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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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Special Emphasis Panel (ZAG1-ZIJ-2 (M2))
Program Officer
Guo, Max
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Scripps Research Institute
La Jolla
United States
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Zhu, Yi; Doornebal, Ewald J; Pirtskhalava, Tamar et al. (2017) New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463. Aging (Albany NY) 9:955-963
Fuhrmann-Stroissnigg, Heike; Ling, Yuan Yuan; Zhao, Jing et al. (2017) Identification of HSP90 inhibitors as a novel class of senolytics. Nat Commun 8:422
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Ngo, Kevin; Pohl, Pedro; Wang, Dong et al. (2017) ADAMTS5 Deficiency Protects Mice From Chronic Tobacco Smoking-induced Intervertebral Disc Degeneration. Spine (Phila Pa 1976) 42:1521-1528
Griffith, Corey M; Williams, Preston B; Tinoco, Luzineide W et al. (2017) 1H NMR Metabolic Profiling of Earthworm (Eisenia fetida) Coelomic Fluid, Coelomocytes, and Tissue: Identification of a New Metabolite-Malylglutamate. J Proteome Res 16:3407-3418
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