Genome maintenance systems in complex organisms act to promote cell survival at the cost of occasional mutations as a consequence of repair or replication errors. When DNA damage levels are high, these systems can induce apoptosis or cellular senescence to prevent a high mutation load, the most serious consequence of which is cancer. Hence, genome maintenance systems protect organisms at early ages when the impact of losing proliferative cells to apoptosis or senescence is low. However, at later ages the impact of accumulating mutations, depleting cells through apoptosis, and accumulating non-dividing, pro-inflammatory senescent cells is high. Therefore, genome maintenance systems and their sequelae are another example of antagonistic pleiotropy. Importantly, this balancing act can be manipulated, as demonstrated by various conditions that extend life span, including dietary restriction, somatotrophic restraint and possibly the microRNA-mediated cell preservation response. In this renewal application, we propose to further characterize the pro-aging effects of DNA damage and explore if human extreme longevity and healthy aging can be related to exceptional genome maintenance. Based on the results we will then use premature aging mouse models to develop and test novel interventions that promote healthy aging and longevity. The results should clarify the relationships in humans and mice between specific defects in genome maintenance and aging phenotypes, better define proximal end points of aging driven by DNA damage and cellular damage responses in humans and mice and lead to molecular and cellular interventions that alleviate genotoxic stress and/or improve genome maintenance. Based on a wealth of evidence suggesting a causal relationship between adverse health effects associated with aging and DNA damage responses, this PPG application is designed to resolve the complex web of cause and effect relationships between DNA damage and aging, establish clear links between human and mouse DNA damage responses, and explore logical routes to modify these responses to ameliorate genome degeneration and its adverse health effects.
The continuing increase of life expectancy and growing proportion of elderly impose severe pressure on healthcare resources. This provides not only a serious financial, socio-economic burden and limits productive years, but is also associated with substantial loss of quality of life in the elderly. To develop rational interventions for increasin health span, new knowledge on the basic mechanisms of aging is needed. Work in this PPG since 1999 has identified DNA damage as a major cause of aging. The main objective of this renewal application is to study the molecular, cellular and physiological consequences of DNA damage in intricate detail and use that new knowledge for developing practical interventions that will relieve genotoxic stress and extend the period of healthy life span.
|Lau, Cia-Hin; Suh, Yousin (2018) In vivo epigenome editing and transcriptional modulation using CRISPR technology. Transgenic Res 27:489-509|
|Wiley, Christopher D; Schaum, Nicholas; Alimirah, Fatouma et al. (2018) Small-molecule MDM2 antagonists attenuate the senescence-associated secretory phenotype. Sci Rep 8:2410|
|Quispe-Tintaya, Wilber; Lee, Moonsook; Dong, Xiao et al. (2018) Bleomycin-induced genome structural variations in normal, non-tumor cells. Sci Rep 8:16523|
|Hébert, Jean M; Vijg, Jan (2018) Cell Replacement to Reverse Brain Aging: Challenges, Pitfalls, and Opportunities. Trends Neurosci 41:267-279|
|Yu, Bo; Dong, Xiao; Gravina, Silvia et al. (2017) Genome-wide, Single-Cell DNA Methylomics Reveals Increased Non-CpG Methylation during Human Oocyte Maturation. Stem Cell Reports 9:397-407|
|Vijg, Jan; Dong, Xiao; Zhang, Lei (2017) A high-fidelity method for genomic sequencing of single somatic cells reveals a very high mutational burden. Exp Biol Med (Maywood) 242:1318-1324|
|Ogrodnik, Mikolaj; Miwa, Satomi; Tchkonia, Tamar et al. (2017) Cellular senescence drives age-dependent hepatic steatosis. Nat Commun 8:15691|
|Dong, Xiao; Zhang, Lei; Milholland, Brandon et al. (2017) Accurate identification of single-nucleotide variants in whole-genome-amplified single cells. Nat Methods 14:491-493|
|Olivieri, Fabiola; Capri, Miriam; Bonafè, Massimiliano et al. (2017) Circulating miRNAs and miRNA shuttles as biomarkers: Perspective trajectories of healthy and unhealthy aging. Mech Ageing Dev 165:162-170|
|Perrott, Kevin M; Wiley, Christopher D; Desprez, Pierre-Yves et al. (2017) Apigenin suppresses the senescence-associated secretory phenotype and paracrine effects on breast cancer cells. Geroscience 39:161-173|
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