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).
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.
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| Mori, Takayasu; Yousefzadeh, Matthew J; Faridounnia, Maryam et al. (2018) ERCC4 variants identified in a cohort of patients with segmental progeroid syndromes. Hum Mutat 39:255-265 |
| Muntifering, Michael; Castranova, Daniel; Gibson, Gregory A et al. (2018) Clearing for Deep Tissue Imaging. Curr Protoc Cytom 86:e38 |
| Gurkar, Aditi U; Robinson, Andria R; Cui, Yuxiang et al. (2018) Dysregulation of DAF-16/FOXO3A-mediated stress responses accelerates oxidative DNA damage induced aging. Redox Biol 18:191-199 |
| Patil, Prashanti; Niedernhofer, Laura J; Robbins, Paul D et al. (2018) Cellular senescence in intervertebral disc aging and degeneration. Curr Mol Biol Rep 4:180-190 |
| Hartman, R; Patil, P; Tisherman, R et al. (2018) Age-dependent changes in intervertebral disc cell mitochondria and bioenergetics. Eur Cell Mater 36:171-183 |
| Robinson, Andria R; Yousefzadeh, Matthew J; Rozgaja, Tania A et al. (2018) Spontaneous DNA damage to the nuclear genome promotes senescence, redox imbalance and aging. Redox Biol 17:259-273 |
| Schmidt, Heidi M; Kelley, Eric E; Straub, Adam C (2018) The impact of xanthine oxidase (XO) on hemolytic diseases. Redox Biol 21:101072 |
| Czerwi?ska, Jolanta; Nowak, Ma?gorzata; Wojtczak, Patrycja et al. (2018) ERCC1-deficient cells and mice are hypersensitive to lipid peroxidation. Free Radic Biol Med 124:79-96 |
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