The long-term objective of this project is to identify the mechanism by which damage, in particular damage to the nuclear genome that arises spontaneously as a consequence of endogenous processes, promotes aging-related degenerative changes. The current model is that stochastic damage promotes aging via a cell autonomous mechanism, i.e., by driving cell senescence or cell death. We seek to challenge this model by carefully examining how spontaneous DNA damage drives aging in a mouse model of a human progeriod syndrome caused by a defect in DNA repair. The approach will be to combine unique genetic and mass spectrometry tools to accomplish the following aims: 1) To use highly sensitive LC-MS/MS/MS assays to measure endogenous oxidative DNA lesions in tissues of progeroid and wild-type mice at multiple ages and determine if the level of damage predicts the extent of aging-related pathology in each of these tissues. 2) To genetically deplete DNA repair in one tissue or cell type at a time and determine the impact on those cells, neighboring cells and distant tissues, to determine if damage drives aging via a cell-autonomous or non-autonomous mechanism. 3) To use parabiosis between normal and progeroid mice to determine if circulating factors can overcome accelerated aging due to too much DNA damage. 4) To use unbiased and targeted proteomics approaches to identify systemic signals activated in response to genotoxic stress and old age. Successful completion of these aims is anticipated to yield novel information about the aging process and if there are common underlying mechanisms for multiple aging-related diseases. The proteomics work may yield new biomarkers of biologic age. In addition, extension of our preliminary work via this project is anticipated to yield rational strategies to extend healthspan ofthe elderly by reducing stochastic damage and/or inhibiting the damage responses that promote aging.

Public Health Relevance

;This project seeks to identify the mechanism by which normal wear-and-tear causes aging and the inevitable loss of function that accompanies aging. The work is anticipated to yield novel biomarkers that can predict if someone is aging well or poorly. The work is also anticipated to yield novel strategies for preventing wear-and-tear and/or its consequences to improve the health ofthe elderly.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAG1-ZIJ-2)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Scripps Research Institute
La Jolla
United States
Zip Code
Niedernhofer, L J; Kirkland, J L; Ladiges, W (2016) Molecular pathology endpoints useful for aging studies. Ageing Res Rev :
Robbins, Paul D; Dorronsoro, Akaitz; Booker, Cori N (2016) Regulation of chronic inflammatory and immune processes by extracellular vesicles. J Clin Invest 126:1173-80
Zhang, Changqing; Ferrari, Ricardo; Beezhold, Kevin et al. (2016) Arsenic Promotes NF-Κb-Mediated Fibroblast Dysfunction and Matrix Remodeling to Impair Muscle Stem Cell Function. Stem Cells 34:732-42
Ivanisevic, Julijana; Stauch, Kelly L; Petrascheck, Michael et al. (2016) Metabolic drift in the aging brain. Aging (Albany NY) 8:1000-20
Zhu, Yi; Tchkonia, Tamara; Fuhrmann-Stroissnigg, Heike et al. (2016) Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors. Aging Cell 15:428-35
Flores, Rafael R; Kim, Eun; Zhou, Liqiao et al. (2015) IL-Y, a synthetic member of the IL-12 cytokine family, suppresses the development of type 1 diabetes in NOD mice. Eur J Immunol 45:3114-25
Wallace, Callen T; St Croix, Claudette M; Watkins, Simon C (2015) Data management and archiving in a large microscopy-and-imaging, multi-user facility: Problems and solutions. Mol Reprod Dev 82:630-4
Kelley, Eric E (2015) Dispelling dogma and misconceptions regarding the most pharmacologically targetable source of reactive species in inflammatory disease, xanthine oxidoreductase. Arch Toxicol 89:1193-207
Reay, Daniel P; Bastacky, Sheldon I; Wack, Kathryn E et al. (2015) D-Amino Acid Substitution of Peptide-Mediated NF-κB Suppression in mdx Mice Preserves Therapeutic Benefit in Skeletal Muscle, but Causes Kidney Toxicity. Mol Med 21:442-52
Mu, Xiaodong; Tang, Ying; Lu, Aiping et al. (2015) The role of Notch signaling in muscle progenitor cell depletion and the rapid onset of histopathology in muscular dystrophy. Hum Mol Genet 24:2923-37

Showing the most recent 10 out of 33 publications