PITTSBURGH, Dec. 20 – The accumulation of genetic damage in our cells is a major contributor to how we age, according to a study being published today in the journal Nature by an international group of researchers. The study found that mice completely lacking a critical gene for repairing damaged DNA grow old rapidly and have physical, genetic and hormonal profiles very similar to mice that grow old naturally. Furthermore, the premature aging symptoms of the mice led to the discovery of a new type of human progeria, a rare inherited disease in which affected individuals age rapidly and die prematurely.
"These progeroid mice, even though they do not live very long, have remarkably similar characteristics to normal old mice, from their physical symptoms, to their metabolic and hormonal changes and pathology, right down to the level of similar changes in gene expression," said corresponding author Jan Hoeijmakers, Ph.D., head of the department of genetics at the Erasmus Medical Center in Rotterdam, Netherlands. "This provides strong evidence that failure to repair DNA damage promotes aging— a finding that was not entirely unexpected since DNA damage was already known to cause cancer. However, it shows how important it is to repair damage that is constantly inflicted upon our genes, even through the simple act of breathing."
The study found that a key similarity between the progeria-like, or progeroid, mice and naturally old mice is the suppression of genes that control metabolic pathways promoting growth, including those controlled by growth hormone. How growth hormone pathways are suppressed is not known, but this response appears to have evolved to protect against stress caused by DNA damage or the wear-and-tear of normal living. The authors speculate that this stress response allows each of us to live as long and as healthy a life as possible despite the accumulation of genetic damage as we age.
Can we design humans to live longer? Or will we have to constantly repair accumulating damage? How to make the DNA in our cells less prone to accumulation of damage? Will the development of massive computer simulations for computer aided biological engineering allow us to find much better designs for enzymes that protect and repair DNA?
The scientists were set off on the road to make this discovery by their investigations into the causes of a boy's genetic disease.
A German physician had contacted the center about a 15-year old Afghan boy who was highly sensitive to the sun and had other debilitating symptoms including weight loss, muscle wasting, hearing loss, visual impairment, anemia, hypertension and kidney failure.
The boy turned out to have a defect in the DNA repair mechanism called nucleotide excision repair (NER). The scientists were able to trace down the mutation to a particular gene:
When the investigators obtained cells from the boy and tested them for NER activity, they found almost none. Further analysis of the boy’s DNA revealed a mutation in a gene known as XPF, which codes for part of a key enzyme required for the removal of DNA damage. The XPF portion of the enzyme harbors the DNA-cutting activity; whereas a second portion, known as ERCC1, is essential for the enzyme to bind to the damaged DNA. Mutations in either XPF or ERCC1 lead to reduced activity of this key DNA repair enzyme.
"We were completely surprised by the finding that the patient had a mutation in XPF, because mutations in this gene typically cause xeroderma pigmentosum, which is a disease characterized primarily by skin and other cancers rather than accelerated aging," said Dr. Hoeijmakers. "This patient, therefore, has a unique disease, which we named XPF-ERCC1, or XFE-progeroid syndrome."
DNA manipulation technologies have become powerful enough to allow creation of lab mice which have any mutation of interest. So these scientists do what many scientists do when faced with the need to better understand a human genetic variation: They created lab mice that contain the same genetic defect.
To understand why this XPF mutation caused accelerated aging, the investigators compared the expression pattern of all of the genes (approximately 30,000) in the liver of 15-day-old mice that had been generated in the laboratory to harbor a defect in their XPF-ERCC1 enzyme and that had symptoms of rapidly accelerated aging to the genes expressed by normal mice of the same age. This comparison revealed a profound suppression of genes in several important metabolic pathways in the progeroid mice. Most notably, the progeroid mice had a profoundly suppressed somatotroph (growth hormone) axis—a key pathway involved in the promotion of growth and development—compared to normal mice.
Damaged aging bodies probably produce less growth hormone as a way to reduce cancer risk. Aging cells with damaged genomes are at risk of becoming cancerous. Growth hormone exposure would make the cells divide. While a cell is dividing it is at increased risk of further DNA damage. Accumulation of DNA damage eventually causes some cells to mutate in their mechanisms for controlling cell growth. Then they start dividing continuously and you get cancer. Better to turn down the growth hormone and reduce the rate of DNA mutation accumulation than get cancer.
The investigators also found low levels of growth hormones in the progeroid mice and ruled out the possibility that this suppression was due to problems with their hypothalamus or pituitary glands, which regulate growth hormone secretion. Furthermore, they demonstrated that if normal adult mice were exposed to a drug that causes DNA damage, such as a cancer chemotherapy agent, the growth hormone axis was similarly suppressed. In other words, DNA damage somehow triggered hormonal changes that halted growth, while also boosting maintenance and repair.
Turns out these mutant mice get the same pattern of gene expression that normal old mice get. So the more rapid rate of accumulation of DNA damage causes mice to age in the same way as normal mice do but at a faster rate.
Because growth hormone levels go down as we get older, contributing to loss of muscle mass and bone density, the investigators systematically compared the gene expression pattern of their progeroid mice to normal old mice to look for other similarities. What they found was a striking similarity pattern between the progeroid and normal-aged mice in several key pathways.
Indeed, for genes that influence the growth hormone pathway, there was a greater than 95 percent correlation in changes in gene expression between the DNA repair-deficient mice and old mice. And, remarkably, there was a near 90 percent correlation between all other pathways affected in the progeroid mice and the older mice.
These results strongly suggest that most of normal aging is driven by accumulation of damage in DNA.
"Because there were such high correlations between these pathways in progeroid and normal older mice, we are quite confident that DNA damage plays a significant role in promoting the aging process. The bottom line is that avoiding or reducing DNA damage caused by sources such as sunlight and cigarette smoke, as well as by our own metabolism, also could delay aging," explained Dr. Niedernhofer.
We need gene therapies that will repair DNA damage. But if DNA damage involves most of a genome then gene therapy might not be practical. Current gene therapy techniques involve adding just a gene or two. Putting in much larger amounts of DNA is a much harder task. How to get completely new copies of entire genomes into hundreds of billions of cells throughout the body?
For neurons in the brain we have got to find ways to do extensive repair or replacement of chromosomes. We can't replace all our neurons without losing our identities. This result provides additional evidence that brain rejuvenation is our toughest rejuvenation challenge.
Update: In the last 5 years the two reports that have done the most to make full body rejuvenation look harder to me are this report above and another report that showed the blood of young mice improves the regenerative ability of the muscles of old mice. In both cases the upshot is that the scale of the changes needed to do rejuvenation came out looking bigger.
In the case of the young mouse blood, old mice, and muscle regeneration the result indicates that perhaps many cells all over the body excrete compounds into the blood that dampen down stem cells. Even if the compounds that cause this effect come from a few places and are easily blockable the fact that old bodies make stem cell suppressor compounds suggests that old bodies really need to make stem cell suppressor compounds in order to reduce the risk of cancer.
This latest report similarly points in the direction of more extensive changes needed to do rejuvenation. This report is worse news than the mouse blood report because development of ability to deliver full genome gene therapy hundreds of millions of cells strikes me as an incredibly difficult problem to solve. We will probably need some pretty sophisticated nanotechnology to solve it. I hope the nanotech optimists are right about how fast nanotech will advance. To do extensive genome repair we'll probably need nanotechnology.
|Share |||Randall Parker, 2006 December 21 10:30 PM Aging Mechanisms|