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

通过 n-3 脂肪酸和热量限制延长寿命

• 批准号: 7372969
• 负责人: GABRIEL J J FERNANDES
• 金额: $ 27.31万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7372969
• 关键词: Age; Age-Related Bone Loss; Aging; Animal Feed; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Applications Grants; Autoimmune Diseases; Autoimmune Process; Blood Glucose; Body Temperature; Bone Density; Caloric Restriction; Cardiovascular system; Cell physiology; Cessation of life; Chronic Disease; Corn Oil; Cytokine Gene; DEXA; Data; Diet; Disease; Elderly; Enzymes; Fatty Acids; Fatty acid glycerol esters; Female; Fish Oils; Free Radicals; Gene Expression; General Population; Genes; Glucose; Goals; Health; Health Benefit; Human; Inflammation; Inflammatory; Inflammatory Response; Insulin; Insulin Receptor; Insulin Resistance; Insulin-Like Growth Factor I; Intake; Kidney; Kidney Diseases; Leptin; Life; Lipids; Liver; Longevity; Lymphoma; Maintenance; Measures; Membrane; Minerals; Mus; Musculoskeletal; Omega-3 Fatty Acids; Osteocalcin; Osteogenesis; Outcome Study; Oxidative Stress; Peritoneal; Peroxisome Proliferator-Activated Receptors; Personal Satisfaction; Plasma; Polyunsaturated Fatty Acids; Primates; Public Health; Rate; Rattus; Reporting; Research Personnel; Rodent; Role; Serum; T-Lymphocyte; Tissues; Transcription Factor AP-1; Transgenic Mice; Work; adipokines; adiponectin; age related; aged; base; bone; bone turnover; cyclooxygenase 2; cytokine; dietary supplements; enzyme activity; experience; feeding; glucose metabolism; human study; immune function; indexing; insulin sensitivity; lipid biosynthesis; mRNA Expression; macrophage; middle age; mouse model; prevent; research study; transcription factor; urinary

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.

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，40% 热量限制 (CR) 还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-3 FA (AL) 的小鼠或饲喂玉米油 (n-6 FA) 和 CR 的小鼠相比，n-3 FA + CR 的组合显着延长了易患自身免疫性疾病的小鼠的寿命。我们假设 n-3 FA+CR 会增加抗氧化酶的活性并减少促炎细胞因子，从而延长寿命。我们现在进一步假设，与喂养 n-6 FA+CR 的饮食相比，喂养 n-3 FA+CR 的饮食时，类似的机制可能会显着延长长寿 C57BL/6 (B6) 小鼠的寿命。此外，n-3 FA 还可以减少胰岛素抵抗和年龄相关的骨质流失。基于强有力的初步数据，我们建议通过饲喂浓缩 n-3 FA 以及纳入携带 fat-1 基因的转基因小鼠进行新的研究，该基因可内源合成 n-3 脂肪酸并降低所有组织中的促炎性 n-6 FA。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，以进一步确定外源或内源性 n-3 脂肪酸（有或没有 CR）对平均寿命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。目标 2：测量抗炎和促炎细胞因子以及长寿 SIRT I 基因表达随年龄的变化。目标 3：测量 AL 和 CR 中是否有 n-3 FA 或 fat-1 基因在衰老过程中脂肪和瘦体重以及脂肪因子和骨矿物质密度的变化。由于 n-3 FA 被发现具有抗炎作用，因此拟议的研究很可能确定 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 喂养的小鼠寿命长得多。总之，这项研究的良好结果可能会加强 n-3 FA 与 CR 的摄入，从而对老年人产生多种健康益处，特别是对抗衰老过程中的炎症和肌肉骨骼损失。 公共健康相关性：本拨款提案旨在密切研究常用的 n-6（玉米油）脂肪酸与含有 n-3（鱼油）脂肪酸的饮食对小鼠随意喂养和 40% 或 20% 热量限制的影响，以测量长寿 C57BL/6 和 fat-1 tg 小鼠的最佳寿命、抗炎细胞因子和骨量。