The new england journal of medicine n engl j med 361;15 nejm.org october 8, 2009 1475 review article MOLECULAR ORIGINS OF CANCER DNA Damage, Aging, and Cancer Jan H.J. Hoeijmakers, Ph.D. From the Department of Genetics, Cancer Genomics Center, Erasmus University Medical Center, Rotterdam, the Nether- lands. Address reprint requests to Dr. Hoeijmakers at the Department of Ge- netics, Cancer Genomics Center, Erasmus University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands, or at j.hoeijmakers@erasmusmc.nl. This article (10.1056/NEJMra0804615) was updated on November 4, 2009, at NEJM. org. N Engl J Med 2009;361:1475-85. Copyright © 2009 Massachusetts Medical Society. D NA damage has emerged as a major culprit in cancer and many diseases related to aging. The stability of the genome is supported by an intricate machinery of repair, damage tolerance, and checkpoint pathways that counteracts DNA damage. In addition, DNA damage and other stresses can trigger a highly conserved, anticancer, antiaging survival response that suppresses metabolism and growth and boosts defenses that maintain the integrity of the cell. Induction of the survival response may allow interventions that improve health and extend the life span. Recently, the first candidate for such interventions, rapamycin (also known as sirolimus), has been identified. 1 Compromised repair systems in tu- mors also offer opportunities for intervention, making it possible to attack malig- nant cells in which maintenance of the genome has been weakened. Time-dependent accumulation of damage in cells and organs is associated with gradual functional decline and aging. 2 The molecular basis of this phenomenon is unclear, 3-5 whereas in cancer, DNA alterations are the major culprit. In this review, I present evidence that cancer and diseases of aging are two sides of the DNA- damage problem. An examination of the importance of DNA damage and the systems of genome maintenance in relation to aging is followed by an account of the derailment of genome guardian mechanisms in cancer and of how this cancer- specific phenomenon can be exploited for treatment. DNA Damage and Aging Biologic molecules are susceptible to spontaneous chemical reactions, mostly hydro- lysis. Enzymatic reactions have an error rate, and their reaction products (including free radicals, such as reactive oxygen and nitrogen species) 2,6 can have harmful effects on other biologic molecules. Furthermore, elements in the environment — x-rays, ultraviolet (UV) radiation, and numerous chemicals — continuously damage cellular structures. 3-5 DNA is an important target for time-dependent deterioration, as high- lighted by the rapidly expanding family of rare inherited disorders called segmental progeroid syndromes, in which genome maintenance is compromised and many features of aging are accelerated 7,8 (for details see the Supplementary Appendix, available with the full text of this article at NEJM.org). These syndromes indicate that DNA is a critical target of aging and that genome maintenance is a major anti- aging mechanism. The Magnitude of DNA Damage DNA is the only biologic molecule that relies solely on repair of existing molecules, without any remanufacture; accumulates damage over a lifetime; and is represented by only one copy in most cells (with maternal and paternal DNA considered to be The New England Journal of Medicine Downloaded from nejm.org on March 21, 2011. For personal use only. No other uses without permission. Copyright © 2009 Massachusetts Medical Society. All rights reserved.