Alzheimer's, Dementia & Mental Health
Delaying Aging Process Best Guard Against
Alzheimer’s Disease
| |
 |
|
| |
Top: This is beta amyloid plaque as
it appears in normally aging Alzheimer's mice. Bottom: This is
tighter packed plaques in long-lived Alzheimer's mice protect
against the disease.
Photo: Dr. Ehud Cohen, Hebrew
University–Hadassah Medical School. Click photo for larger view.
|
|
Looking at the way we age may have more impact on
treatment, prevention of AD than studying basic biology of the disease
Dec. 24, 2009 – Aging, something most senior
citizens try to resist, is the single greatest risk factor for
Alzheimer's disease. In a study released this month, researchers at the
Salk Institute for Biological Studies found that simply slowing the
aging process in mice prone to develop Alzheimer's disease prevented
their brains from turning into a neuronal wasteland.
"Our study opens up a whole new avenue of looking
at the disease," says the study's leader, Howard Hughes Medical
Investigator Andrew Dillin, Ph.D., a professor in the Salk Molecular and
Cell Biology Laboratory.
"Going forward, looking at the way we age may
actually have more impact on the treatment and prevention of Alzheimer's
disease than studying the basic biology of the disease itself."
Their finding, published in the Dec. 11, 2009 issue
of the journal Cell, is the latest clue in the Salk scientists' ongoing
quest to shed light on the question of whether Alzheimer's disease onset
late in life is a disastrous consequence of the aging process itself or
whether the beta amyloid aggregates that cause the disease simply take a
long time to form.
Age is the major risk factor for the development of
Alzheimer's disease. Beyond age 65, the number of people with the
disease doubles every five years. Centenarians, however, seem to escape
most common age-related diseases, including the ravages of Alzheimer's
disease.
"In this study, we went directly to the root cause
of Alzheimer's disease and asked whether we could influence the onset of
the disease by modulating the aging process," says first author Ehud
Cohen, Ph.D., formerly a postdoctoral researcher in Dillin's lab and now
an assistant professor at the Hebrew University–Hadassah Medical School
in Jerusalem, Israel.
To answer this intriguing question, he slowed the
aging process in a mouse model for Alzheimer's by lowering the activity
of the IGF-1 signaling pathway. "This highly conserved pathway plays a
crucial role in the regulation of lifespan and youthfulness across many
species, including worms, flies, and mice and is linked to extreme
longevity in humans," he explains. As a result, mice with reduced IGF-1
signaling live up to 35 percent longer than normal mice.
Cohen then employed a battery of behavioral tests
to find out whether it was simply the passage of time or aging per se
that determined the onset of the disease. Chronologically old but
biologically young animals appeared nearly normal long after
age-matched, normal-aging Alzheimer's mice exhibited severe impairments
in their ability to find a submerged platform in the Morris water maze
or stay atop a revolving Rota Rod.
"These behavioral differences between normal and
long-lived mice were apparent at nine months of age, but the big
surprise came when we took a closer look at the plaques in their
brains," says Cohen.
One of the telltale signs of Alzheimer's disease is
the buildup of toxic clumps of beta amyloid plaques in the brain. Beta
amyloid production probably occurs in all brains, but healthy cells
clear away excess amounts. Brains of people with Alzheimer's disease, on
the other hand, are unable to control beta amyloid accumulation. The
same is true for Alzheimer's mouse models, which are genetically
engineered to overproduce beta amyloid.
Although long-lived mice didn't show any of the
cognitive or behavioral impairments typical of Alzheimer's disease till
very late in life, their brains were riddled with highly compacted
plaques.
"Although before it was thought that plaques are
the causative agents of Alzheimer's disease, our results clearly support
the emerging theme that they have a protective function," says Cohen.
"As mice age, they become less efficient at stowing away toxic beta
amyloid fibrils in tightly packed aggregates."
An earlier study by Cohen, Dillin, and colleagues,
in which they had used roundworms to study the effects of the aging
process on protein aggregation, had indicated that high molecular weight
aggregates of beta amyloid might actually be less toxic than smaller
beta amyloid fibrils. "But worms don't have brains as we do, and it
wasn't clear whether these results would be relevant for mammals," he
says.
And what about those lucid centenarians?
"Interestingly, three studies found that some very long-lived humans
carry mutations in components of the IGF-1 signal pathway—the same
pathway that we perturbed to increase the lifespan of the mice in our
study," says Dillin.
"The reporting of this work is a celebration for
the entire field of aging researchers, as it validates the long-held
hypothesis that genetic and pharmacologic changes to create a healthy
lifespan, or 'healthspan,' can greatly reduce the onset of some of the
most devastating diseases that afflict mankind," he adds.
Notes:
The work was funded in part by the National
Institutes of Health and the McKnight Endowment for Neuroscience.
Researchers who also contributed to the work
include Johan F. Paulsson, Deguo Du and Jeffery W. Kelly at the Skaggs
Institute of Chemical Biology, The Scripps Research Institute, Pablo
Blinder in the Department of Physics at the University of California,
San Diego, Tal Burstyn-Cohen in the Molecular Neurobiology Laboratory at
the Salk Institute, Anthony Adame, Hang M. Pham and Eliezer Masliah in
the Department of Neurosciences at University of California, San Diego,
and Gabriela Estepa in the Molecular and Cell Biology Laboratory at the
Salk Institute.
About the Salk Institute for Biological Studies:
The Salk Institute for Biological Studies is one of
the world's preeminent basic research institutions, where
internationally renowned faculty probe fundamental life science
questions in a unique, collaborative, and creative environment. Focused
both on discovery and on mentoring future generations of researchers,
Salk scientists make groundbreaking contributions to our understanding
of cancer, aging, Alzheimer's, diabetes, and cardiovascular disorders by
studying neuroscience, genetics, cell and plant biology, and related
disciplines.
