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.
Aging is associated with progressive loss of musculoskeletal tissue mass, quality and function. Both n-3 fatty acids and calorie restriction improve muscle function and n-3 fatty acids improve bone mineral density due to their anti-inflammatory and anti-oxidative properties. Therefore, I hypothesize that n-3 fatty acids and mild calorie restriction (20% less than ad libitum without reduction in vitamins and minerals) will prevent age-associated decline in musculoskeletal tissue mass, quality and function, thereby ensuring healthy aging and prolonging lifespan.
|Rahman, Md Mizanur; Fernandes, Gabriel; Williams, Paul (2014) Conjugated linoleic Acid prevents ovariectomy-induced bone loss in mice by modulating both osteoclastogenesis and osteoblastogenesis. Lipids 49:211-24|
|Rahman, Md Mizanur; Veigas, Jyothi Maria; Williams, Paul J et al. (2013) DHA is a more potent inhibitor of breast cancer metastasis to bone and related osteolysis than EPA. Breast Cancer Res Treat 141:341-52|
|Rahman, Md M; Halade, Ganesh V; Williams, Paul J et al. (2011) t10c12-CLA maintains higher bone mineral density during aging by modulating osteoclastogenesis and bone marrow adiposity. J Cell Physiol 226:2406-14|
|Williams, Paul J; Nishu, Kazi; Rahman, Md Mizanur (2011) HDAC inhibitor trichostatin A suppresses osteoclastogenesis by upregulating the expression of C/EBP-? and MKP-1. Ann N Y Acad Sci 1240:18-25|