Sci. Aging Knowl. Environ., 21 May 2003
Cellular heat-protection system works with insulin-like pathway to bestow long life
Key Words: Caenorhabditis elegans daf-2 polyglutamine-repeat RNAi age-1
New work unites two life-extending methods not previously known to collaborate. The results also show that reducing the accumulation of wrecked proteins leads to longer life; this observation suggests a molecular link between the mechanisms of aging and certain diseases.
Many creatures respond to heat spikes by activating a master switch, heat shock factor-1 (HSF-1). This regulator jacks up production of so-called heat shock proteins (HSPs) that stabilize other proteins and keep them from clumping. Overproduction of some HSPs enhances life span in flies and worms, and reducing the amount of HSF-1 causes worms to die young (see "Gauging Aging"), so Hsu and colleagues wanted to find out whether more of the factor increases longevity. To do so, the team overproduced the protein in lab worms. Animals with extra HSF-1 lived 40% longer than their normal counterparts did; this observation demonstrates that keeping proteins in their proper shapes promotes longevity.
Previous work showed that a life-extending mutation in the worm insulin-like signaling pathway boosts HSP-16 quantities, suggesting that the insulin-like signaling pathway and the heat shock system communicate with each other (see "Good Housekeeping" and "Stress for Success"). To probe this potential link, the researchers tested whether HSF-1 requires DAF-16, a gene activator in the insulin-like pathway, to promote long life. Worms that overproduced HSF-1 but lacked DAF-16 no longer reaped extra time. Similarly, DAF-16 required HSF-1 to prolong life. Additional biochemical experiments suggested that HSF-1 and DAF-16 work together to turn on some genes--those required for life span extension--but not others.
Using microarrays, the researchers identified genes for four small HSPs that require both regulators for activation, and sequence analysis revealed that each HSP gene carries separate landing spots for the two proteins. The result bolsters the idea that DAF-16 and HSF-1 team up to extend life. How extra doses of either individual protein delay aging is unclear, says co-author Cynthia Kenyon, a geneticist at the University of California, San Francisco. She suggests that ramping up production of one molecule might, through some unknown mechanism, stimulate the life-promoting abilities of the other.
Because HSPs fix mangled proteins, the researchers wanted to examine the molecular mechanisms that connect longevity and disease caused by protein globs. They tested whether the small HSPs influenced the accumulation of a type of protein found in Huntington's disease. Loss of any one of the four small HSPs decreased a worm's life span and accelerated the buildup of these proteins, suggesting that the same tactics that keep proteins healthy also prolong life. "Nobody knows what the connection between aging and aging-related disease is," says Kenyon. The result "makes the small HSPs look really interesting."
"I got a tingle reading [this] paper" because seemingly different longevity mechanisms are merging, says molecular geneticist Gordon Lithgow of the Buck Institute for Age Research in Novato, California. Life extension by heat shock is "completely dependent on the insulin-like signaling pathway." Furthermore, independent labs are concluding that aging is a condition caused by misshapen proteins, he says. Any intervention that improves the ability of animals to deal with stress-triggered protein damage extends life, he says (see, for example, "Hungering for Simplicity"). The new findings pinpoint another life-extension pathway--insulin-like signaling--that also heats up this general system.
May 21, 2003
Science of Aging Knowledge Environment. ISSN 1539-6150