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

Summary

Principal Investigator: Md Mizanur Rahman
Abstract: 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.
Funding Period: 2010-05-01 - 2015-04-30
more information: NIH RePORT

Top Publications

  1. pmc t10c12-CLA maintains higher bone mineral density during aging by modulating osteoclastogenesis and bone marrow adiposity
    Md M Rahman
    Department of Medicine, University of Texas Health Science Center at San Antonio, Texas 78229 3900, USA
    J Cell Physiol 226:2406-14. 2011
  2. pmc HDAC inhibitor trichostatin A suppresses osteoclastogenesis by upregulating the expression of C/EBP-β and MKP-1
    Paul J Williams
    Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
    Ann N Y Acad Sci 1240:18-25. 2011
  3. pmc DHA is a more potent inhibitor of breast cancer metastasis to bone and related osteolysis than EPA
    Md Mizanur Rahman
    Department of Medicine, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229 3900, USA
    Breast Cancer Res Treat 141:341-52. 2013
  4. pmc Conjugated linoleic Acid prevents ovariectomy-induced bone loss in mice by modulating both osteoclastogenesis and osteoblastogenesis
    Md Mizanur Rahman
    Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX, 78229 3900, USA
    Lipids 49:211-24. 2014

Research Grants

  1. Cellular Senescence and Aging
    James L Kirkland; Fiscal Year: 2013
  2. Mitochondrial Dysfunction in Neurodegeneration of Aging
    Gary E Gibson; Fiscal Year: 2013
  3. Osteocyte Regulation of Bone/Muscle with Age
    Lynda F Bonewald; Fiscal Year: 2013
  4. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
  5. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
  6. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013
  7. Functional Consequences of Impaired Autophagy in Aging
    ANA M CUERVO; Fiscal Year: 2013
  8. DEGENERATIVE AND DEMENTING DISEASES OF AGING
    Stanley B Prusiner; Fiscal Year: 2013
  9. Cadiorenal and Metabolic Diseases Research Center
    John E Hall; Fiscal Year: 2013
  10. Semi-volatile PCBs: Sources, Exposures, Toxicities
    Larry W Robertson; Fiscal Year: 2013

Detail Information

Publications4

  1. pmc t10c12-CLA maintains higher bone mineral density during aging by modulating osteoclastogenesis and bone marrow adiposity
    Md M Rahman
    Department of Medicine, University of Texas Health Science Center at San Antonio, Texas 78229 3900, USA
    J Cell Physiol 226:2406-14. 2011
    ..In conclusion, these findings suggest that t10c12-CLA is the most potent CLA isomer and it exerts its anti-osteoporotic effect by modulating osteoclastogenesis and bone marrow adiposity...
  2. pmc HDAC inhibitor trichostatin A suppresses osteoclastogenesis by upregulating the expression of C/EBP-β and MKP-1
    Paul J Williams
    Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
    Ann N Y Acad Sci 1240:18-25. 2011
    ..7 cells. These findings suggest that TSA upregulates the expression of C/EBP-β and MKP-1, which may downregulate pro-osteoclastogenic factors and signaling molecules, ultimately suppressing osteoclastogenesis...
  3. pmc DHA is a more potent inhibitor of breast cancer metastasis to bone and related osteolysis than EPA
    Md Mizanur Rahman
    Department of Medicine, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229 3900, USA
    Breast Cancer Res Treat 141:341-52. 2013
    ..In conclusion, DHA attenuates breast cancer bone metastasis and associated osteolysis more potently than EPA, possibly by inhibiting migration of breast cancer cell to the bone as well as by inhibiting osteoclastic bone resorption. ..
  4. pmc Conjugated linoleic Acid prevents ovariectomy-induced bone loss in mice by modulating both osteoclastogenesis and osteoblastogenesis
    Md Mizanur Rahman
    Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX, 78229 3900, USA
    Lipids 49:211-24. 2014
    ..CLA might be a potential alternative therapy against osteoporotic bone loss. ..

Research Grants30

  1. Cellular Senescence and Aging
    James L Kirkland; Fiscal Year: 2013
    ..Our approach will provide timely, innovative, and clinically relevant interventional results based on addressing the fundamental question of the role of cellular senescence that has remained unanswered for many years. ..
  2. Mitochondrial Dysfunction in Neurodegeneration of Aging
    Gary E Gibson; Fiscal Year: 2013
    ..Successful completion of the goals of these projects can be expected to provide new insights into neurodegenerative processes and contribute to novel approaches to ameliorating age-related neurodegenerations. ..
  3. Osteocyte Regulation of Bone/Muscle with Age
    Lynda F Bonewald; Fiscal Year: 2013
    ..The results of these experiments should lead to novel therapeutics for the prevention and treatment of both osteoporosis and sarcopenia. ..
  4. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
    ..This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins. ..
  5. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
    ..The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD. ..
  6. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013
    ..5) To prepare and empower our diverse Native and Pacific People communities to take ownership of their own health and wellness. ..
  7. Functional Consequences of Impaired Autophagy in Aging
    ANA M CUERVO; Fiscal Year: 2013
    ..Significance: These studies may ultimately lead to fundamental insights for understanding, treating or preventing the metabolic alterations and declined cognitive and immune function characteristic of elders. ..
  8. DEGENERATIVE AND DEMENTING DISEASES OF AGING
    Stanley B Prusiner; Fiscal Year: 2013
    ..The ultimate goal of all the proposed studies is to define the molecular events that feature in the formation of human prions in order to develop therapeutics that cure the human prion diseases. ..
  9. Cadiorenal and Metabolic Diseases Research Center
    John E Hall; Fiscal Year: 2013
    ..abstract_text> ..
  10. Semi-volatile PCBs: Sources, Exposures, Toxicities
    Larry W Robertson; Fiscal Year: 2013
    ..These data and dietary studies in the last Aim will provide a scientific basis for risk assessment and advice for stakeholders with the ultimate goal to protect highly-exposed individuals and populations. ..