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 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 latest 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."
