Effects of Sex, Strain, and Energy Intake on Hallmarks of Aging in Mice.
Effects of Sex, Strain, and Energy Intake on Hallmarks of Aging in Mice.
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DOI：
10.1016/j.cmet.2016.05.027
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发表时间：
2016-06-14
期刊：
影响因子：
29
通讯作者：
de Cabo R
中科院分区：
文献类型：
--
作者：
Mitchell SJ;Madrigal-Matute J;Scheibye-Knudsen M;Fang E;Aon M;González-Reyes JA;Cortassa S;Kaushik S;Gonzalez-Freire M;Patel B;Wahl D;Ali A;Calvo-Rubio M;Burón MI;Guiterrez V;Ward TM;Palacios HH;Cai H;Frederick DW;Hine C;Broeskamp F;Habering L;Dawson J;Beasley TM;Wan J;Ikeno Y;Hubbard G;Becker KG;Zhang Y;Bohr VA;Longo DL;Navas P;Ferrucci L;Sinclair DA;Cohen P;Egan JM;Mitchell JR;Baur JA;Allison DB;Anson RM;Villalba JM;Madeo F;Cuervo AM;Pearson KJ;Ingram DK;Bernier M;de Cabo R
热量限制（CR）是延缓衰老的最强大的非遗传干预措施。然而，有一些新出现的实验变量，改变CR反应。我们研究了性别、品系和CR水平对小鼠健康和生存的作用。CR并不总是与寿命延长相关，尽管它始终改善了不同品系和性别的健康状况。肝脏中由CR驱动的转录和代谢组学变化表明克雷布斯循环的回补填充以及线粒体的脂肪酸燃料。CR防止了肝脏蛋白质稳态网络中与年龄相关的下降，同时增加了线粒体数量，保留了线粒体超微结构和功能。线粒体功能的消除否定了CR在酵母和蠕虫中的延长寿命的作用。我们的数据说明了CR在老龄化背景下的复杂性，与健康和生存相关的结果明确分离，突出了CR转化为人类干预措施的复杂性。在本文中，米切尔等系统地解决性别和应变依赖的反应，各种水平的热量限制。值得注意的是，热量限制通过维持能量代谢和蛋白质稳定来普遍增加健康寿命。然而，在通过热量限制延长寿命方面存在应变/性别依赖性差异，可能会使健康寿命和寿命脱钩。
Calorie restriction (CR) is the most robust non-genetic intervention to delay aging. However, there are a number of emerging experimental variables that alter CR responses. We investigated the role of sex, strain, and level of CR on health and survival in mice. CR did not always correlated with lifespan extension, though it consistently improved health across strains and sexes. Transcriptional and metabolomics changes driven by CR in liver indicated anaplerotic filling of the Krebs cycle together with fatty acid fueling of mitochondria. CR prevented age-associated decline in the liver proteostasis network while increasing mitochondrial number, preserving mitochondrial ultrastructure and function with age. Abrogation of mitochondrial function negated life-prolonging effects of CR in yeast and worms. Our data illustrate the complexity of CR in the context of aging, with a clear separation of outcomes related to health and survival, highlighting complexities of translation of CR into human interventions. In this paper Mitchell et al systematically addresses sex and strain dependent responses to various levels of caloric restriction. Notably, caloric restriction universally increases healthspan through maintenance of energy metabolism and proteostasis with aging. However, there are strain/sex dependent differences in lifespan extension by caloric restriction perhaps uncoupling healthspan and lifespan.