Drugged Up: Compound that fights human diseases confers long life on flies (Chromatin structure/Life-extension treatment)
Authors: Beckman Mary 
Published: August 2003

Fruit flies just got a lucky break. Most strategies to defy aging require genetic alterations or calorie restriction (see
Genes/Interventions Database
), but now researchers have found a drug that achieves the goal--for
Drosophila
, at least. Less than a handful of chemicals are known to prolong life in worms and the new drug is the first to benefit fruit flies. It alters the activities of many genes, perhaps by instigating changes in the way DNA packs together with proteins, a process that has previously been implicated in aging. Future experiments aim to identify which genes give the drug its life-span-boosting effect, which should provide insight into how fruit flies age.

The magic potion for
Drosophila
takes the form of 4-phenylbutyrate (PBA), a chemical approved by the U.S. Food and Drug Administration for treating several human diseases such as cystic fibrosis and sickle cell anemia. While testing PBA on
Drosophila
mutants that go blind, Kang and colleagues noticed that the treated flies lived longer. PBA inhibits human cells' ability to remove a molecular protuberance called an acetyl group on histones--proteins that roll DNA around themselves and prevent the cellular protein-making machinery from accessing genes in that region of the chromosome. The bulging acetyl group interferes with the histones' DNA-bundling competency and allows stimulation of genes that would otherwise be turned off. In yeast and worms, overproduction of the
SIR2
gene (see
Kaeberlein Perspective
), which trims acetyl groups from histones, prolongs life-span. It apparently accomplishes this feat by tightening the packing of the DNA-histone conglomeration--called chromatin--in a particular stretch of the genome. The team wanted to know whether PBA acts similarly.

Before they probed that issue, the researchers measured the life-extending ability of PBA by feeding newborn flies with the drug and counting the days until they went belly up. The optimal concentration of PBA increased the age at which half of the flies die by 33% compared with untreated controls; it also allowed the oldest fly to live 50% longer than its untreated counterpart. A second
Drosophila
strain required only half the amount of PBA in its diet to achieve similar life extension. This result indicates that a fly's genetic makeup influences the power of PBA's magic. To rule out the potential effects of calorie restriction--if the flies dislike the taste of the PBA-doctored food, they might eat less and persist abnormally long for that reason--the researchers weighed the animals. They also judged their well-being through tests such as climbing ability. The unusually long-lived animals were just as fat and healthy as the normal-aged ones, suggesting that PBA prolongs fly life-span directly rather than through calorie restriction and that the drug slows the overall aging process.

The researchers then assessed how PBA affects chromatin packing by examining the histone proteins H3 and H4. The team found that PBA increased the number of acetyl groups on H3 and H4--which raises the possibility that the drug prevents the histones from wadding up the DNA properly. Because this looser packing might change which genes are turned on or off, the group measured the expression of 7500 genes in both untreated and PBA-fed flies. Expression of more than 150 genes shifted up or down in the drugged flies. The researchers propose that enhanced fly longevity might require simultaneous alterations in the expression of many genes. A simpler possibility exists, however: The most highly cranked-up gene encodes the protein superoxide dismutase, which mops up oxygen radicals. This observation suggests that PBA might extend life-span by bolstering resistance to oxidative stress (see
"The Two Faces of Oxygen"
). Future studies should reveal whether the flies endure because of changes in a single gene or an ensemble.

Although the researchers didn't assess chromatin structure directly, this study implies that the state of chromatin packing affects
Drosophila
aging. The results also open up a new approach for probing the relation between chromatin structure and life-span. In addition, researchers who study
Drosophila
now have an easy way to increase longevity and can exploit this strategy to study aging. Humans won't be popping a pill for longer life yet, however; no one knows whether PBA will work in people. Much more work is required before researchers establish whether we can share in the laboratory flies' good fortune. Otherwise,
Drosophila
's elixir could just mean more flies in our ointment.

--Mary Beckman

H.-L. Kang, S. Benzer, K.-T. Min, Life extension in
Drosophila
by feeding a drug.
Proc. Natl. Acad. Sci. U.S.A.
99
, 838-843 (2002).
[Abstract]
[Full Text]