of Progress: In the previous funding period, we found that DNA damage in cells or tissues drives altered metabolism, activation of NF- B, FOXO3a, and UPRmit, an increase in reactive oxygen species and senescence. This clearly demonstrates cell autonomous mechanisms in response to endogenous DNA damage. This work relied heavily on reporter mouse strains. In addition, using tissue-specific mutant mice, we discovered that in some but not all cases, cells or tissues with increased endogenous DNA damage can drive loss of tissue homeostasis and aging in other non-damaged tissues. Our preliminary work indicates that damaged immune cells are the most potent in driving aging via cell non-autonomous mechanisms. Considerable effort and resources were dedicated to developing these unique transgenic mice that enable us to drill down and discover where, when and how spontaneous time-dependent accumulation of stochastic damage drives aging. During the previous funding period, we developed 85 unique strains of transgenic mice in which the DNA repair complex ERCC1-XPF is depleted or knocked-out systemically or tissue-specifically +/- a variety of reporter constructs to measure senescence markers, autophagy, or stress response activation +/- mutation of key regulators of lifespan/healthspan (e.g., mTOR, catalase, NRF2, NF- B, ATM, p53, p21Cip1 or p16Ink4a).
| Xu, Ming; Pirtskhalava, Tamar; Farr, Joshua N et al. (2018) Senolytics improve physical function and increase lifespan in old age. Nat Med 24:1246-1256 |
| Domingo-Almenara, Xavier; Montenegro-Burke, J Rafael; Benton, H Paul et al. (2018) Annotation: A Computational Solution for Streamlining Metabolomics Analysis. Anal Chem 90:480-489 |
| 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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