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

描述（由申请人提供）：最近，美国公众越来越多地使用鱼油中的n-3脂肪酸（n-3 FA）作为膳食补充剂来预防炎症性疾病。此外，还已知40%卡路里限制（CR）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）或喂食玉米油（n-6 FA）的CR小鼠相比，n-3 FA + CR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增加抗氧化酶的活性，减少促炎细胞因子，从而延长寿命。我们现在进一步假设，与喂食n-6 FA+CR相比，喂食n-3 FA+CR的饲料可显著延长长寿C57 BL/6（B6）小鼠的寿命，这可能是一种类似的机制。此外，n-3 FA还可以降低胰岛素抵抗和年龄相关的骨丢失。基于强有力的初步数据，我们建议进行新的研究，喂养浓缩的n-3 FA，以及包括转基因小鼠携带的脂肪-1基因，内源性合成n-3脂肪酸和降低促炎性n-6 FA在所有组织。我们将使用喂食n-3 FA、AL或CR的B6小鼠和喂食AL或CR的fat-1+ x B6小鼠，并与喂食n-6 FA、AL或CR的小鼠进行比较，以进一步确定外源性或内源性n-3脂肪酸在有和没有CR的情况下对平均和最大寿命的保护作用。具体目标是：目标1：从4个月和20% CR 15个月开始饲喂n-3脂肪酸AL或CR（40%）的影响，以测量B6小鼠存活率的变化，并与饲喂AL或CR（40%）的fat-1+ x B6 F1和fat-1- x B6 F1小鼠进行比较。目的2：检测抗、促炎细胞因子及长寿SIRT I基因表达随年龄的变化.目标3：在AL和CR中测量在有或没有n-3 FA或fat-1基因的衰老过程中脂肪和瘦体重以及脂肪因子和骨密度的变化。由于发现n-3 FA具有抗炎作用，因此拟定的研究可能确定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喂养的小鼠长得多。总之，本研究的有利结果可能会加强n-3 FA与CR的摄入，以诱导老年人的几种健康益处，特别是对抗衰老过程中的炎症和肌肉骨骼损失。 公共卫生相关性：该拨款提案密切关注研究通常消耗的n-6（玉米油）脂肪酸与n-3（鱼油）脂肪酸的影响，这些脂肪酸含有自由采食和40%或20%卡路里限制的小鼠饲料，以测量长寿C57 BL/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.