? 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.

Public Health Relevance

? 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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
2P01AG017242-24
Application #
9718907
Study Section
Special Emphasis Panel (ZAG1)
Program Officer
Guo, Max
Project Start
1999-04-01
Project End
2024-04-30
Budget Start
2019-07-01
Budget End
2020-04-30
Support Year
24
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Type
DUNS #
081266487
City
Bronx
State
NY
Country
United States
Zip Code
10461
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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
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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
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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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