Prolongation of lifespan by n-3 fatty acids and calorie restriction

描述(由申请人提供)：使用鱼油中的n-3脂肪酸(n-3 FA)作为饮食补充剂来预防炎症性疾病最近在美国的普通公众中呈上升趋势。此外，40%卡路里限制(CR)也被认为可以通过减少各种促炎基因、细胞因子和胰岛素抵抗的表达来延长啮齿动物的寿命。我们最近报道，与随意饲喂n-3FA(AL)或饲喂玉米油(n-6FA)加CR的小鼠相比，n-3FA+CR的组合显著延长了自身免疫性疾病易患小鼠的寿命。我们推测，n-3FA+CR可增加抗氧化酶活性，减少促炎细胞因子，从而延长寿命。我们现在进一步假设，与饲喂n-6FA+CR时相比，当饲喂n-3FA+CR时，类似的机制可能显著延长长寿C57BL/6(B6)小鼠的寿命。此外，n-3FA还可以减少胰岛素抵抗和年龄相关的骨丢失。基于强大的初步数据，我们建议进行新的研究，通过喂养浓缩的n-3FA以及包括携带脂肪-1基因的转基因小鼠，该基因内源性合成n-3脂肪酸，并降低所有组织中的促炎性n-6FA。我们将使用饲喂n-3FA、AL或CR的B6小鼠和饲喂AL或CR的FAT-1+x B6小鼠，并与饲喂n-6 FA、AL或CR的小鼠进行比较，以进一步证实外源性或内源性n-3脂肪酸对平均寿命和最长寿命的保护作用。其具体目的是：目的1：从4mo和20%CR15个月起饲喂n-3脂肪酸AL或CR(40%)，以测定B6小鼠存活率的变化，并与饲喂AL或CR(40%)的FAT-1+xB6F1和FAT-1-xB6F1小鼠进行比较。目的：检测抗炎和促炎细胞因子及长寿SIRT I基因表达随增龄的变化。目的：检测AL和CR在有或无n-3FA或FAT-1基因作用下衰老过程中脂肪和瘦体质量以及脂肪因子和骨密度的变化。由于n-3FA被发现具有抗炎作用，建议的研究可能证实n-3FA+CR在下调氧化应激和炎症基因表达从而延长寿命方面的保护作用，远远长于喂食n-6FA+CR的小鼠。综上所述，这项研究的良好结果可能会加强n-3FA与CR的摄入量，从而为老年人带来几项健康益处，特别是在抗衰老期间的炎症和肌肉骨骼丢失方面。与公共卫生相关：这项拨款提案旨在研究经常食用的n-6(玉米油)脂肪酸与n-3(鱼油)脂肪酸对小鼠随机饮食和40%或20%热量限制的影响，以衡量长寿C57BL/6和Fat-1TG小鼠的最佳寿命、抗炎细胞因子和骨量。

DESCRIPTION (provided by applicant): The use of n-3 fatty acids (n-3 FA) from fish oil as dietary supplements to protect against inflammatory disorders is recently on the rise by the general public in US. Further, 40% calorie restriction (CR) is also known to prolong lifespan of rodents by decreasing the expression of various pro-inflammatory genes, cytokines and insulin resistance. We recently reported that combination of n-3 FA + CR significantly extend lifespan of autoimmune-disease prone mice when compared to mice fed n-3 FA ad-libitum (AL) or mice fed corn oil (n-6 FA) with CR. We hypothesize that n-3 FA+CR increases activity of antioxidant enzymes and decreases pro-inflammatory cytokines leading to increased lifespan. We now further hypothesize that a similar mechanism may operate in prolonging significantly the lifespan of long-lived C57BL/6 (B6) mice when fed a diet with n-3 FA+CR than when fed n-6 FA+CR. In addition, n-3 FA may also decrease insulin resistance and age-related bone loss. Based on strong preliminary data, we propose to undertake new studies by feeding concentrated n-3 FA as well as by including transgenic mice carrying the fat-1 gene which endogenously synthesizes n-3 fatty acids and lowers pro-inflammatory n-6 FA in all tissues. We will use both B6 mice fed n-3 FA, AL or CR and fat-1+ x B6 mice fed AL or CR and compare with mice fed n-6 FA, AL or CR to further establish the protection induced by exogenous or endogenous n-3 fatty acids with and without CR on mean and maximal lifespan. The specific aims are: Aim 1: Effect of feeding n-3 fatty acids, AL or CR (40%), from 4 mo and 20% CR 15 mo onwards to measure changes in the survival of B6 mice and to compare with fat-1+ x B6 F1 and fat-1- x B6 F1 mice fed AL or CR (40%). Aim 2: Measure changes in anti- and pro- inflammatory cytokines and expression of longevity SIRT I gene with age. Aim 3: Measure changes in fat and lean body mass as well as adipokines and bone mineral density during aging with or without n-3 FA or fat-1 gene in AL and CR. Since n-3 FA are found to be anti-inflammatory, the proposed studies are likely to establish the protective role of n-3 FA + CR in down-regulating oxidative stress and inflammatory gene expression thereby prolonging lifespan, much longer than n-6 FA + CR fed mice. In summary, favorable outcome of this study is likely to reinforce the intake of n-3 FA with CR to induce several health benefits in elderly, particularly against inflammation and musculoskeletal loss during aging. PUBLIC HEALTH RELEVANCE: This grant proposal is directed closely to study the effect of commonly consumed n-6 (corn oil) fatty acids vs. n-3 (fish oil) fatty acids containing diets fed to mice ad-libitum and 40% or 20% calorie restriction to measure optimal lifespan, anti-inflammatory cytokines and bone mass, in long-lived C57BL/6 and fat-1 tg mice.