Sci. Aging Knowl. Environ., 12 March 2003
Extra CRISPy, Please
Hormone candidate staves off stress and helps worms live longer
Key Words: RNAi forkhead transcription factor insulin/IGF-1 oxidative damage
Surging hormone concentrations mean oily skin and temporary insanity for adolescents, but hormones also usher in old age (see Tatar Perspective), and investigators are eagerly seeking the ones that promote late-life transformations. New results unveil a candidate: a protein that exits the cell--a necessary trait for a hormone--alters life span, and seems to act in a known longevity pathway.
Several worm genes collaborate in an insulin-like signaling pathway that influences longevity. daf-2 spurs age-1, which suppresses daf-16. Without the smothering signal, the protein encoded by daf-16 turns on genes that prolong life, and researchers are beginning to uncover their identities (see "Genetic Ducklings").
Seeking other possible DAF-16 targets, Ookuma and colleagues sifted through the Caenorhabditis elegans genome in search of genes that contain a landing site for the protein. Because inactivating daf-2 in some cells extends the life span of the whole animal, researchers in the field have reasoned that the pathway relies on hormones that travel throughout the body. Given its capacity to activate genes, DAF-16 might help produce these molecular messengers (see Sonntag and Ramsey Perspective). One hundred fifty-nine genes contained DAF-16-binding sequences, and one also contained a sequence expected to expedite its protein product's departure from the cell. This gene, which the researchers named scl-1, encodes a protein that belongs to a family called CRISP.
As expected, crippling daf-16 eliminated production of SCL-1. To test scl-1's role in aging, the researchers fed the worms bacteria containing double-stranded RNA that squelched production of the SCL-1 protein. Gobbling the gene-blocker shortened the worms' life span nearly as much as inactivating daf-16 did. Worms that lack DAF-2 or AGE-1 proteins usually live longer than normal; however, consuming RNA that impedes SCL-1 construction somewhat reduced the mutants' longevity gain.
Some evidence suggests that daf-16 lengthens life by helping worms cope with stress (see "Stay Mellow, Stay Young"), so the researchers tested whether scl-1 also helps thwart the effects of cell enemies such as heat and ultraviolet light. Faced with each of those stresses, the worms shifted scl-1 into high gear. After being hit with either insult, worms that couldn't make SCL-1 died sooner than normal worms did, suggesting that SCL-1 somehow helps the worm withstand adversity.
"This work is exciting because [the researchers] have their hands on a secreted molecule that, by inference, promotes stress resistance and longevity," says Adam Antebi, a geneticist at the Max Planck Institute for Molecular Genetics in Berlin. "If it's a hormone and acts systemically, you can start thinking about developing an injectable drug." Therefore, Antebi adds, finding out whether SCL-1 disperses throughout the body is one of the next big questions. The results don't conclusively establish that SCL-1 normally retards a worm's decline, however, because interfering with scl-1 might render the animals short-lived by making them sick rather than by accelerating aging, says Antebi. Showing that overproduction of SCL-1 extends life span would resolve that issue. Such a result would reveal whether extra portions of this CRISP protein keep worms fresh.
--Caroline Seydel; suggested by Nick Bishop
March 12, 2003
Science of Aging Knowledge Environment. ISSN 1539-6150