Researchers Seek Key to Antiaging In Calorie Cutback

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Researchers Seek Key to Antiaging In Calorie Cutback

A Controversial Hypothesis Draws Scientists, Investors;

Will It Work in Humans? Fighting Fat in Lab Mice

By DAVID STIPP

October 30, 2006

The Wall Street Journal

In the 1930s, researchers stumbled onto a surprisingly simple way to slow the

biological forces of aging: cutting normal calorie intake by about a third.

Scientists found it boosts animals' life spans by 30% to 40%, and considerable

evidence suggests that calorie restriction, or CR, would slow human aging too.

But only steely ascetics could hack its hunger pangs. So the finding remained a

little-known curiosity in the back halls of science.

Now a coterie of scientists and biotech ventures are rekindling interest in CR

as they try to mimic its antiaging effects with medicines. It is still a highly

speculative quest, and many researchers fret that it hasn't completely shaken

its association with centuries of dubious nostrums to slow aging, from inhaling

virgins' breath to eating gold to implanting monkey glands.

Much of the new focus is on a substance in red wine called resveratrol. The

interest in it started three years ago when a group led by Harvard Medical

School biologist Sinclair reported that it boosted yeast cells' life span

by 70% via a mechanism resembling CR. He later co-authored a study showing that

it also boosts life span in fruit flies and roundworms. But his tendency to make

bold leaps based on tentative data has also sparked intense controversy. One big

question: Does he really understand the workings of CR well enough to mimic them

in a drug?

Last spring, Italian scientists reported that resveratrol boosted life span more

than 50% in a kind of short-lived fish. Intriguingly, fish on resveratrol had

much faster swimming speeds as they aged, and spent far more time moving around,

than did undosed control fish.

At least two groups of researchers are now testing whether resveratrol can

extend life span in mice -- the first such studies in mammals. At a meeting of

the American Aging Association in June, Dr. Sinclair and colleagues presented

preliminary results from a study showing that resveratrol had " CR-like

protective effects " against the buildup of fatty deposits in the livers of mice

on high-calorie diets. That suggests that resveratrol could lead to new drugs

for diseases of aging associated with rich diets, such as adult-onset diabetes.

A company that Dr. Sinclair co-founded in 2004, Sirtris Pharmaceuticals Inc., of

Cambridge, Mass., has begun testing a resveratrol-based drug in diabetic

patients. It has raised $82 million from venture capitalists, a hefty sum for an

early-stage biotech. (Sirtris's chief executive, Christoph Westphal, is married

to a reporter for this newspaper.)

It faces competition from Elixir Pharmaceuticals Inc., also based in Cambridge,

which Dr. Sinclair's former mentor, Massachusetts Institute of Technology

biologist Leonard Guarente, co-founded in 1999 to develop drugs based on gene

variants that slow aging. The niche also includes BioMarker Pharmaceuticals of

, Calif., and LifeGen Technologies of Madison, Wis., both of which focus

on mimicking CR with drugs.

The companies hope to develop therapies for diseases, not antiaging pills. One

reason is that the Food and Drug Administration doesn't recognize aging as a

problem warranting treatment. But if a drug could retard aging, it might delay

the onset and possibly the progression of age-related diseases. " When you slow

aging, " says University of Illinois epidemiologist S. Jay Olshansky, " you push a

host of diseases to later ages at one fell swoop -- cancer, heart disease,

Alzheimer's, diabetes, as well as everything else that's negative about growing

older. "

Some researchers believe antiaging drugs could also improve health in late life

-- rather than prolong misery -- letting people stay in relatively good shape

until a swift demise. Their case rests partly on the svelte, energetic look of

old animals on CR. " Often it's hard to identify the cause of death " in

post-mortem studies on such animals, says Weindruch, a University of

Wisconsin CR researcher. " The only apparent problem is that they died. "

THE BATTLE AGAINST AGING

Key antiaging medical advances:

• 1935: Cornell scientists report calorie restriction's antiaging effect in

rodents.

• 1956: University of Nebraska researcher proposes that " free radicals " cause

aging, indicating that antioxidants may slow it.

• 1989: U.S. and British scientists propose that calorie restriction triggers

an evolutionarily ancient " starvation response " to slow aging.

• 1992: University of California at San Francisco researchers find a gene

mutation that doubles life span in roundworms.

• 1996: Southern Illinois University scientists report gene mutation that

extends life span in mice.

• 2000: MIT's Leonard Guarente and colleagues report that " SIR " genes actuate

calorie restriction's antiaging effects in yeast.

• 2003: Harvard's Sinclair and others report that resveratrol, a

substance in red wine, extends yeast life span.

• February 2006: Italian scientists report resveratrol extends life span of a

fish species.

Still, some experts on aging doubt that enough is known about CR to guide the

development of drugs that mimic its effects. " We know a lot about CR's effects, "

says Masoro, a leading gerontologist. " But what bothers me is that I

don't think we've figured out CR's basic mechanism yet. "

Dr. Sinclair's idea that resveratrol mimics CR has come under heavy fire. His

main adversaries are two researchers who used to rub elbows with him when they

all studied together with MIT's Dr. Guarente. The skeptics maintain that

resveratrol's mode of action is still murky; instead, they are looking at other

mechanisms that may account for how CR works.

The resveratrol doses used in the life-span-extension studies in animals were

far higher than the amount people can get by drinking wine -- they were roughly

equivalent to hundreds of glasses a day. Resveratrol is available as a dietary

supplement, but to replicate the doses used in the studies, a person would need

to take scores of pills a day. (Sirtris says it is developing prescription drugs

that work like resveratrol but are hundreds of times more potent.) The dietary

supplements haven't been tested in clinical trials, so their efficacy isn't

proven, nor is it clear what dose might make people live healthier or longer.

And although they seem safe at modest doses, megadoses may not be.

Nevertheless Dr. Sinclair, a 37-year-old Australia native, thinks taking small

doses over time may yield health benefits and has been taking the supplements

for three years.

The story of resveratrol has its roots in scientists' increased understanding of

CR. In 1989 researchers theorized that it activates a " starvation response "

whose genetic machinery evolved eons ago to enable survival through periods of

food shortage -- such as droughts -- by retarding the rate of aging. The

response blocks growth and reproduction in order to free up energy to slow

aging. The energy is siphoned to cellular systems that limit damage from harmful

" free radical " molecules and other toxins produced as metabolic byproducts in

cells.

The theory explained longstanding mysteries about CR, such as the fact that

animals on CR become resistant to toxic chemicals and temporarily lose the

ability to reproduce. It also had a dismaying implication: Our

obesity-fostering, high-calorie diets are putting us in

fast-aging-and-reproducing mode. That may be why childhood obesity is closely

linked to early puberty, which now begins before age eight in many girls, and

why adult obesity is linked to such a wide swath of aging diseases -- cancer,

heart disease, diabetes, arthritis, even Alzheimer's.

But an important piece of CR's machinery remained hidden: the activator that

senses calorie intake and, when it is low, triggers cellular changes that retard

aging. This CR off-on switch is the holy grail of gerontology, the study of

aging. In principle, drugs that turn it on could ward off or ameliorate

degenerative diseases of aging, just as CR does in animals.

Many scientists are looking for the switch. And to the consternation of some of

them, Dr. Guarente, 54, and Dr. Sinclair assert that they know what it is.

Further, Dr. Sinclair's research indicates that resveratrol toggles it in order

to slow aging. Their shared view on CR's basic mechanism has sparked a furious

debate.

Its roots go back to 1991, when Dr. Guarente's lab at MIT began hunting for

life-span-boosting mutations in baker's yeast.

The grandson of Italian immigrants, Dr. Guarente grew up in Revere, Mass., a

blue-collar town near Boston. In his memoir " Ageless Quest, " he recalls that as

a child, " I was precocious by local standards -- I quit smoking in third grade. "

By the mid-1990s, Dr. Guarente's lab had zeroed in on so-called SIR, or silent

information regulator, genes. SIR mutations enabled yeast cells to divide an

abnormally large number of times before dying, a form of extended life span. But

how they worked wasn't clear until the group made further discoveries, one of

which was Dr. Sinclair's first claim to fame.

Dr. Guarente recalls that Dr. Sinclair, who came to MIT in 1995 to do

post-doctoral studies, breezed into his lab as if out of a Crocodile Dundee

movie, greeting everyone with a cheery, " Hello, mate. " The eldest son of parents

who both worked in medical diagnostics, he was known in high school as a

talented class clown and risk-taker, a kid who aced science classes but got in

trouble for setting off minor explosions in chemistry lab. The idea of taking

part in unorthodox, high-risk studies on aging suited him.

In a key experiment, Dr. Sinclair showed that yeast cells' machinery for copying

chromosomes runs amok as the cells age, eventually killing them. Hailed as a

major advance, the discovery got Dr. Guarente on Good Morning America. It also

helped him formulate a theory positing that proteins made by SIR genes activate

CR's antiaging action. A SIR gene found in mammals, dubbed SIRT1, seems

especially important: It makes a protein that Drs. Guarente and Sinclair believe

triggers the slowed-aging mode in mammals when calorie intake is low. In their

view, it's either the gerontological grail or a crucial part of it -- hence,

stimulating it might slow aging.

Drugs that juice up proteins' activity are very rare. But in 2003, Dr. Sinclair,

then at Harvard, heard that scientists at Biomol International LP, a Plymouth

Meeting, Pa., biotech firm, had observed signs of SIRT1 activation in test-tube

experiments with certain plant compounds. The most promising one was

resveratrol. That was doubly exciting, for dozens of studies on the red-wine

ingredient had previously suggested that it lowered the risks of heart disease,

cancer and various other disorders of aging -- just what a substance that slows

aging should do.

Dr. Sinclair soon began the study about resveratrol's effects on yeast aging.

But a year after it appeared, studies by other researchers cast doubt on the

idea that SIR genes are key actuators of CR.

The sharpest questions were raised by two researchers who also studied under Dr.

Guarente: University of Washington biologists Kennedy and Matt Kaeberlein.

Their data suggest that CR can exert antiaging effects independently of SIR

genes, and that other genes are more central to CR -- at least in yeast. " My

view is that CR probably has nothing to do " with SIR genes in lower animals,

says Dr. Kaeberlein. In short, according to him, Drs. Guarente and Sinclair

haven't necessarily found the grail.

Undaunted, Dr. Sinclair joined forces with a researcher at the National

Institute on Aging, de Cabo, to plan one of the ongoing studies of

resveratrol in mice. But he had a problem: He lacked the $20,000 needed to buy

mice. Then he got a call out of the blue from Tom LoGiudice, foreman at the U4EA

( " euphoria " ) Ranch near Thousand Oaks, Calif. Mr. LoGiudice had phoned on behalf

of the ranch's owner, Harman Rasnow, who was considering taking resveratrol

pills and wanted to know more about them. When Mr. LoGiudice heard about Dr.

Sinclair's problem, he arranged for his boss to talk directly to the researcher.

" I have an 85-year-old passion for longevity, " says Mr. Rasnow, pinpointing his

age. " sounded like he was really onto something. So I told him, 'I'll send

you a check for $20,000.' "

Dr. Sinclair later got another call from Mr. LoGiudice, this time inviting him

to make a pitch for funding to one of Mr. Rasnow's wealthy acquaintances,

Glenn, a venture capitalist and a longtime supporter of research on aging. After

Dr. Sinclair did so, the Glenn Foundation for Medical Research in Santa Barbara,

Calif., awarded $5 million to Harvard Medical School to launch a center on the

basic mechanisms of aging with Dr. Sinclair as its founding director. Now plans

are afoot to expand the center into a leading institute on aging, says Mr.

Glenn, with start-up funding of $75 million to $100 million.

Sirtris, the company Dr. Sinclair co-founded, says it has made progress.

Test-tube and animal studies suggest that its early-stage drugs may help treat

various neurological killers as well as diabetes, says Dr. Westphal. The company

plans soon to begin testing a drug in people with MELAS syndrome, a rare

metabolic disorder that afflicts youngsters with potentially fatal brain and

muscle deterioration.

At a recent meeting on aging research, a Sirtris scientist reported that

SIRT1-activating compounds, including resveratrol, dramatically lowered blood

levels of glucose and insulin in mice that get diabetes on high-fat diets, as

well as helped to keep their weight down -- just as CR does.