NEWS
Team reports genetic link
between aging, neurodegenerative disorders
Work could lead to new drugs against Alzheimer's, more
Deborah Halber, News Office Correspondent
July 9, 2007
A group of enzymes known as sirtuins have gained fame in recent years for
their ability to slow the aging process. Now, researchers at MIT's Picower
Institute for Learning and Memory and Harvard Medical School report that one
particular sirtuin-producing gene is a link between aging and human
neurodegenerative disorders.
The work may lead to new drugs against Alzheimer's disease, amyotrophic
lateral sclerosis (also known as Lou Gehrig's disease) and other
debilitating neurological diseases.
The SIR2 (silent information regulator) gene and sirtuin, the enzyme it
produces, promote longevity in a variety of organisms and may be tied to the
health benefits of caloric restriction, which delays aging and
neurodegeneration in mammals.
In work published in a recent issue of the journal of the European
Molecular Biology Organization, Li-Huei Tsai, Picower Professor of
Neuroscience in the Department of Brain and Cognitive Sciences, and
colleagues reported that SIRT1, the analogous human version of SIR2,
"constitutes a unique molecular link between aging and human
neurodegenerative disorders and provides a promising avenue for therapeutic
intervention."
Progressive loss of nerve cells, or neurons, with age underlies a variety
of debilitating neurological disorders, including Alzheimer's and Lou
Gehrig's disease, yet few effective treatments are currently available, Tsai
said. "In our cell and mouse models for those two disorders, SIRT1 and
resveratrol, a SIRT1-activating molecule, both promoted neuronal survival,
reduced neurodegeneration and prevented learning impairment," she said.
The latest study is an extension of work reported over the past several
years by co-author Dr. David A. Sinclair of Harvard Medical School. He has
shown that resveratrol, a natural plant substance found in red wines, is one
of a class of chemicals that mimics the effects of a very low-calorie diet,
which is known to lengthen the life span of rodents. Scientists say that
human life spans could be extended by 30 percent if humans respond to the
chemicals in the same way as rats and mice do to low calories.
Preventing loss of neurons
SIRT1 is thought to be a key regulator of an evolutionarily conserved
pathway that allows organisms to cope with adversity. These genes and the
enzymes they produce are part of a feedback system that enhances cell
survival during times of stress, especially if that stress is a lack of
food.
In the current study, the researchers increased SIRT1 activation in mice.
Furthermore, injecting SIRT1 directly into the brains of mice genetically
engineered to experience neurotoxic conditions "conferred significant
protection against neurodegeneration," the authors wrote.
While SIRT1 is the human counterpart of the SIR2 gene previously studied
in rodents, it is common to use the human counterparts of genes for
transgenic models for neurodegeneration, Tsai said. "Such an approach may
make it slightly more relevant to studying human disease. Likewise, while
the mouse version of the gene will probably have a similar effect, our
positive results showing therapeutic potential of human SIRT1 overexpression
provides a little bit more promise that such an approach may translate to
benefits in humans."
Exploring the underlying mechanisms for inducing SIRT1 through neurotoxic
stresses and investigating compounds that may activate SIRT1 are among the
lab's future goals.
In addition to Tsai and Sinclair, co-authors included Dohoon Kim, a
graduate student in the MIT Department of Brain and Cognitive Sciences;
Picower Institue technical assistant Matthew M. Dobbin; Picower Institute
research affiliate Andre Fischer; MIT affiliate Farahnaz Sananbenesi;
Picower Institute research affiliate Ivana Delalle, and other researchers
from Harvard Medical School.
This work was supported by the National Institutes of Health, the
National Institute of Aging, the Canadian Institutes of Health Research and
the Paul F. Glenn Foundation for Medical Research.
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