The Longevity Gene

[David Farber <dave () farber net>]

Begin forwarded message:

From: Dewayne Hendricks <dewayne () warpspeed com>
Date: September 23, 2004 7:55:06 PM EDT
To: Dewayne-Net Technology List <dewayne-net () warpspeed com>
Subject: [Dewayne-Net] The Longevity Gene
Reply-To: dewayne () warpspeed com

The Longevity Gene
 A gene that releases stored fat may be the key to a longer life.
By Lisa Scanlon
 MIT News
October 2004
<http://www.technologyreview.com/articles/04/10/scanlon1004.asp?trk=nl>

On his laptop computer, biology professor Leonard Guarente plays a 
video clip of 29-month-old mice hobbling around a cedar-chip-filled 
cage. They’re scruffy, fat, slow moving, and over the hill by rodent 
standards. Then he plays a clip of another group of 29-month-old mice. 
They’re svelte, frisky, and scrambling around like adolescents. What’s 
their secret? These mice have eaten about two-thirds as many calories 
as their portly peers. Not only does the meager diet seem to keep them 
light in the limbs, but they tend to live 30 percent longer than their 
well-fed friends and are less likely to contract age-related diseases, 
such as diabetes and cancer.

Scientists have known for nearly 70 years that calorie restriction 
extends the life spans of mammals by as much as 50 percent, but just 
how it works has remained a mystery. Guarente believes he has found the 
answer, and that it could potentially lead to extended life spans for 
people, too. For more than a decade, Guarente has been gradually 
solving the puzzle with the ambitious goal of discovering how to slow 
the aging process in humans without imposing a thousand-calorie-a-day 
diet. In 1999, he came to the surprising conclusion that manipulating 
just one gene, SIR2, could affect longevity. Guarente became so 
convinced that his findings could lead to antiaging pills that in 1999 
he cofounded Cambridge-based Elixir Pharmaceuticals to commercialize 
them. In June, Guarente and his colleagues published a paper in the 
scientific journal Nature that detailed how a version of the SIR2 gene 
in mice releases fat from storage tissue, which seems to have a direct 
effect on how fast the animals age. Although Guarente’s lab has yet to 
determine exactly why a reduction in fat allows animals to live longer, 
he’s confident that medicines that cause the mechanism to spring into 
action aren’t too far around the corner. “I think there’s going to be 
an ever growing clamor to take advantage of this,” Guarente says. And 
he believes life-span-lengthening medicines will be available within a 
decade.

Just One Gene
When Guarente first decided to study the causes of aging in the early 
1990s, it was a topic tackled by few researchers. No one knew how to 
approach it. “The early ideas, which were really quite persistent, were 
that if you eat less, everything just slows down,” says Guarente. But 
he and two postdoctoral students decided to see if they could find a 
genetic cause for the phenomenon. In 1996, they found mutant yeast 
cells that lived 50 percent longer than normal cells and analyzed them, 
gene by gene. “I said, ‘We have a year to work on this, because I’m not 
sure if there’s anything to study,’” Guarente recalls. “We got really 
interested, and it took a lot more than a year before I was sure we had 
something. We were seduced.”

Over the next few years, the researchers tied the unusual longevity in 
the mutant yeast to one gene: SIR2. In other experiments, they 
discovered that when they inserted extra copies of SIR2 into normal 
yeast, it lived longer; when they deleted the gene, the yeast died 
prematurely. In 2000, the researchers found that a similar gene in 
worms worked the same way. It was exciting, Guarente says, because 
yeast and worms are such different creatures that in order to share a 
similar gene, they must have had a common ancestor. “That means that 
any descendant of that ancestor, including us, has the same mechanism,” 
he says.

At the very least, mice have it. In their Nature article, Guarente and 
his colleagues reported that when food is scarce, a mouse’s genetic 
equivalent of SIR2, SIRT1, produces a protein that turns off other 
genes that help store fat. The fat moves into the bloodstream, travels 
to other tissues, and gets burned. This keeps the mice lean and, for 
some as yet unknown reason, young looking and healthy into old age. 
Frédéric Picard, a research scientist who worked with Guarente on the 
paper, remembers the day that he got clear results from the experiment. 
“I was very happy, dancing all over. It was great,” Picard says.

Racing to Finish the Puzzle
Although the finding is exciting, it still leaves some questions 
unanswered. Researchers at the Joslin Diabetes Center in Boston found 
that it’s possible to genetically engineer a mouse that automatically 
burns fat without calling the SIRT1 gene into action. These mice will 
live longer than others but not as long as mice on calorie-restricted 
diets. Guarente therefore suspects that the gene has other effects 
beyond triggering fat release. Some dozen researchers in his lab are 
now trying to figure out what they might be. For example, Kayvan 
Zainabadi, a biology graduate student, is trying to determine if SIRT1 
also signals cells in the liver to break down fat, essentially cranking 
up metabolism. Graduate student Ed van Veen is investigating whether 
fat may produce something like a hormone that could regulate aging. 
Calorie restriction also increases sensitivity to insulin, a good 
indicator that an animal won’t become diabetic. Several researchers are 
trying to find a connection between the SIRT1 gene and sensitivity to 
insulin.

As the members of Guarente’s lab pore over cell cultures to the sound 
of hungry mice rustling in their cages, another group of scientists a 
short walk away at Elixir Pharmaceuticals is doing much the same thing. 
This group is hoping to find a medicine that will switch on the human 
equivalent of SIR2 and prevent age-related diseases, such as type 2 
diabetes, cancer, and Alzheimer’s. “We’re not necessarily in the 
business of trying to find a longevity pill,” says Peter DiStefano, 
Elixir’s chief scientific officer. Right now, Elixir is testing 
promising potential drugs in animals and looking for pharmaceutical 
companies interested in licensing them. DiStefano hopes that within the 
next year or two, the company will begin clinical trials in humans. But 
once that process is well under way, he says, “It’s not far fetched at 
all to state that there may be a longevity benefit to this. But you 
have to caution that proving longevity is a pretty long endeavor. And a 
lot of us aren’t going to be around to see the outcome of it.”

Nevertheless, plenty of other research groups at universities and 
companies around the world are salivating at the thought of SIR2’s 
potential. Indeed, one of Guarente’s main competitors is David 
Sinclair, one of his former postdoctoral fellows. Sinclair, now an 
associate professor of pathology at Harvard Medical School, disagrees 
with Guarente about what activates SIR2 in yeast. He believes that a 
molecule called nicotinamide and a gene called PNC1 control the 
activity of SIR2. Guarente, on the other hand, believes that the 
relative concentration of two molecules, NAD and NADH, determines 
SIR2’s activity in yeast cells. In recent years, Sinclair has published 
several papers that attempt to disprove some of Guarente’s theories and 
support his own. “There’s been a big uproar over this,” Guarente says. 
“My feeling on this—and I told [Sinclair]—was, A, I think we’re right, 
and B, I don’t think it’s that important.” The dispute about yeast is 
almost a moot point, Guarente says, because the way in which the SIR2 
equivalent is activated in mammals, which is more relevant to how it 
works in humans, is probably different. “But nonetheless, I think we’re 
right about yeast,” Guarente says firmly.

Apart from the public battles in scientific journals, Sinclair is also 
competing with Guarente on the pharmacological side, having recently 
formed a company, Sirtris Pharmaceuticals, to create the same kinds of 
drugs that Elixir is pursuing. “It’s a race now between the two,” says 
Picard, who left MIT this summer for a position at Laval University in 
Québec City. “They both have very big labs working hard. They both have 
companies working hard, too.”
Guarente is aware that many people believe a pill that extends human 
life is not necessarily a good thing, potentially leading to 
overpopulation and possibly helping only the few wealthy people who 
could afford it. Guarente’s own college-age son has argued with him 
about the validity of his research. “He says, ‘You’re only going to 
help people who already have long and healthy lives. Why not work on 
malaria?’” Guarente says he was not interested in medical implications 
when he started his research. “I thought it was an interesting 
biological problem, an intellectual problem, and it drove me….I wasn’t 
thinking practically at all. It was curiosity.”

Even with all the attention SIR2 is getting—in large part because of 
his own efforts—Guarente still suspects that much of the scientific 
community resists the idea that a single gene could have the power to 
control longevity. “I think it’s increasingly more accepted than it 
was, but I think there [are] still a lot of people [who] cannot get 
their arms around the idea that there would be one critical gene.” 
Guarente, however, hopes to live long enough to prove these naysayers 
wrong.

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