Prevention of age-associated musculoskeletal loss by n-3 fatty acids

n-3 脂肪酸预防与年龄相关的肌肉骨骼损失

• 批准号: 8252178
• 负责人: MD MIZANUR RAHMAN
• 金额: $ 12.69万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8252178
• 关键词: Adenosine; Adult; Advisory Committees; Age; Aging; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antiatherogenic; Antioxidants; Applications Grants; Area; Arthritis; Atherosclerosis; Attenuated; Basic Science; Binding; Biochemical Markers; Biology; Biology of Aging; Biomechanics; Bone Density; Bone Resorption; Bone remodeling; Breeding; Caloric Restriction; Cardiovascular Diseases; Cells; Chronic Disease; Clinical; Clinical Trials; Comparative Biology; Complex; Corn Oil; Data; Deterioration; Development Plans; Diabetes Mellitus; Diet; Disease; Drug Prescriptions; Dual-Energy X-Ray Absorptiometry; Elderly; Electron Transport; Elements; Ensure; Enzymes; Equilibrium; FDA approved; Fall prevention; Fatty Acids; Fatty acid glycerol esters; Female; Femur; Fiber; Fish Oils; Fracture; Funding; Gene Expression; Genes; Goals; Grant; Health; Human; Hypertriglyceridemia; Infection; Inflammation; Inflammatory; Institutes; International; Iron; Journals; Knowledge; Leg; Life; Life Support Care; Linoleic Acids; Liver; Longevity; Malignant Neoplasms; Malnutrition; Mammals; Materials Testing; Measures; Mediating; Membrane; Membrane Potentials; Menopause; Mentors; Metabolic syndrome; Minerals; Mitochondria; Monitor; Mus; Muscle; Muscle Fibers; Muscle function; Musculoskeletal; Musculoskeletal System; Nuclear Magnetic Resonance; Obesity; Omega-3 Fatty Acids; Organism; Osteogenesis; Osteopenia; Osteoporosis; Oxidation-Reduction; Oxidative Stress; Paper; Population; Porosity; Postmenopause; Predisposition; Prevention; Process; Production; Property; Publishing Peer Reviews; Reactive Oxygen Species; Reporting; Research; Research Personnel; Resources; Role; Safflower Oil; Scientist; Serum; Staining method; Stains; Testing; Therapeutic; Tissues; Training; Training and Education; Transgenic Mice; Transgenic Organisms; Translational Research; Vascular Diseases; Vitamins; Water; Work; Writing; Yeasts; age group; age related; aging population; attenuation; bone; bone health; bone loss; bone mass; bone quality; bone strength; bone toughness; bone turnover; career; career development; cytokine; diabetic; dietary restriction; fall risk; feeding; functional decline; functional improvement; grasp; healthy aging; improved; indexing; inorganic phosphate; interest; male; muscle form; muscle strength; new technology; oxidative damage; prevent; prophylactic; protective effect; reproductive; respiratory; sarcopenia; skills; spine bone structure; symposium

DESCRIPTION (provided by applicant): Aging is associated with increased inflammation and oxidative stress leading to progressive decline in musculoskeletal tissue mass, quality and function which increases the risk of falls and fractures in the elderly. Both n-3 fatty acids (FA) and calorie restriction (CR) are anti-inflammatory and anti-oxidative. CR improves muscle mass, quality and function and n-3 FA improves bone mineral density (BMD) and muscle function and prevents bone loss. We observed increased hind leg lean mass in n-3 FA fed mice. However, 40% CR is associated with increased bone loss. Therefore, I proposed to study the combined effect of n-3 FA and mild CR (20% CR) in preventing age-associated musculoskeletal loss. I speculate that mild CR will have very minimal dietary restriction associated bone loss. The muscles and bones act as two parts of the same functional unit of the musculoskeletal system. To determine the beneficial effect of n-3 FA+ mild CR on muscle health during aging, I will perform dual energy absorptiometry (DXA) to determine muscle mass; analyze fiber types, fat content, iron content, antioxidant enzymes and oxidative damage levels of muscle to determine muscle quality; analyze mitochondrial functions by measuring reactive oxygen species and ATP production, membrane potential, respiratory rates, and electron transport complex activities to determine muscle activity; analyze grip strength and treadmill endurance capacity to determine muscle strength. I anticipate that n-3 FA+ mild CR will prevent aging related decline in muscle mass, quality and function by maintaining muscle fiber numbers with reduced fat and iron accumulation and redox balance, thereby maintaining proper mitochondrial functions to provide sufficient energy. To determine the beneficial effect of n-3 FA with/without mild CR on bone health during aging, I will perform DXA to determine bone mass; analyze bone porosity, pore size distribution and fractions of mobile and bound water by nuclear magnetic resonance (NMR) to determine bone quality; analyze bone formation and bone resorption activities to determine bone remodeling status; analyze material testing of femur and biomechanical tests of vertebrae to determine bone strength and toughness against bone fracture. I anticipate that bone quality of n-3 FA with/without mild CR animals will be maintained due to balanced activities of bone forming and resorbing cells leading to superior BMD, less bone porosity, and better bone bound water, thereby improving bone quality and strength and reducing bone fragility and associated fractures. Recently, human and animal studies were carried out using 10-30% CR and showed certain protective effects including muscle function improvement. However, mild CR is expected to provide benefits only at median lifespan but may not cause a maximal lifespan as of 40% CR. We observed extended survival of mice fed n-3 FA+40% CR. It is of interest if mild CR in the presence of n-3 FA can extend the life span similar to that of 40% CR. I will also determine whether n-3 FA+ mild CR mediated healthy aging and prolongation of life is associated with reduction of genes related to inflammation and oxidative stress. This proposal will establish the prophaylactic efficacy of n-3 FA and mild CR against age-associated musculoskeletal loss, thereby ensuring healthy aging and prolongation of lifespan. My immediate career goal is to gain sufficient additional skills and knowledge necessary to be an independent researcher in the field of aging and aging-associated musculoskeletal biology under the guidance of mentors and advisors and generate sufficient preliminary data to apply for independent R01 grants. My long term career goal is to establish myself as a productive, grant-funded, independent investigator through sustained basic and translational research in the area of aging. I would like to develop dietary prophylactic and therapeutic strategies to prevent/treat age-associated deterioration of musculoskeletal health. After successful animal study, my ultimate goal is to pursue clinical trials to establish these strategies to improve human health during aging. The key elements of my research career development plan are: (1) gain education/training on new technologies/advanced basic and clinical knowledge relevant to the field of aging by taking didactic courses and intensive mentoring interactions (2) acquire specific training in grant writing (3) generate sufficient preliminary data to support competitive R01 grant application (4) submit grant proposals (5) present my work at national and international conferences (6) publish peer-reviewed papers (7) attend conferences and journal clubs and (8) establish a strong network with prominent scientists in the field of my research. My institute provides an excellent venue that has a remarkable depth of expertise and resources that are highly supportive of my scientific project, as well as my career development plans. My overall career development will be monitored by an advisory committee consists of nationally and internationally reputed scientists in the field of inflammation, oxidative stress, muscle biology, bone biology and aging.

描述（由申请人提供）：衰老与炎症和氧化应激增加有关，导致肌肉骨骼组织质量、质量和功能的进行性下降，从而增加老年人跌倒和骨折的风险。n-3脂肪酸（FA）和热量限制（CR）都具有抗炎和抗氧化作用。CR可改善肌肉质量、质量和功能，n-3 FA可改善骨密度（BMD）和肌肉功能，防止骨质流失。我们观察到饲喂n- 3fa的小鼠后腿瘦质量增加。然而，40% CR与骨质流失增加有关。因此，我建议研究n- 3fa和轻度CR （20% CR）在预防年龄相关性肌肉骨骼损失方面的联合作用。我推测轻度CR会有很少的饮食限制和骨质流失。肌肉和骨骼是肌肉骨骼系统中同一个功能单元的两个部分。为了确定n-3 FA+轻度CR对衰老过程中肌肉健康的有益影响，我将使用双能量吸收法（DXA）来确定肌肉质量；分析纤维类型、脂肪含量、铁含量、抗氧化酶和肌肉氧化损伤水平，以确定肌肉质量；通过测量活性氧和ATP生成、膜电位、呼吸速率和电子传递复合物活动来分析线粒体功能，以确定肌肉活动；分析握力和跑步机耐力来确定肌肉力量。我预计n-3 FA+轻度CR将通过减少脂肪和铁的积累和氧化还原平衡来维持肌纤维数量，从而维持适当的线粒体功能以提供足够的能量，从而防止与衰老相关的肌肉质量、质量和功能下降。为了确定n-3 FA加/不加轻度CR对衰老过程中骨骼健康的有益影响，我将进行DXA测定骨量；通过核磁共振（NMR）分析骨孔隙度、孔隙大小分布以及流动水和结合水的组分，以确定骨质量；分析骨形成和骨吸收活动，确定骨重塑状态；分析股骨的材料测试和椎骨的生物力学测试，以确定骨的强度和韧性。我预计n-3 FA有/没有轻度CR的动物的骨质量将保持，因为骨形成和再吸收细胞的平衡活动导致更好的骨密度，更少的骨孔隙率和更好的骨结合水，从而提高骨质量和强度，减少骨脆性和相关骨折。最近，使用10-30% CR进行了人体和动物研究，显示出一定的保护作用，包括肌肉功能的改善。然而,轻微的CR预计将提供好处只有在平均寿命,但可能不会引起最大寿命40% CR。我们观察到延长老鼠的生存感兴趣的n - 3 FA + 40% CR。如果轻微CR的n - 3 FA可以扩展寿命相似40% CR。我还将确定n - 3 FA +轻度CR介导健康生命的衰老和延长与减少炎症和氧化应激相关基因。该建议将确定n-3 FA和轻度CR对年龄相关肌肉骨骼损失的预防作用，从而确保健康衰老和延长寿命。我近期的职业目标是在导师和顾问的指导下，获得足够的额外技能和知识，成为衰老和衰老相关肌肉骨骼生物学领域的独立研究人员，并产生足够的初步数据，以申请独立的R01资助。我的长期职业目标是通过在老龄化领域持续的基础研究和转化研究，使自己成为一名富有成效、获得资助的独立研究者。我想发展饮食预防和治疗策略，以预防/治疗与年龄相关的肌肉骨骼健康恶化。在动物实验成功后，我的最终目标是进行临床试验，建立这些策略，以改善人类在衰老过程中的健康。我的研究职业发展计划的关键要素是：(1)通过参加教学课程和密集的指导互动，获得与衰老领域相关的新技术/先进基础和临床知识的教育/培训(2)获得拨款写作方面的具体培训(3)生成足够的初步数据，以支持有竞争力的R01拨款申请(4)提交拨款提案(5)在国内和国际会议上展示我的工作(6)发表同行评审的论文(7)参加会议和期刊俱乐部(8)建立一个与我研究领域的杰出科学家有着密切的联系。我所在的研究所提供了一个非常好的场所，拥有丰富的专业知识和资源，这对我的科学项目以及我的职业发展计划都非常支持。我的整体职业发展将由一个由国内外知名科学家组成的咨询委员会进行监督，这些科学家来自炎症、氧化应激、肌肉生物学、骨骼生物学和衰老等领域。