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Discovery of How Klotho Gene Works Could Lead to
Anti-Aging Therapy
Klotho works on insulin: making an animal resistant
to insulin increases its lifespan
Aug. 26, 2005 Led by one of the scientist that
first discovered and named the Klotho gene in 1997, researchers at UT
Southwestern Medical Center have discovered that a protein prolonging
life in mice works by controlling insulin, a discovery possibly
significant in developing anti-aging therapy.
Therapies based on this hormone could prove to be a
way to extend life or slow its effects, said
Dr. Makoto Kuro-o, assistant professor of pathology and senior
author of the study published in the online issue of Science Express and
appearing in an upcoming issue of Science. It could be one of the
significant steps for developing anti-aging therapy.
Dr. Kuro-o and his colleagues originally discovered
the Klotho gene in 1997, naming it after one of the mythical Greek fates
who controlled the length of human life. Their previous studies have
shown that mutant mice lacking the Klotho gene appear normal until about
3 to 4 weeks old, and then begin showing signs of age, such as skin
atrophy, osteoporosis, arteriosclerosis and emphysema. The mice died
prematurely at about two months.
The protein, Klotho, is found in several species.
In mice, the researchers discovered, it acts as a hormone, circulating
through the blood and binding to cells.
For the current study, they created a second strain of mutant mice in
which the Klotho gene generated more of the protein than in normal mice.
Those mice lived between 19 percent to 31 percent longer than normal
mice.
The researchers were especially interested in how
the hormone affected insulin, because making an animal resistant to
insulin increases its lifespan a phenomenon found in animals ranging
from worms to fruit flies to mice.
The mice with higher levels of Klotho had more
insulin in their system than the normal mice, suggesting that the Klotho
mice were resistant to insulin; they had to make more of it to make up
for the resistance. The opposite was true with the mice deficient in
Klotho. They were more sensitive to insulin and had reduced levels of
it.
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2002 Findings on Klotho Gene Association
with Life Expectancy
In 2002, scientist studying more than 2,000
anonymous samples found that having two copies of a less-common
version of klotho is twice as prevalent in infants as in people
over age 65. These results, they said, suggest that people born
with the two copies die sooner than others, although the gene's
exact influence on health and aging are not known, the
scientists say.
"The less-common klotho variant has a clear
association with life expectancy in the groups we studied," says
Hal Dietz, Ph.D., a Howard Hughes Medical Institute investigator
and a member of the McKusick-Nathans Institute of Genetic
Medicine at Hopkins.
"What's so striking about the klotho variant
is that it is relatively common and has its effect by age 65,"
explains Dan Arking, Ph.D., who conducted the klotho study as
part of his doctoral work with Dietz. "About 3 percent of the
infant population had two copies of the klotho variant,
indicating they might be at increased risk for earlier death.
About a quarter of the population had one variant copy, making
them carriers."
Despite its association with longevity,
klotho is not functionally related to genes that create
accelerated aging diseases in humans, says Dietz. Instead, the
klotho protein seems to belong to a family of enzymes that
modifies other proteins by cutting off their attached sugars.
However, even after much searching, no one has found a target
for klotho, so the effects of the variant on the protein's
function aren't yet known.
The Johns Hopkins scientists reported their
findings in the Jan. 15, 2002 online version of the Proceedings
of the National Academy of Sciences. |
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The influence on insulin creates a problem for
Klotho should it be used as a therapy against aging: It may extend life,
but it could also make an animal diabetic.
Mice with the excessive Klotho also had fewer offspring than normal
mice, said Dr. Kuro-o, a Southwestern Medical Foundation Scholar in
Biomedical Research.
Other UT Southwestern researchers involved in the
study were Dr. Hiroshi Kurosu, senior research associate in pathology
and lead author; Dr. Masaya Yamamoto, postdoctoral researcher in
pathology; Jeremy Clark, research technician in pathology; Johanne
Pastor, senior research associate in pathology; Dr. Animesh Nandi,
research scientist in pathology; Prem Gurnani, research associate in
pathology; Dr. Yoshiharu Takayama, postdoctoral researcher in molecular
genetics; Dr. Joachim Herz, professor of molecular genetics and in the
Center for Basic Neuroscience, and Dr. Kevin Rosenblatt, assistant
professor in pathology. Researchers from Vanderbilt University School of
Medicine, the University of Tokyo, Osaka University and Joslin Diabetes
Center also participated.
The work was supported by the Endowed Scholars
Program in Medical Science at UT Southwestern, The Pew Scholars Program
in the Biomedical Sciences, the Eisai Research Fund, the High
Impact/High Risk Research Program at UT Southwestern and the National
Institutes of Health.
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