(PROJECT 2) The overarching theme of the Program Project Grant (PPG) is that spontaneous DNA damage drives major components of aging by causing DNA mutations and eliciting adverse cellular responses, e.g., apoptosis, cellular senescence. The central hypothesis of Project 2 is that low levels of the highly toxic DNA double-strand breaks (DSBs) are a cause of aging, both through cellular end points and through DNA mutations. In the new Project 2 we will test this hypothesis by studying the role of DSBs in promoting the molecular and cellular phenotypes associated with aging. In two specific aims we will (1) further analyze the pro-aging effects of DSBs in WT and Ercc1-/?7 and Ku80-/- mice and (2) comprehensively determine the landscape of somatic mutations in liver of WT and Ercc1-/?7 and Ku80-/- mice, with a focus on genome structural variations that typically result from erroneous repair of DSBs. We will also test if the pro-longevity interventions developed by our collaborators do not only affect survival of cells and tissues, but also prevent or dampen genome instability.
(PROJECT 2) Project 2 of this proposed program project renewal will test the causal role of the highly toxic DNA double- strand breaks in aging and age-related pathology. It is expected that the results will bring us closer to understand the mechanisms of aging and disease and provide new starting points for the development of interventions to promote healthy aging and longevity.
|Lau, Cia-Hin; Suh, Yousin (2016) Genome and Epigenome Editing in Mechanistic Studies of Human Aging and Aging-Related Disease. Gerontology :|
|Andriani, Grasiella A; Faggioli, Francesca; Baker, Darren et al. (2016) Whole chromosome aneuploidy in the brain of Bub1bH/H and Ercc1-/Î”7 mice. Hum Mol Genet 25:755-65|
|Sepe, Sara; Milanese, Chiara; Gabriels, Sylvia et al. (2016) Inefficient DNA Repair Is an Aging-Related Modifier of Parkinson's Disease. Cell Rep 15:1866-75|
|Kruiswijk, F; Hasenfuss, S C; Sivapatham, R et al. (2016) Targeted inhibition of metastatic melanoma through interference with Pin1-FOXM1 signaling. Oncogene 35:2166-77|
|Ryu, Seungjin; Atzmon, Gil; Barzilai, Nir et al. (2016) Genetic landscape of APOE in human longevity revealed by high-throughput sequencing. Mech Ageing Dev 155:7-9|
|Kato, Kaori; Zweig, Richard; Schechter, Clyde B et al. (2016) Positive attitude toward life, emotional expression, self-rated health, and depressive symptoms among centenarians and near-centenarians. Aging Ment Health 20:930-9|
|Quispe-Tintaya, Wilber; Gorbacheva, Tatyana; Lee, Moonsook et al. (2016) Quantitative detection of low-abundance somatic structural variants in normal cells by high-throughput sequencing. Nat Methods 13:584-6|
|Gravina, Silvia; Dong, Xiao; Yu, Bo et al. (2016) Single-cell genome-wide bisulfite sequencing uncovers extensive heterogeneity in the mouse liver methylome. Genome Biol 17:150|
|Vermeij, Wilbert P; Hoeijmakers, Jan H J; Pothof, Joris (2016) Genome Integrity in Aging: Human Syndromes, Mouse Models, and Therapeutic Options. Annu Rev Pharmacol Toxicol 56:427-45|
|Vijg, Jan; Kennedy, Brian K (2016) The Essence of Aging. Gerontology 62:381-5|
Showing the most recent 10 out of 224 publications