Sci. Aging Knowl. Environ., 19 May 2004
Shining a Light on Long Life
Scientists identify key step in fruit fly longevity pathway
For fruit flies, longevity is only a mutation away. A new study sheds light on one of the insects' most famous life-extending gene glitches. The work identifies molecules that activate a protein that adjusts fly aging, and the results might help clarify whether the same protein shapes human survival.
Six years ago, scientists discovered that flies with a faulty methuselah gene--named for the biblical patriarch who allegedly survived for 969 years--live 35% longer than normal. Although methuselah was one of the first fly genes shown to stretch life span, it remains puzzling. The Methuselah protein belongs to a large family of receptors that span the cell membrane, but researchers aren't sure what it does or how it influences aging, says molecular physiologist Xin-Yun Huang of Cornell University's Weill Medical College in New York City.
To probe how Methuselah modifies life span, Huang and colleagues sought molecules that activate the protein. They tested compounds isolated from ground-up flies on human cells that had been genetically altered to produce the normal version of the fly protein. Jolting receptors in Methuselah's family hikes calcium quantities in the cell, and the researchers found more calcium after treatment with two slightly different variants of a protein known as Sun.
The team then determined whether disabling the Sun gene stretches longevity. Insects without an operational version of the gene die, so the researchers cross-bred fly lines to create animals that bore one normal and one faulty gene. Carrying a disabled copy didn't increase life span to biblical proportions, but the flies did outlive controls by about 50%. The modified bugs were also more resistant to the oxidant paraquat, as are the methuselah fly mutants. The Sun proteins closely resemble a segment of a multiprotein machine that makes the energy-carrying molecule adenosine triphosphate (ATP); Sun molecules might even compose a crucial portion of this conglomerate that can fall off and float free. One hypothesis is that cutting the amount of Sun might lengthen life by disrupting the ATP maker and thus diminishing cells' energy supplies. However, the researchers found similar ATP quantities in control and experimental flies, suggesting that the Methuselah pathway prolongs life through a different mechanism. For now, they can conclude that Sun proteins bind to Methuselah and alter fly longevity, says Huang. With these proteins in hand, researchers might be able to determine whether Methuselah-like molecules also influence human life span, he says.
Fly geneticist Robert Arking of Wayne State University in Detroit, Michigan, praises the study. The source of Sun proteins in the cell might hint at how they control aging, he says. One place the ATP-making protein resides is mitochondrial membranes. Sun proteins released there might adjust mitochondrial metabolism, possibly by cutting the amount of destructive reactive oxygen species spilled from these cellular power plants, he proposes. "It's exciting work," adds molecular biologist John Tower of the University of Southern California in Los Angeles. The study supplies another link in a pathway that shapes life span--the next job is to fill in the gaps, he says. That work could help explain how flies follow in the footsteps of Methuselah.
May 19, 2004
Science of Aging Knowledge Environment. ISSN 1539-6150