Sci. Aging Knowl. Environ., 2 April 2003
Staying junk-free helps worms live longer
Key Words: age-1(hx546) daf-16(m27) hsp27
A clean desk might be a sign of a sick mind, but a clean cell could signify long life. New work shows that a protein that keeps other proteins neatly folded and prevents messy molecular pileups lengthens life in worms.
The Caenorhabditis elegans age-1 gene lies in a signaling pathway that influences aging of the nematode; related pathways modulate life span in various animals. Normally, the protein encoded by age-1 stifles production of DAF-16, a protein that appears to turn on genes that help the worm cope with stress--and prolong life (see "Extra CRISPy, Please"). Worms with a defective copy of age-1 live about two-thirds longer than normal. Nearly a decade ago, molecular geneticist Gordon Lithgow, now at the Buck Institute for Age Research in Novato, California, and his colleagues noticed that age-1 mutants survive high temperatures unusually well. Later, they discovered that these animals accumulate excess amounts of a protein called HSP-16, a so-called molecular chaperone that helps other proteins take their proper shape. Worms produce more HSP-16 as they age or when they encounter heat--situations in which proteins might need stabilization.
Lithgow and Glenda Walker, a molecular biologist at the University of Glasgow, U.K., have now found that genetically boosting worms' HSP-16 ration increases longevity. Animals without DAF-16, however, did not benefit from the extra HSP-16, suggesting that the chaperone depends on the gene regulator to extend life span. Worms lacking DAF-16 produce less HSP-16 when given extra copies of hsp-16 than do those with DAF-16, yet hsp-16 doesn't contain the DNA sequence recognized by DAF-16. The researchers speculate that DAF-16 rouses a hormone that then travels out of the cell, eventually turning on hsp-16 and other stress-response genes in other parts of the body. The fruit fly equivalent of hsp-16, which also influences life span, responds to an insect hormone, and a similar system could be operating in the worm, says Lithgow. Because the increase in life span endowed by adding HSP-16 is small compared with that achieved by inactivating age-1, Lithgow says, other proteins likely act with HSP-16 to prolong youth.
Because adding HSP-16 to worms extends life--and possibly the period of reproductive fitness--one might wonder why they don't make more of it. Too much of the sticky protein could gum up cellular processes, Lithgow says. Cranking up production of a similar protein in fruit flies, for instance, kills the animals early in life--but "they would be long-lived if they made it to adulthood," he speculates.
"The whole thing fits nicely," says molecular biologist Richard Morimoto of Northwestern University in Evanston, Illinois, whose lab has shown that worms that produce a protein implicated in Huntington's disease carry fewer clumps of the molecule when they also harbor the age-1 mutation. The new results, Morimoto says, "close the loop," tying together his own findings, other observations that extra quantities of molecular chaperones curtail clumping, and Lithgow's earlier results showing that long-lived animals manufacture additional HSP-16. In old age, Lithgow suggests, HSP-16 might help break down the protein globs that typify neurodegenerative diseases such as Huntington's or Parkinson's in people; possibly the human version of HSP-16 does the same. And that, as Martha Stewart would say, is a good thing.
April 2, 2003
Science of Aging Knowledge Environment. ISSN 1539-6150