Researchers discover common cause for aging and age-related disease
Public release date: 15-May-2003

Contact: Wallace Ravven
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University of California - San Francisco

Why 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.

The molecules, 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 disease.

"By preventing 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.

Kenyon made 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.

In neurodegenerative 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 animals aged.


Other researchers 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 life-span.

(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.)

Small heat-shock 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 aggregation.

Small heat-shock 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.

"The small 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.

###

Lead author on the SCIENCE paper is Ao-Lin Hsu, PhD; co-author is
Coleen T. Murphy. Both are post-doctoral scientists in Kenyon's lab.

The research was funded by the Ellison Foundation and the National
Institute of Aging.

SOURCE: EurekAlert
http://www.eurekalert.org/pub_releases/2003-05/uoc--rdc051303.php

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