title: Do DNA Double-Strand Breaks Drive Aging?
abstract: DNA double-strand breaks (DSBs) are rare, but highly toxic, lesions requiring orchestrated and conserved machinery to prevent adverse consequences, such as cell death and cancer-causing genome structural mutations. DSBs trigger the DNA damage response (DDR) that directs a cell to repair the break, undergo apoptosis, or become senescent. There is increasing evidence that the various endpoints of DSB processing by different cells and tissues are part of the aging phenotype, with each stage of the DDR associated with specific aging pathologies. In this Perspective, we discuss the possibility that DSBs are major drivers of intrinsic aging, highlighting the dynamics of spontaneous DSBs in relation to aging, the distinct age-related pathologies induced by DSBs, and the segmental progeroid phenotypes in humans and mice with genetic defects in DSB repair. A model is presented as to how DSBs could drive some of the basic mechanisms underlying age-related functional decline and death.
authors: Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Ave., Bronx, NY 10461, USA. Electronic address: rwhite@rockefeller.edu.
authors: Ryan R
authors: RR
authors: White
authors: Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Ave., Bronx, NY 10461, USA. Electronic address: jan.vijg@einstein.yu.edu.
authors: Jan
authors: J
authors: Vijg
mesh_terms: D017766:Acid Anhydride Hydrolases; D000375:Aging / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D016922:Cellular Senescence; D004247:DNA / Q000235:genetics* / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004720:Endonucleases / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D000072200:Ku Autoantigen / Q000235:genetics / Q000378:metabolism; D000076228:MRE11 Homologue Protein; D051379:Mice; D008957:Models, Genetic; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011371:Progeria / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; C112156:NBN protein, human; D009687:Nuclear Proteins; D004247:DNA; C071447:ERCC1 protein, human; D004720:Endonucleases; D000076228:MRE11 Homologue Protein; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D000072200:Ku Autoantigen; D045643:DNA Repair Enzymes