The oxidative, genotoxic and inflammatory stress-regulated transcription factor NF-KB is activated with aging and in numerous aging-related degenerative diseases, but how it is activated with aging and its role in driving aging is unclear. Using an NF-KBeGFP reporter mouse, we demonstrated that NF-KB is indeed activated in a greater percent of cells in multiple tissues of old and progeroid Ercc1-/delta mice compared to young adult mice. Interestingly, although we only detect age-associated activation of NF-KB in a small fraction of cells, for example in the podocytes of the glomeruli of the kidney, there is clear evidence of senescence, cell death and degenerative changes in other cell types in the kidney and distant tissues where NF-KB activation is limited or not detected. NF-KB also plays a key role in driving aging, demonstrated by the fact that genetic depletion of the key subunit of NF-KB, p65, delay the onset of numerous age-related pathologies including osteoporosis, sarcopenia, intervertebral disc degeneration, anemia, vision loss, loss of islets, urinary incontinence and neurodegeneration in Ercc1-/delta mice as well as reduced cellular senescence. Similarly, inhibition of NF-KB activation by systemic administration of several different inhibitors ofthe NF-KB activating IkB Kinase (IKK) delay the onset of age-related pathology, reduced the percent of senescent cells and extended the healthspan of Ercc1-/delta mice. Surprisingly, inhibition of IKK/NF-KB activity, either genetically or pharmacologically, significantly reduce the amount of oxidative DNA damage in Ercc1-delta and in naturally aged mice. Collectively, these data suggest that NF-KB also functions via cell non-autonomous mechanisms to promote aging. We hypothesize that NF-KB activation by cellular damage in not only cell autonomous effects such as senescence, but also regulates secretion of soluble factors that can effect the levels of reactive oxygen species (ROS), DNA damage, cell senescence and tissue degeneration both locally and systemically. Thus the goal of this Project is to determine if stochastic damage to cells, in particular DNA damage, preferentially drives NF-KB activation in a cell autonomous or non-autonomous manner and to determine the impact this has on neighboring cells and distant tissues in driving aging.
|Kelley, Eric E; Baust, Jeff; Bonacci, Gustavo et al. (2014) Fatty acid nitroalkenes ameliorate glucose intolerance and pulmonary hypertension in high-fat diet-induced obesity. Cardiovasc Res 101:352-63|
|Robbins, Paul D; Morelli, Adrian E (2014) Regulation of immune responses by extracellular vesicles. Nat Rev Immunol 14:195-208|
|Fu, Lijuan; Guerrero, Candace R; Zhong, Na et al. (2014) Tet-mediated formation of 5-hydroxymethylcytosine in RNA. J Am Chem Soc 136:11582-5|
|Lu, Aiping; Poddar, Minakshi; Tang, Ying et al. (2014) Rapid depletion of muscle progenitor cells in dystrophic mdx/utrophin-/- mice. Hum Mol Genet 23:4786-800|
|Vaezi, Alec E; Bepler, Gerold; Bhagwat, Nikhil R et al. (2014) Choline phosphate cytidylyltransferase-? is a novel antigen detected by the anti-ERCC1 antibody 8F1 with biomarker value in patients with lung and head and neck squamous cell carcinomas. Cancer 120:1898-907|
|Takayama, Koji; Kawakami, Yohei; Lee, Sahnghoon et al. (2014) Involvement of ERCC1 in the pathogenesis of osteoarthritis through the modulation of apoptosis and cellular senescence. J Orthop Res 32:1326-32|
|Fox, Ira J; Daley, George Q; Goldman, Steven A et al. (2014) Stem cell therapy. Use of differentiated pluripotent stem cells as replacement therapy for treating disease. Science 345:1247391|