X-Message-Number: 28773
Date: Sun, 24 Dec 2006 10:51:07 -0500
From: Keith Henson <>
Subject: Buildup of damaged DNA in cells drives aging

[I am an agnostic about what causes aging, but this is probably of interest 
here.  Keith]

Buildup of damaged DNA in cells drives aging

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.

Findings from this study help to reconcile two conflicting hypotheses 
currently favored in the field of aging research about why we get old, 
according to the authors. The first is that our lifespan and how well we 
age is determined by the genes inherited from our parents. The second is 
that lifespan and fitness in old age is determined by how much damage we 
incur over our lifetime.

"Our study suggests that both of these hypotheses are correct. Damage, 
including DNA damage, drives the functional decline we all experience as we 
age. But how we respond to that damage is determined genetically, in 
particular by genes that regulate the growth hormone and insulin pathways," 
said Laura Niedernhofer, M.D., Ph.D., assistant professor of molecular 
genetics and biochemistry, University of Pittsburgh School of Medicine, and 
first author of the study.

How the researchers came to study the relationship between DNA damage and 
aging began almost serendipitously in the late 1990s while Dr. Niedernhofer 
was a post-doctoral fellow in Dr. Hoeijmakers' laboratory at Erasmus 
Medical Center, a well-known European center for medical genetics, 
including the diagnosis of people with unusual sensitivity to sunlight.

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's family had immigrated to 
Germany to seek better medical treatment for his condition.

Extreme sensitivity to ultraviolet (UV) radiation from sunlight is a 
hallmark of diseases caused by defective DNA repair-an important mechanism 
by which skin and other cell types normally cut out, or excise, damage to 
their DNA caused by UV light. Defects in one DNA repair mechanism, 
nucleotide excision repair (NER), causes xeroderma pigmentosum, a rare 
disease in which people have a 2,000-fold increased risk of skin cancer 
from sun exposure.

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."

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.

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.

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.

"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.

Source: University of Pittsburgh Medical Center
http://www.eurekalert.org/pub_releases/2006-12/uopm-bod121406.php  

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