DNA damage repair defect unifies theories of aging

A novel form of progeria shows aging has both DNA damage and genetic components

Dec 20, 2006
Jeffrey M. Perkel
Analysis of a novel form of progeria caused by a mutation in a DNA repair gene has unified two competing theories of aging, according to a report in Nature. DNA damage induces aging, but at a rate that is genetically determined, Jan Hoeijmakers, head of the department of genetics at Erasmus Medical Center, Rotterdam, the Netherlands, and colleagues determined after studying a patient with the disease as well as a knockout mouse model.The novel disease, which the authors called XFE progeroid syndrome, presented as a blend of progeria, or premature aging, and symptoms more typically seen in DNA damage repair-related diseases like xeroderma pigmentosum (XP) or Cockayne syndrome. The 15-year-old patient studied showed delayed growth and problems with kidney and liver function, as well as features normally associated with aging, like hypertension. But he also displayed the increased sun sensitivity that is the hallmark of a DNA repair defect. In the knockout mouse model of the disease, the researchers found a transcriptome profile at the age of 15 days that was similar to that of normally aged mice at 2.5 years of age, with a shift toward DNA repair and cell maintenance functions and away from growth activities. Aging can thus 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, they concluded. In progeria patients, this shift occurs early in life, while in normal individuals it occurs much later. The study arose from the unexpected finding that mutation of the DNA repair gene ERCC1, which is implicated in nucleotide excision repair of DNA, induced symptoms associated with old age in mice. "If you knock out other genes required for nucleotide excision repair to model the human disease xeroderma pigmentosum, you don't get accelerated aging, you get a cancer predisposition, so ERCC1 was a big surprise," said lead author Laura Niedernhofer, assistant professor of molecular genetics and biochemistry at the University of Pittsburgh School of Medicine.That surprise led the team to look for human patients with a similar disease. A 15-year-old Afghan boy was referred to the Erasmus clinic genetics service because of severe and chronic sunburn, suggestive of XP, but showed progeroid symptoms as well. Genetic analysis of DNA repair pathway components in cells from this patient indicated a mutation in XPF, a gene normally associated with mild XP. XPF, in complex with ERCC1, is involved in nucleotide excision repair of both intrastrand and interstrand DNA lesions. XP patients normally are deficient in intrastrand repair, but this patient's cells were also deficient in repairing interstrand crosslinks, which disrupt DNA replication and transcription processes. The inability to remove these more severe lesions could be an important factor in the premature aging symptoms seen in both the patient and ERCC1 mice, according to Hoeijmakers.In particular, genes in the so-called somatotroph axis, which Niedernhofer calls "a fancy word for growth hormone and IGF1 signaling," were downregulated. The somatotroph axis governs whether cells focus on growth or maintenance functions; mutations in this axis can extend the life of model organisms, while caloric restriction, which also extends life, downregulates it. "If the system is very high [and] insulin levels are high, you grow rapidly. If that system is tuned down, then you don't grow that abundantly, but you invest more in maintenance and repair. We call this a 'survival response,'" Hoeijmakers said. Frederick Alt, a Howard Hughes Medical Institute Investigator and professor of genetics at Children's Hospital, Boston, who did not participate in the study, told The Scientist that the research "provides probably some of the best support to date that accumulation of unrepaired DNA damage can contribute to normal aging." Also exciting, he said, is the paper's support for a connection between DNA damage and the IGF1/insulin signaling pathway in aging. According to Alt, who earlier this year described a different knockout mouse that also suggested a link between DNA damage, insulin signaling and aging, the key unanswered question is how the DNA repair and IGF1/insulin pathways communicate.Leslie Gordon, medical director of the Progeria Research Foundation, praised the new study as "carefully constructed" and told The Scientist in an email that she thinks it "supports the body of evidence that shows that aging likely has many contributing elements, but perhaps feeding in to only a few common pathways downstream."Jeffrey M. Perkel jperkel@the-scientist.comLinks within this article:I. Oransky, "Progeria effort pays off," The Scientist, April 1, 2006. http://www.the-scientist.com/article/display/23290/L.J. Niedernhofer et al., "A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis," Nature, 444:1038 - 43, 21/28 December 2006. http://www.nature.comJan Hoeijmakers http://www.biomedicalgenetics.nl/Members/Hoeijmakers/hoeijmakers.htmlLaura Niedernhofer http://www.mgb.pitt.edu/personnel/view.asp?uid=niedernhFrederick Alt http://www.hms.harvard.edu/dms/bbs/fac/alt.html"Hot Paper: DNA Repair," The Scientist, Jan. 6, 1997 http://www.the-scientist.com/article/display/17343R. Mostoslavsky et al., "Genomic instability and aging-like phenotype in the absence of mammalian SIRT6," Cell, 124:315 - 29, 2006. http://dx.doi.org/10.1016/j.cell.2005.11.04The Progeria Research Foundation http://www.progeriaresearch.org/S. Jay Olshansky et al. "The Longevity Dividend," The Scientist, March 1, 2006 http://www.the-scientist.com/article/display/23191