The goal of this Program Project Grant, entitled """"""""Cell Autonomous and Non-autonomous Mechanisms of Aging"""""""" is to examine the mechanisms by which spontaneous, stochastic damage drives aging. This Program seeks to challenge the current notion that stochastic cellular damage, in particular, DNA damage promotes aging through a predominantly cell-autonomous mechanism by triggering programmed cell death or senescence. Although it is well-established that in response to high doses of genotoxic stress cells can secrete senescence-associated factors, which have a paracrine effect on neighboring cells, no one has established that non-cell autonomous events drive aging in response to physiological levels of endogenous DNA damage in vivo. The proposed experiments will address a model of aging where age-dependent accumulation of stochastic damage, including DNA damage, drives aging through both cell autonomous and non-autonomous pathways. This Program Project is comprised of three highly integrated projects. Project 1 (Laura Niedernhofer) will examine the cell autonomous and non-autonomous effects of DNA damage, measuring oxidative DNA damage, cellular senescence, ROS levels and aging-related pathology. Project 2 (Paul Robbins) will examine the cell autonomous and non-autonomous roles of NF-KB, a transcription factor activated in response to cellular damage and stress, in driving senescence, ROS and oxidative DNA damage with aging. Finally, Project 3 (Johnny Huard) will analyze the cell autonomous and non-autonomous pathways involved in age-related loss of stem cell function, as well as identify the factors secreted by functional adult stem cells that extend lifespan and healthspan. All projects will use tissues and cells from naturally aged mice and mouse models of accelerated aging, including mice in which ERCC1 is deleted tissue-specifically to affect the rate of DNA damage one tissue at a time. The projects will be supported by four cores, A) Administrative (Paul Robbins);B) Mouse Models (Laura Niedernhofer);C) Imaging (Simon Watkins) and D) Proteomics (Nathan Yates).

Public Health Relevance

In order to develop therapeutic strategies for delaying onset of age-related pathology, a better understanding of the underlying cause(s) of aging is required. The goal of this Program Project Grant is to identify key mechanisms driving aging and age-related pathologies through both cell autonomous and non-autonomous mechanisms using mouse models of accelerated and natural aging.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG043376-02
Application #
8700287
Study Section
Special Emphasis Panel (ZAG1-ZIJ-2 (M2))
Program Officer
Guo, Max
Project Start
2013-07-15
Project End
2018-04-30
Budget Start
2014-08-15
Budget End
2015-04-30
Support Year
2
Fiscal Year
2014
Total Cost
$2,098,576
Indirect Cost
$541,276
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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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

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