Previously, Kenyon and others have shown that mutations interrupting insulin/insulin-like growth factor signaling, such as those in the insulin receptor daf-2, allow C. elegans to live almost twice as long as usual; the insulin response has also been implicated in determining human longevity (see ARF related news story). Now, first author Nuno Arantes-Oliveira and coworkers have used RNA interference to more fully attenuate insulin signaling in daf-2 partial loss-of-function mutants, which can live as long as about 50 days. This RNAi increased lifespan by about another third, allowing the oldest animals to survive to a ripe old age of about 80 days. As if this were not enough, the authors combined daf-2 RNAi with ablation of the gonads and, indeed, some worms lived to a staggering age of 180 days.

Longevity in insulin-signaling mutants is often accompanied by lethargy, suggesting some metabolic tradeoff between quality and length of life. However, daf-2 mutations normally fall into two camps—those that cause lethargy and those that do not. When Arantes-Oliveira combined daf-2 RNAi with gonadectomy in the latter (e1368 daf mutants), the animals appeared to be as active as were normal animals, and still lived up to six times as long. In fact, over the first 90 days of life, few of these animals died (about 15 percent) and the mean lifespan in this group was 124 days versus 20 days for wild-type worms.

The work builds on a previous report from the Kenyon lab that implicated the reproductive system in the regulation of lifespan (see Hsin and Kenyon 1999). It also suggests that “remarkable lifespan extensions can be produced with no apparent loss of health or vitality by perturbing a small number of genes and tissues in an animal,” write the authors. It will be interesting to see if similar results can be obtained with vertebrates.—Tom Fagan.

Reference:
Arantes-Oliveira N, Berman JR, Kenyon C. Healthy animals with extreme longevity. Science. 2003 October24;302:611. Abstract