? Overall Progress in aging research over the last two decades has now firmly established an important role for DNA damage and genome instability in age-related cellular degeneration and death. Since its inception in 1999 investigators in this PPG demonstrated that genetic defects in some but not all DNA repair pathways are associated with premature aging phenotypes in mice, developed the first methods to detect spontaneous DNA mutations in primary tissues, identified transcription stress as a novel age-related molecular phenotype, developed a mouse model to detect and eliminate senescent cells in mice and subsequently demonstrated causality in aging phenotypes, and provided the first evidence that rare genetic variants in genome maintenance pathways are enriched in human centenarians. Studies from other groups have confirmed many of our conclusions, and genome instability is now regarded a hallmark of aging. However, what remains lacking is specific insight into the genetic control and molecular mechanisms that link DNA damage and genome instability to aging and longevity in humans. This renewal application is organized around three major research questions that remain in this field: (1) the key genome maintenance genotypes that control human aging and longevity; (2) the genetic and molecular basis of DNA damage-driven aging; and (3) How DNA damage and its molecular sequelae affect cell fate diversity in aging. These key questions will be addressed jointly and in an integrated manner by four research projects, an Administrative Core and a Bioinformatics Core. We expect that the resulting specific insight into the role of DNA damage and repair in human aging will give us the means to develop interventions to minimize the adverse effects of DNA damage metabolism.
? Overall Multiple lines of evidence indicate a major role of DNA damage in the aging process. Here we propose to study how the role of DNA damage in aging humans is genetically controlled, what the mechanisms are that define the molecular and cellular end points of DNA damage in aging humans, and how the adverse effects of DNA damage can be minimized, thereby promoting healthy human longevity.
|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|
|Jeon, Ok Hee; Kim, Chaekyu; Laberge, Remi-Martin et al. (2017) Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat Med 23:775-781|
|Andriani, Grasiella A; Vijg, Jan; Montagna, Cristina (2017) Mechanisms and consequences of aneuploidy and chromosome instability in the aging brain. Mech Ageing Dev 161:19-36|
|Vijg, Jan; Dong, Xiao; Milholland, Brandon et al. (2017) Genome instability: a conserved mechanism of ageing? Essays Biochem 61:305-315|
|Lau, Cia-Hin; Suh, Yousin (2017) Genome and Epigenome Editing in Mechanistic Studies of Human Aging and Aging-Related Disease. Gerontology 63:103-117|
|Lau, Cia-Hin; Suh, Yousin (2017) In vivo genome editing in animals using AAV-CRISPR system: applications to translational research of human disease. F1000Res 6:2153|
|Hernandez-Segura, Alejandra; de Jong, Tristan V; Melov, Simon et al. (2017) Unmasking Transcriptional Heterogeneity in Senescent Cells. Curr Biol 27:2652-2660.e4|
Showing the most recent 10 out of 253 publications