The heat shock factor HSF-1 is involved in the processes of cellular maintenance relating to ensuring correct protein folding and clearing out misfolded proteins. Protein shape is vital to the operation of cellular machinery, and the presence of misfolded proteins should be considered a form of damage. It has been demonstrated that more HSF-1 extends life and improves tolerance to damage-inducing stress in laboratory animals, and thus a number of research groups are interested in producing treatments based on this effect.
For 35 years, researchers have worked under the assumption that when cells undergo heat shock, as with a fever, they produce a protein that triggers a cascade of events that field even more chaperones to refold unraveling proteins that could kill the cell. The protein, HSF-1 (heat shock factor-1), does this by binding to promoters upstream of the 350-plus chaperone genes, upping the genes' activity and launching the army of chaperones, which originally were called "heat shock proteins."
Injecting animals with HSF-1 has been shown not only to increase their tolerance of heat stress, but to increase lifespan. Because an accumulation of misfolded proteins has been implicated in aging and in neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's diseases, scientists have sought ways to artificially boost HSF-1 in order to reduce the protein plaques and tangles that eventually kill brain cells. To date, such boosters have extended lifespan in lab animals, including mice, but greatly increased the incidence of cancer.
[Researchers] found in experiments on the nematode worm C. elegans that HSF-1 does a whole lot more than trigger release of chaperones. An equal if not more important function is to stabilize the cell's cytoskeleton, which is the highway that transports essential supplies - healing chaperones included - around the cell. "We are suggesting that, rather than making more of HSF-1 to prevent diseases like Huntington's, we should be looking for ways to make the actin cytoskeleton better."
[The researchers compare] a cell experiencing heat shock to a country under attack. In a war, an aggressor first cuts off all communications, such as roads, train and bridges, which prevents the doctors from treating the wounded. Similarly, heat shock disrupts the cytoskeletal highway, preventing the chaperone "doctors" from reaching the patients, the misfolded proteins. "We think HSF-1 not only makes more chaperones, more doctors, but also insures that the roadways stay intact to keep everything functional and make sure the chaperones can get to the sick and wounded warriors." The researchers found specifically that HSF-1 up-regulates another gene, pat-10, that produces a protein that stabilizes actin, the building blocks of the cytoskeleton. By boosting pat-10 activity, they were able to cure worms that had been altered to express the Huntington's disease gene, and also extend the lifespan of normal worms.