DNA Damage Theory

The DNA, due to its central role in life, was bound to be implicated in aging. One hypothesis then is that damage accumulation to the DNA causes aging, as first proposed by physicist Leo Szilard (Szilard, 1959). The theory has changed a bit over the years as new forms of DNA damage and mutation are discovered, and several theories of aging argue that DNA damage or mutation accumulation causes aging (Gensler and Bernstein, 1981 for arguments). As briefly mentioned before, progeroid syndromes are rare genetic diseases that appear as accelerated aging. Interestingly, the most impressive progeroid syndromes, Werner's, Hutchinson-Gilford's, and Cockayne syndrome originate in genes that are related to DNA repair/metabolism (Martin and Oshima, 2000). Werner's syndrome (WS) originates in a recessive mutation in a gene, WRN, encoding a RecQ helicase (Yu et al., 1996; Gray et al., 1997). Since WRN is unique among its family in also possessing an exonuclease activity (Huang et al., 1998), it may be involved in DNA repair. Although the exact functions of WRN remain a mystery, it is undeniable that WRN plays a role in DNA biology, particularly in solving unusual DNA structures (reviewed in Shen and Loeb, 2000; Bohr et al., 2002; Fry, 2002). In fact, cells taken from patients with WS have increased genomic instability (Fukuchi et al., 1989). Topoisomerases are enzymes that regulate the supercoiling in duplex DNA. WS cells are hypersensitive to topoisomerase inhibitors (Pichierri et al., 2000). As such, WS is an indicator that alterations in the DNA over time play a role in aging. As with WRN, the protein whose mutation causes Hutchinson-Gilford's syndrome is also a nuclear protein: lamin A/C (Eriksson et al., 2003). Recent results also suggest that some atypical cases of WS may be derived from mutations in lamin A/C (Chen et al., 2003). The exact functions of lamin A/C remain unknown, but it appears to be involved in the biology of the inner nuclear membrane. Further evidence suggests that the DNA machinery is impaired in Hutchinson-Gilford's syndrome (Wang et al., 1991; Sugita et al., 1995), again suggesting that changes in the DNA are important in these diseases and, maybe, in normal aging. The protein involved in Cockayne Syndrome Type I participates in transcription and DNA metabolism (Henning et al., 1995). Other progeroid syndromes exist, though the classification is subjective. For example, Nijmegen breakage syndrome, which derives from a mutated DNA double-strand break repair protein (Carney et al., 1998; Matsuura et al., 1998; Varon et al., 1998), has been considered as progeroid (Martin and Oshima, 2000). Mouse accelerated aging syndromes have also been implicated in DNA repair such as the mouse homologues of xeroderma pigmentosum, group D (de Boer et al., 2002), ataxia telangiectasia mutated or ATM (Wong et al., 2003), p53 (Donehower et al., 1992; Donehower, 2002; Tyner et al., 2002; Cao et al., 2003), and Ercc1 (Weeda et al., 1997). Thus many progeroid syndromes of mice involve the DNA machinery (Hasty et al., 2003). Please take a look at the list of genes that can modulate the aging phenotype present in GenAge. It appears well-established that DNA mutations and chromosomal abnormalities increase with age in mice (Martin et al., 1985; Dolle et al., 1997; Vijg, 2000; Dolle and Vijg, 2002) and humans (e.g., Esposito et al., 1989). It is impossible, however, to tell whether these changes are effects or causes of aging. In addition, there is no consensus as to what type, if any, of DNA changes are crucial in aging. Correlations have been found between DNA repair mechanisms and rate of aging in some mammalian species (Hart and Setlow, 1974; Grube and Burkle, 1992; Cortopassi and Wang, 1996), though this may be an artifact of long-lived species being on average bigger (Promislow, 1994). On the other hand, mice overexpressing a DNA repair gene called MGMT had a lower cancer incidence but did not age slower (Zhou et al., 2001). Mice deficient in Pms2, another DNA repair protein, had elevated levels of mutations in multiple tissues and yet did not appear to age faster than controls (Narayanan et al., 1997). Embryos of mice and flies irradiated with x-rays do not age faster (reviewed in Cosgrove et al., 1993; Strehler, 1999), though one report argued that Chernobyl victims do (Polyukhov et al., 2000). Certain mutations in DNA repair proteins, such as p53 in humans (Varley et al., 1997), despite affecting longevity and increasing cancer incidence, fail to accelerate aging. One possibility is that ROS damage to DNA plays a role in aging, and some circumstantial evidence exists in favor of such hypothesis (Hamilton et al., 2001). Damage from free radicals to nuclear DNA remains an unproven cause of aging but since ROS originate in the mitochondria, and since mitochondria possess their own genome, many advocates of the free radical theory of aging consider that oxidative damage to mitochondria and the mitochondrial DNA (mtDNA) is more important (Harman, 1972; Linnane et al., 1989; de Grey, 1997; Barja, 2002). Indeed, some evidence exists that under CR oxidative damage to mtDNA is more important than oxidative damage to nuclear DNA (reviewed in Barja, 2002). At present, and despite contradictory evidence in favor (Khaidakov et al., 2003 for arguments) and against the theory (Rasmussen et al., 2003 for arguments), current technology does not appear capable of assessing the true relevance of damage to mtDNA in aging (Lightowlers et al., 1999; DiMauro et al., 2002). Interestingly, disruption of the mitochondrial DNA polymerase resulted in an accelerated aging phenotype, for the first time directly implicating the mtDNA in aging (Trifunovic et al., 2004). This appears to be unrelated to oxidative damage but instead result from increased apoptosis and accumulated mtDNA damage (Kujoth et al., 2005). As such, mtDNA may play a role in age-related diseases and aging, though much research remains to confirm such hypothesis and elucidate the exact mechanisms involved. Animal cloning involving somatic cells to create new organisms is an interesting technique for gerontologists (e.g., Lanza et al., 2000; Yang and Tian, 2000). Clones from adult frogs do not show signs that differentiation affects the genome (Gurdon et al., 1975). Dolly was "created" by transferring the DNA-containing nucleus of a post-mitotic mammary cell into an egg and from there a whole new organism was formed. We know Dolly had some genetic (Shiels et al., 1999) and epigenetic defects (Young et al., 2001), so maybe her arthritis and the pathologies leading to her death are a result of damage present in the DNA, perhaps in the telomeres. Nonetheless, she was remarkably "normal," having endured a complete developmental process and being fertile (Wilmut et al., 1997). Moreover, mice have been cloned for six generations without apparent harm (Wakayama et al., 2000). Perhaps the highly proliferative nature of the embryo can, by recombination, dilute the errors present in the DNA, but results from cloning experiments suggest that at least some cells in the body do not accumulate great amounts of DNA damage. It will be interesting to see the longevity of more cloned animals. If progeroid syndromes represent a phenotype of accelerated aging then changes in DNA over time likely play a role in aging. Nevertheless, the essence of those changes remains to be determined. Since many genetic perturbations affecting DNA repair do not influence aging, it is doubtful overall DNA repair is related to aging or that DNA damage accumulation alone drives aging. Understanding which aspects, if any, of DNA biology play a role in aging remains a great challenge in gerontology. The next step to give strength to this theory would be to delay aging in mice based on enhanced DNA repair systems, but that has so far eluded researchers. In conclusion, changes in DNA over time might play some kind a role in aging, but the essence of those changes and the exact mechanisms involved remain to be determined.