Previous results of this Program Project Grant (PPG) have firmly established the important role of genome stability mechanisms in longevity and healthy aging using genetically manipulated mouse models and mouse and human cell cultures. Key publications resulting from the PPG have led to a more general acceptance of DNA repair defective mouse models of premature aging as critical tools for studying aging and developing interventions. The long-term objectives of this second renewal application are to unravel the mechanisms that underlie DNA damage-driven premature aging and its relationship with normal aging, explore potential intervention strategies and translate genome maintenance as a key factor determining health span to the human situation. Observations made during the first and second grant periods, with results from work by others, point towards two major, pro-aging end points of defects in genome stability systems: (1) Cellular responses to DNA damage, including apoptosis and cellular senescence, likely play a role in premature aging of most DNA repair defective mouse models, with stem cell compartments as a likely important target;and (2) DNA mutations and epimutations (chromatin alterations) as the irreversible consequence of errors during DNA damage processing play a key role in the age-related increase in cancer and, possibly (in the form of large genome rearrangements and chromatin alterations), also in non-cancer, degenerative aging phenotypes by causing a loss of transcriptional homeostasis. This renewal application consists of 5 research projects, an Animal and Pathology Core and an Administrative Core. A new project (Project 5) has been added to translate findings regarding genome maintenance from a pro-longevity system in mice to the human situation and will increase the PPG's significance for human aging. One core, the Array and Informatics Core, has served its function and is no longer included. For the renewal application, we now propose work in 4 main areas of research: (1) unraveling DNA damage based mechanisms of premature and normal aging using mouse models as well as mouse and human cell cultures;(2) Testing the role of genome maintenance as a pro-longevity system in humans by genetic association and functional genomics analyses;(3) Developing sets of blood-based biomarkers for premature aging in the mouse, which will be validated in normally aging mice and in a human cohort;and (4) Developing new, experimental interventions, the effects of which will be tested by using non-invasive mouse reporter models and the developed biomarker set. All five projects together with the Animal and Pathology Core will jointly work on these topics, with their research plans fully integrated, yet maintaining their own, unique spheres of interest.
Genome maintenance systems comprise a network of proteins repairing DNA damage. In the proposed Project we will investigate basic mechanisms underlying the role of genome maintenance as a pro-longevity system in humans. The results of this study will help us to identify new approaches to prevent or eradicate age-related disease and provide us with new insights as to the mechanistic basis of aging and longevity processes.
|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