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Researchers discover common cause
for aging and age-related disease
Eurekalert, May 15, 2003
do serious diseases such as cancer, Alzheimer's and Huntington's mainly
hit us in middle age or later? The links between aging and age-related
diseases have proved elusive.
In studies of the
powerfully informative roundworm, C. elegans, UCSF scientists have
discovered that a class of molecules found in the worms and in people can
both prolong life in the worm and prevent the harmful accumulation of
abnormal proteins that cause a debilitating Huntington's-like disease. The
finding appears to be the first evidence in an animal of a link between
aging and age-related disease.
called "small heat-shock proteins," are known to assemble into
complexes that bind to damaged or unfolded cellular proteins and prevent
them from forming into harmful aggregations.
"We think we've
found an important physiological explanation for both aging and
age-related disease," said Cynthia Kenyon, PhD, the Herbert Boyer
Professor of Biochemistry and Biophysics at UCSF and senior author on a
paper describing the work in the May 16 issue of SCIENCE. "The
question of why older people are more susceptible to so many diseases has
been a fundamental, unsolved problem in biology. Our findings suggest a
beautiful molecular explanation, at least for this protein-aggregation
damaged and unfolded proteins from aggregating, this one set of proteins
may be able to stave off both aging and age-related disease. The small
heat-shock proteins are the molecular link between the two."
The growing roster
of diseases thought to be caused by protein clumping or aggregation --
Alzheimer's, Huntington's, Parkinson's, prion diseases -- suggests that
the small heat shock proteins may influence the onset of many age-related
ailments, the researchers say. The pharmaceutical industry is already
exploring ways to increase the activity of heat-shock proteins. The
research by Kenyon's laboratory indicates that if these drugs work, they
may not only protect protein function, but also extend life.
international news 10 years ago when her laboratory showed that modifying
a single gene in C. elegans doubled the worm's healthy life-span. The
gene, known as daf-2, encodes a receptor for insulin as well as for a
hormone called insulin-like growth factor. The same or related pathways
have since been shown to affect longevity in fruit flies and mice and are
likely to control life-span in humans as well.
Huntington's disease, brain cells produce proteins with an abnormally high
number of repeating subunits called glutamine. The proteins aggregate,
disrupting their function. Ultimately, people with Huntington's disease
lose control of their movements. Recently, researchers traced a similar
morbid course in C. elegans, using fluorescent tags to follow the
debilitating accumulation of the damaged protein. They found that in
worms, as in humans, the proteins formed aggregates, but only as the
have shown that Kenyon's long-lived daf-2 mutant worms accumulate the
disabling proteins later in life than normal worms, so the worms have both
increased life-span and delayed onset of age-related disease -- the best
of both worlds.
In the new research,
Kenyon's team used DNA microarrays to find that the expression of genes
for four small heat-shock proteins "sharply increased" in the
long-lived daf-2 mutants.
They also found that
the boost in this gene expression required two key proteins in the
daf-2-insulin/IGF-1 receptor pathway -- the proteins DAF-16 and HSF-1,
both "transcription factors" that direct gene activity. The
involvement of HSF-1 in the daf-2 pathway had not been known.
To determine if the
small heat-shock proteins influenced life-span, the scientists used a
fairly new technique called RNA interference, or RNAi, to partially
disable the small heat-shock protein genes. They showed that the
heat-shock proteins account for a substantial part of the worms' increased
(In a related study,
researchers at the Buck Institute for Aging led by Gordon Lithgow have
recently shown that raising the levels of small heat-shock proteins can
extend the lifespan of C. elegans.)
proteins are known to inhibit protein aggregation, so Kenyon and her
colleagues used the powerful RNAi technique to show that decreased
heat-shock protein gene expression accelerated the onset of
Huntington's-like "polyglutamine" protein aggregation -- strong
evidence that small heat shock proteins normally delay the harmful protein
proteins, they conclude, may influence the rates of aging and of
polyglutatmine aggregation "coordinately." Mutations in the
DAF-2 pathway, they write, may delay both aging and susceptibility to this
age-related disease, at least in part by increasing small heat-shock
protein gene expression.
heat-shock proteins appear to be the link between aging and at least this
age-related disease," Kenyon stresses. "And by regulating the
small heat-shock proteins, the insulin/IGF-1 pathway can influence both
aging and age-related disease coordinately."
Kenyon, who was elected this month to the National Academy of Sciences, directs UCSF's Hillblom Center for the Biology of Aging at the University's new Mission Bay campus.