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DNA and DNA DamageThis has lead to an aging theory that says that aging can be viewed as a gradual shift, in the face of unrepaired DNA damage or other cellular stress, from a cellular emphasis on growth to an emphasis on staying alive. In human cells, normal metabolic activities and environmental factors can cause DNA damage, resulting in as many as 1 million individual molecular lesions per cell per day. Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes. Other lesions induce potentially harmful mutations in the cell's genome. Thus, the DNA repair process must be constantly active. In addition, many genes that were initially shown to influence lifespan have turned out to be involved in DNA damage repair and protection, making this one of the leading theories for the causes of aging. This theory has gained support as experimental studies with animals with genetic deficiencies in DNA repair have shown decreased lifespans and increased cancer incidences. DNA and DNA Damage - StudiesL.J. Niedernhofer et al. A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis. Nature, 444:1038 - 43, 21/28 December 2006. R. Mostoslavsky et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell, 124:315 - 29, 2006. Browner WS, Kahn AJ, Ziv E, Reiner AP, Oshima J, Cawthon RM, Hsueh WC, Cummings SR. (2004). The genetics of human longevity. Am J Med 117(11):851-60. Fry RC, Begley TJ, Samson LD. (2004). Genome-wide responses to DNA-damaging agents. Annu Rev Microbiol. 59 pp 357 - 77 de Boer J, Andressoo JO, de Wit J, Huijmans J, Beems RB, van Steeg H, Weeda G, van der Horst GT, van Leeuwen W, Themmen AP, Meradji M, Hoeijmakers JH. (2002). Premature aging in mice deficient in DNA repair and transcription. Science 296(5571):1276-9. Dolle ME, Busuttil RA, Garcia AM, Wijnhoven S, van Drunen E, Niedernhofer LJ, van der Horst G, Hoeijmakers JH, van Steeg H, Vijg J. (2006). Increased genomic instability is not a prerequisite for shortened lifespan in DNA repair deficient mice. Mutat Res 596(1-2):22-35. Stuart JA, Karahalil B, Hogue BA, Souza-Pinto NC, Bohr VA. (2004). Mitochondrial and nuclear DNA base excision repair are affected differently by caloric restriction. FASEB J 18(3):595-7. O'Brien PJ. (2006). Catalytic promiscuity and the divergent evolution of DNA repair enzymes. Chem Rev 106(2):720-52.
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