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- 3fa）作为膳食补充剂来预防炎症性疾病，最近在美国公众中越来越多。此外，40%卡路里限制（CR）也被认为可以通过降低各种促炎基因、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，与随意喂食n-3 FA （AL）的小鼠或喂食玉米油（n-6 FA）的小鼠相比，n-3 FA+CR的组合显著延长了自身免疫性疾病易感小鼠的寿命。我们假设n-3 FA+CR增加了抗氧化酶的活性，降低了促炎细胞因子，从而延长了寿命。我们现在进一步假设，与n-6 FA+CR相比，n-3 FA+CR可以显著延长长寿的C57BL/6 （B6）小鼠的寿命，这可能存在类似的机制。此外，n- 3fa还可能降低胰岛素抵抗和年龄相关性骨质流失。基于强有力的初步数据，我们建议通过喂食浓缩的n-3脂肪酸以及引入携带脂肪-1基因的转基因小鼠进行新的研究，该基因内源性合成n-3脂肪酸并降低所有组织中的促炎n-6脂肪酸。我们将使用饲喂n-3脂肪酸、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脂肪酸、AL或CR的小鼠进行比较，进一步确定外源性或内源性n-3脂肪酸对平均寿命和最长寿命的保护作用。具体目的是：目的1：饲喂n-3脂肪酸AL或CR（40%）的影响，从4个月和20% CR 15个月开始测量B6小鼠的生存变化，并与饲喂AL或CR（40%）的脂肪-1+ x B6 F1和脂肪-1- x B6 F1小鼠进行比较。目的2：测量抗炎和促炎细胞因子的变化以及长寿SIRT基因的表达随年龄的变化。目的3：在有或没有n-3 FA或AL和CR中fat-1基因的情况下，测量衰老过程中脂肪和瘦体重、脂肪因子和骨密度的变化。由于n-3 FA被发现具有抗炎作用，本研究可能建立n-3 FA + CR在下调氧化应激和炎症基因表达方面的保护作用，从而延长寿命，比n-6 FA + CR喂养的小鼠要长得多。综上所述，本研究的有利结果可能是加强n-3脂肪酸与CR的摄入，从而在老年人中产生多种健康益处，特别是对抗炎症和衰老过程中的肌肉骨骼损失。公共卫生相关性：本拨款提案旨在密切研究通常食用的n-6（玉米油）脂肪酸与n-3（鱼油）脂肪酸的影响，这些脂肪酸含有随意喂食小鼠和40%或20%卡路里限制，以测量长寿的C57BL/6和fat-1 tg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.