Aging is characterized by the progressive erosion of homeostasis and function of all organ systems leading to increased risk of morbidity and mortality. Demographics indicate that the number of individuals over the age of 65 will double in the next 25 years. Therefore, identifying strategies to preserve tissue function and homeostasis is a pressing healthcare issue. Aging is generally accepted to arise as a consequence of the accumulation of cellular damage. Many types of cellular damage, including DNA damage, produce an inflammatory response. Not surprisingly, many of the degenerative diseases associated with aging are associated with chronic inflammation, including atherosclerosis, arthritis, dementia, osteoporosis and cardiovascular disease. A key mediator of inflammation, the transcription factor NF-KB, is up-regulated in response to cellular stress and in tissues of aged organisms. Thus I hypothesize that NF-KB activation due to the accumulation of cellular damage has a causal role in the aging process and age-associated diseases. Preliminary data obtained using a mouse model of accelerated aging caused by reduced repair of DNA damage (Ercc1-/A mice) supports this hypothesis. In this study, I propose to test this hypothesis by chronically inhibiting kB kinase (IKK)-mediated activation of NF-KB in progeroid Ercc1-/A mice using a peptide inhibitor of IKK (8K-NBD), with proven efficacy in numerous animal models of autoimmune disease, to determine if it delays onset of symptoms and improves histopathology associated with aging. Similarly, the role of NF-KB in aging will be analyzed using ERCC1 mutant mice heterozygous for the p65 subunit of NF-KB. In vitro, I will evaluate the correlation between NF-KB activity and cellular markers of senescence. To begin to explore the mechanism of this NF-KB inhibtion, I will use microarray analysis of Ercc1-/A mouse livers with chronic NF-KB suppression compared to control littermates, to determine which pathways are effected, and furthermore, I will then analyze how NF-KB upregulated cells in Ercd-/- aged tissue alters the cellular pathways in these and surrounding cells. The successful completion of the proposed experiments will serve to document the role of the IKK/NF-KBpathway in age-associated degenerative disease.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1-F05-K (20))
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Mccormick, Anna M
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University of Pittsburgh
Schools of Medicine
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Tilstra, Jeremy S; Gaddy, Daniel F; Zhao, Jing et al. (2014) Pharmacologic IKK/NF-?B inhibition causes antigen presenting cells to undergo TNF? dependent ROS-mediated programmed cell death. Sci Rep 4:3631
Tilstra, Jeremy S; Robinson, Andria R; Wang, Jin et al. (2012) NF-?B inhibition delays DNA damage-induced senescence and aging in mice. J Clin Invest 122:2601-12
Lavasani, Mitra; Robinson, Andria R; Lu, Aiping et al. (2012) Muscle-derived stem/progenitor cell dysfunction limits healthspan and lifespan in a murine progeria model. Nat Commun 3:608
Tilstra, Jeremy S; Clauson, Cheryl L; Niedernhofer, Laura J et al. (2011) NF-?B in Aging and Disease. Aging Dis 2:449-65