Sci. Aging Knowl. Environ., 15 December 2004
Switching On Longevity
Energy-measuring molecule might stretch life span
Growing older is exhausting, even for nematodes, but a particular protein serves as a worm tonic, according to new research. The molecule senses energy shortages and fortifies the animals, extending their lives. The work also uncovers the molecule's interplay with the much-studied insulin-like signaling pathway.
Scientists have long known that going hungry stretches life in nematodes and other animals, but they don't understand how energy availability alters longevity. The amount of ATP, the cell's energy-storage molecule, declines as cell cultures age, while quantities of the spent form, AMP, rise. Molecular biologist Javier Apfeld of Elixir Pharmaceuticals in Cambridge, Massachusetts, and colleagues hypothesized that animals can detect energy supplies and adjust their life span accordingly. The mechanism, they speculated, involves AMPK, a protein conglomeration that can gauge AMP quantities and trigger measures that boost energy supplies (see "Stop a Tumor, Save a Cell"). To test their idea, the researchers wanted to find out whether AMPK alters longevity.
The team first determined the ratio of AMP to ATP in worms of different ages, showing that it climbs over time. Then they divided elderly worms into two groups based on their amount of activity. The more vigorous worms not only lived longer but also had a lower AMP:ATP ratio.
To probe AMPK's role in setting life span, the researchers focused on one of its components, AAK-2, which AMP turns on. Brief periods of stress increase worm survival, and the team found that heat and other harsh conditions temporarily boosted the AMP:ATP ratio. At first glance, this observation seems to contradict the other findings. But rather than causing aging, an increased ratio might prompt the animal to activate protective mechanisms, says Apfeld. Worms with nonfunctional AAK-2 don't gain extra days from these stresses. Because AMP rouses AAK-2, that finding suggests that a rising AMP:ATP ratio hikes AAK-2 activity, which boosts life span. Throttling the insulin-like signaling pathway also prolongs worm life. However, worms with mutations in daf-2, a key pathway component, and aak-2 don't survive as long as those with mutations in daf-2 alone, although they outlive nematodes with only defective aak-2. That result implies that AAK-2 is necessary for some, but not all, of daf-2's life-stretching effects. Together, the results indicate that AAK-2 responds to falling energy levels by lengthening life. But it can only delay the inevitable. "The increase in AMP:ATP ratio with age reflects the fact that AAK-2 ultimately loses the battle as the animals age and die," says Apfeld.
The paper deserves praise because it is one of the first in this field to combine biochemical and genetic findings, says mitochondrial geneticist Philip Morgan of Case Western Reserve University in Cleveland, Ohio. Physiologist Wayne Van Voorhies of New Mexico State University in Las Cruces wants to see stronger evidence that AAK-2 keys on metabolism, because the AMP:ATP ratio provides only a "snapshot" rather than a long-term indication of energy availability. Future research might reveal how getting tuckered out leads to longer life.
December 15, 2004
Suggested by Greg Liszt.
Science of Aging Knowledge Environment. ISSN 1539-6150