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

描述（由申请方提供）：衰老与炎症和氧化应激增加相关，导致肌肉骨骼组织质量、质量和功能进行性下降，从而增加老年人福尔斯和骨折的风险。n-3脂肪酸（FA）和卡路里限制（CR）都是抗炎和抗氧化的。CR改善肌肉质量、质量和功能，n-3 FA改善骨矿物质密度（BMD）和肌肉功能，并防止骨质流失。我们观察到n-3 FA喂养小鼠的后腿瘦体重增加。然而，40% CR与骨丢失增加相关。因此，我建议研究n-3 FA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将有非常小的饮食限制相关的骨丢失。肌肉和骨骼作为肌肉骨骼系统的同一功能单位的两个部分。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，我将进行双能吸收法（DXA）测定肌肉质量;分析肌肉的纤维类型、脂肪含量、铁含量、抗氧化酶和氧化损伤水平，以确定肌肉质量;通过测量活性氧和ATP的产生、膜电位、呼吸频率来分析线粒体功能，和电子传递复合物活动来确定肌肉活动;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将通过维持肌纤维数量、减少脂肪和铁积累以及氧化还原平衡，从而维持适当的线粒体功能以提供足够的能量，来预防与衰老相关的肌肉质量、质量和功能下降。为了确定n-3 FA伴/不伴轻度CR对衰老过程中骨健康的有益作用，我将进行DXA以测定骨量;通过核磁共振（NMR）分析骨孔隙率、孔径分布以及移动的和结合水的分数以测定骨质量;分析骨形成和骨吸收活性以测定骨重建状态;分析股骨的材料测试和椎骨的生物力学测试，以确定骨强度和抗骨折的韧性。我预计，由于骨形成和再吸收细胞的平衡活性，导致上级BMD、更低的骨孔隙率和更好的骨结合水，从而改善骨质量和强度，并降低骨脆性和相关骨折，因此n-3 FA伴/不伴轻度CR动物的骨质量将得到维持。最近，使用10- 30%CR进行了人体和动物研究，并显示出一定的保护作用，包括肌肉功能改善。然而，预计轻度CR仅在中位寿命时提供益处，但可能不会导致40% CR的最长寿命。我们观察到喂食n-3 FA+40%CR的小鼠的存活时间延长。如果在存在n-3 FA的情况下轻度CR可以延长与40%CR相似的寿命，则值得关注。我还将确定n-3 FA+轻度CR介导的健康衰老和寿命延长是否与炎症和氧化应激相关基因的减少有关。 该提案将确定n-3 FA和轻度CR对与年龄相关的肌肉骨骼损失的丙乳酸功效，从而确保健康衰老和延长寿命。 我的近期职业目标是获得足够的额外技能和知识，成为导师和顾问指导下的衰老和衰老相关肌肉骨骼生物学领域的独立研究人员，并生成足够的初步数据以申请独立R 01赠款。 我的长期职业目标是通过在老龄化领域的持续基础和转化研究，使自己成为一个富有成效的，赠款资助的独立调查员。我想开发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。在成功的动物研究之后，我的最终目标是进行临床试验，以建立这些策略来改善人类衰老过程中的健康。 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，获得与老龄化领域相关的新技术/先进基础和临床知识的教育/培训（2）获得撰写资助的具体培训（3）生成足够的初步数据以支持竞争性R 01资助申请（4）提交资助提案（5）在国家和国际会议上介绍我的工作（6）发表同行评审的论文（7）参加会议和期刊俱乐部（8）与我研究领域的杰出科学家建立强大的网络。 我的研究所提供了一个很好的场所，有一个显着的专业知识和资源，高度支持我的科学项目，以及我的职业发展计划的深度。我的整体职业发展将由一个咨询委员会监测，该委员会由炎症，氧化应激，肌肉生物学，骨生物学和衰老领域的国内外知名科学家组成。

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.