑制蛋白质合成。热量限制或雷帕霉素延长小鼠寿命，并改善许多与衰老相关的疾病;然而，较短的治疗对心脏衰老的有益影响还没有得到很好的理解。使用最近开发的氘代亮氨酸标记方法，我们研究了短期（10周）CR或雷帕霉素对衰老小鼠心脏蛋白质组学周转和重塑的影响。在功能上，我们观察到短期CR和雷帕霉素都逆转了预先存在的年龄依赖性心脏肥大和舒张功能障碍。随着年龄的增长，心脏整体蛋白质组（823种蛋白质）的周转没有显著变化，5个月大的心脏中位半衰期为9.1天，27个月大的心脏中位半衰期为8.8天。然而，老年心脏的蛋白质组半衰期在短期CR（30%）或雷帕霉素（12%）后显著增加。这伴随着年龄依赖性蛋白质氧化损伤和泛素化的衰减。定量蛋白质组学和途径分析显示，参与线粒体功能，电子传递链，柠檬酸循环和脂肪酸代谢的蛋白质丰度随年龄的增加而减少，以及参与糖酵解和氧化应激反应的蛋白质丰度增加。这种年龄依赖性心脏蛋白质组重塑被短期CR或雷帕霉素显著逆转，表明与对心脏生理学的有益作用一致。代谢组学分析证实了雷帕霉素诱导的代谢转变。
Chronic caloric restriction (CR) and rapamycin inhibit the mechanistic target of rapamycin (mTOR) signaling, thereby regulating metabolism and suppressing protein synthesis. Caloric restriction or rapamycin extends murine lifespan and ameliorates many aging-associated disorders; however, the beneficial effects of shorter treatment on cardiac aging are not as well understood. Using a recently developed deuterated-leucine labeling method, we investigated the effect of short-term (10 weeks) CR or rapamycin on the proteomics turnover and remodeling of the aging mouse heart. Functionally, we observed that short-term CR and rapamycin both reversed the pre-existing age-dependent cardiac hypertrophy and diastolic dysfunction. There was no significant change in the cardiac global proteome (823 proteins) turnover with age, with a median half-life 9.1 days in the 5-month-old hearts and 8.8 days in the 27-month-old hearts. However, proteome half-lives of old hearts significantly increased after short-term CR (30%) or rapamycin (12%). This was accompanied by attenuation of age-dependent protein oxidative damage and ubiquitination. Quantitative proteomics and pathway analysis revealed an age-dependent decreased abundance of proteins involved in mitochondrial function, electron transport chain, citric acid cycle, and fatty acid metabolism as well as increased abundance of proteins involved in glycolysis and oxidative stress response. This age-dependent cardiac proteome remodeling was significantly reversed by short-term CR or rapamycin, demonstrating a concordance with the beneficial effect on cardiac physiology. The metabolic shift induced by rapamycin was confirmed by metabolomic analysis.
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影响因子：
16
作者：
Sengupta S;Peterson TR;Sabatini DM
通讯作者：
Sabatini DM
DOI：
10.1126/science.1173635
发表时间：
2009-07-10
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Colman RJ;Anderson RM;Johnson SC;Kastman EK;Kosmatka KJ;Beasley TM;Allison DB;Cruzen C;Simmons HA;Kemnitz JW;Weindruch R
通讯作者：
Weindruch R
影响因子：
10.8
作者：
Dai, Dao-Fu;Hsieh, Edward J.;Rabinovitch, Peter S.
通讯作者：
Rabinovitch, Peter S.
影响因子：
15.9
作者：
Anderson, Ethan J.;Lustig, Mary E.;Neufer, P. Darrell
通讯作者：
Neufer, P. Darrell
影响因子：
7.8
作者：
Flynn JM;O'Leary MN;Zambataro CA;Academia EC;Presley MP;Garrett BJ;Zykovich A;Mooney SD;Strong R;Rosen CJ;Kapahi P;Nelson MD;Kennedy BK;Melov S
通讯作者：
Melov S