title: DNA Damage: A Main Determinant of Vascular Aging.
abstract: Vascular aging plays a central role in health problems and mortality in older people. Apart from the impact of several classical cardiovascular risk factors on the vasculature, chronological aging remains the single most important determinant of cardiovascular problems. The causative mechanisms by which chronological aging mediates its impact, independently from classical risk factors, remain to be elucidated. In recent years evidence has accumulated that unrepaired DNA damage may play an important role. Observations in animal models and in humans indicate that under conditions during which DNA damage accumulates in an accelerated rate, functional decline of the vasculature takes place in a similar but more rapid or more exaggerated way than occurs in the absence of such conditions. Also epidemiological studies suggest a relationship between DNA maintenance and age-related cardiovascular disease. Accordingly, mouse models of defective DNA repair are means to study the mechanisms involved in biological aging of the vasculature. We here review the evidence of the role of DNA damage in vascular aging, and present mechanisms by which genomic instability interferes with regulation of the vascular tone. In addition, we present potential remedies against vascular aging induced by genomic instability. Central to this review is the role of diverse types of DNA damage (telomeric, non-telomeric and mitochondrial), of cellular changes (apoptosis, senescence, autophagy), mediators of senescence and cell growth (plasminogen activator inhibitor-1 (PAI-1), cyclin-dependent kinase inhibitors, senescence-associated secretory phenotype (SASP)/senescence-messaging secretome (SMS), insulin and insulin-like growth factor 1 (IGF-1) signaling), the adenosine monophosphate-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR)-nuclear factor kappa B (NFκB) axis, reactive oxygen species (ROS) vs. endothelial nitric oxide synthase (eNOS)-cyclic guanosine monophosphate (cGMP) signaling, phosphodiesterase (PDE) 1 and 5, transcription factor NF-E2-related factor-2 (Nrf2), and diet restriction.
authors.affiliation: Department of Internal Medicine, Division of Vascular Medicine and Pharmacology, Erasmus Medical Center, Rotterdam 3015 CN, The Netherlands. p.bautistanino@erasmusmc.nl.|Department of Epidemiology, Erasmus Medical Center, Rotterdam 3015 CN, The Netherlands. p.bautistanino@erasmusmc.nl.
authors.forename: Paula K
authors.initials: PK
authors.lastname: Bautista-Niño
authors.affiliation: Department of Internal Medicine, Division of Vascular Medicine and Pharmacology, Erasmus Medical Center, Rotterdam 3015 CN, The Netherlands. e.portillafernandez@erasmusmc.nl.|Department of Epidemiology, Erasmus Medical Center, Rotterdam 3015 CN, The Netherlands. e.portillafernandez@erasmusmc.nl.
authors.forename: Eliana
authors.initials: E
authors.lastname: Portilla-Fernandez
authors.affiliation: Department of Medicine &amp; Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. d-vaughan@northwestern.edu.
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Vaughan
authors.affiliation: Department of Internal Medicine, Division of Vascular Medicine and Pharmacology, Erasmus Medical Center, Rotterdam 3015 CN, The Netherlands. a.danser@erasmusmc.nl.
authors.forename: A H Jan
authors.initials: AH
authors.lastname: Danser
authors.affiliation: Department of Internal Medicine, Division of Vascular Medicine and Pharmacology, Erasmus Medical Center, Rotterdam 3015 CN, The Netherlands. a.roks@erasmusmc.nl.
authors.forename: Anton J M
authors.initials: AJ
authors.lastname: Roks
mesh_terms: D000375:Aging / Q000235:genetics*; D000818:Animals; D002318:Cardiovascular Diseases / Q000235:genetics*; D004249:DNA Damage; D004260:DNA Repair; D042822:Genomic Instability; D006801:Humans
keywords: DNA damage; PAI-1; aging; dietary restriction; eNOS; endothelium; genomic instability; phosphodiesterase; senescence; vascular