Omega-3 fatty acids partially revert the metabolic gene expression profile induced by long-term calorie restriction

Calorie restriction (CR) consistently extends longevity and delays age-related diseases across several animal models. We have previously shown that different dietary fat sources can modulate life span and mitochondrial ultrastructure, function and membrane fatty acid composition in mice maintained on a 40% CR. In particular, animals consuming lard as the main fat source (CR-Lard) lived longer than CR mice consuming diets with soybean oil (CR-Soy) or fish oil (CR-Fish) as the predominant lipid source. In the present work, a transcriptomic analysis in liver and skeletal muscle was performed in order to elucidate possible mechanisms underlying the changes in energy metabolism and longevity induced by dietary fat in CR mice. After 8 months of CR, transcription downstream of several mediators of inflammation was inhibited in liver. In contrast, proinflammatory signaling was increased in the CR-Fish versus other CR groups. Dietary fish oil induced a gene expression pattern consistent with increased transcriptional regulation by several cytokines (TNF, GM-CSF, TGF-b) and sex hormones when compared to the other CR groups. The CR-Fish also had lower expression of genes involved in fatty acid biosynthesis and increased expression of mitochondrial and peroxisomal fatty acid b-oxidation genes than the other CR diet groups. Our data suggest that a diet high in n-3 PUFA, partially reverts CR-related changes in gene expression of key processes, such as inflammation and steroid hormone signaling, and this may mitigate life span extension with CR in mice consuming diets high in fish oil.

热量限制（Calorie restriction, CR）可在多种动物模型中稳定延长寿命并延缓年龄相关性疾病的发生。我们既往研究表明，在饲喂40%热量限制膳食的小鼠中，不同膳食脂肪来源可调节其寿命、线粒体超微结构、功能及膜脂肪酸组成。其中，以猪油作为主要脂肪来源的小鼠（CR-Lard组）寿命长于以大豆油（CR-Soy组）或鱼油（CR-Fish组）为主要脂质来源的热量限制小鼠。本研究通过对肝脏与骨骼肌开展转录组分析，旨在阐明热量限制小鼠中膳食脂肪诱导的能量代谢与寿命变化的潜在机制。在实施8个月的热量限制干预后，肝脏内多种炎症介质的下游转录活动受到抑制。与之相反，与其他热量限制组相比，CR-Fish组的促炎信号通路出现上调。与其他CR组相比，膳食鱼油可诱导出与多种细胞因子（肿瘤坏死因子TNF、粒细胞-巨噬细胞集落刺激因子GM-CSF、转化生长因子βTGF-β）及性激素的转录调控增强相一致的基因表达谱。相较于其他CR膳食组，CR-Fish组的脂肪酸生物合成相关基因表达水平更低，而线粒体与过氧化物酶体脂肪酸β氧化相关基因的表达水平更高。本研究数据表明，富含n-3多不饱和脂肪酸（n-3 PUFA）的膳食可部分逆转热量限制相关的关键生物学过程基因表达变化，如炎症与类固醇激素信号通路，这或会削弱饲喂高鱼油膳食的小鼠通过热量限制获得的寿命延长效应。