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Is CR "cutting energy intake below energy expenditure"?
Although, "Japanese
people have a daily energy intake nearly 20% less than the
average of
developed countries, and that the mean life-expectancy of
Japanese women is
85 years - not significantly more than that of women in all
developed
countries", do they not weigh more than 20% less those from
all developed
countries? Is ours a "punishing lifestyle"? "Sirtuin
something", is it, or
is it "un-sirtuin somethin' or 'nother"? If they found "19
plant-derived
molecules", why did they concentration on resveratrol, and
what were the
other 18?

Spinney L.
Gerontology: eat your cake and have it.
Nature. 2006 Jun 15;441(7095):807-9. No abstract available.
PMID: 16778860

Reducing your calorie intake makes you live longer - if
you're a rat or a
worm. Laura Spinney asks whether the same holds for humans -
and if it does,
whether the benefits could be put in a pill.

It may be just a dot in the Pacific Ocean, but the Japanese
island of
Okinawa has long held a fascination for researchers into
ageing. Its
inhabitants include an unusually high number of
centenarians, and fewer of
its people die from diseases of old age such as cancer and
stroke. Some have
suggested the islanders' secret is their frugal diet. Now
scientists are
attempting to put this idea to the test - and are even
developing drugs that
they hope will produce the same effect. Could the path to a
long and healthy
life really be as easy as swallowing a tablet?

The issue divides researchers. Calorie restriction, or
cutting energy intake
below energy expenditure, can slow ageing, reduce mortality,
and extend
maximum lifespan in rats, mice, fish, flies, worms and
yeast. But to date,
the only evidence that it works in humans is anecdotal. A
1978 study of
inhabitants of Okinawa1 showed that energy intake among
adults was roughly
80% of the Japanese average. Some researchers have held this
up as evidence
that restricting diet reduces age-related diseases and
extends longevity.
But gerontologist Sataro Goto of Toho University in Chiba,
Japan, points out
that Japanese people have a daily energy intake nearly 20%
less than the
average of developed countries, and that the mean
life-expectancy of
Japanese women is 85 years - not significantly more than
that of women in
all developed countries.

Hungry for life
This hasn't stopped thousands of people all over the world
intentionally
going hungry in the hope of living longer and healthier. But
no one yet
knows if their punishing lifestyle will pay off. So an
experiment designed
to find out is being watched closely by researchers into ageing.

The CALERIE (Comprehensive Assessment of Long-term Effects
of Reducing
Intake of Energy) study, sponsored by the US National
Institute on Aging
(NIA), published the outcome of its first phase in April2.
Forty-eight men
and women were randomly assigned to diets that would either
maintain their
weight, or reduce their calorie intake by up to 25% below
the level required
to maintain their weight. After six months, those on
restricted diets showed
lower body temperature and levels of insulin in their blood
when they had
not had a meal, both characteristics of long-lived people
and animals. This
slowing of the metabolism explains why people on
calorie-restricted diets
don't starve to death: their body's energy requirements drop
to meet the
number of calories in their diet.

CALERIE is a departure in this hype-infested field, because
the volunteers
are of normal weight or slightly overweight, but not obese.
Most studies so
far have used obese individuals, muddying the waters with
the health
benefits of reducing obesity. The second phase of the study
will begin this
summer, observing 200 subjects over two years. But according
to one of the
present study's authors, physiologist Eric Ravussin of the
Pennington
Biomedical Research Center in Baton Rouge, Louisiana, there
are already
hints that calorie restriction affects ageing processes in
cells.

Participants on restricted diets lost weight exponentially,
and were still
losing weight after six months. They had reduced insulin
resistance and
reduced levels of low-density lipoprotein cholesterol, high
levels of which
are risk factors for type 2 diabetes and heart disease,
respectively. The
researchers also measured significantly reduced damage to
volunteers' DNA.
"We asked if there is a metabolic adaptation over and above
what is expected
due to the weight loss," says Ravussin, "and the answer is
yes, there is."

He says the findings are consistent with the theory that
calorie restriction
reduces metabolic rate and lowers the production of harmful
molecules called
reactive oxygen species, also known as free radicals. These
strip electrons
from other molecules in the body; this is thought to harm
cells and
contribute to ageing. This metabolic change, Ravussin
believes, could be
what causes calorie-restricted rodents to live up to 40%
longer than their
unrestricted counterparts.

Clearly it will be a long wait before the CALERIE study
reveals a similar
effect in humans, if it ever does. Meanwhile, the research
community is
divided over whether calorie restriction will extend
lifespan in humans.

The most recent online edition of the journal Biogerontology
asked a number
of experts to address this question3, in response to a new
theory of
longevity championed by mathematical biologist Lloyd
Demetrius of Harvard
University. Demetrius argues that the main factor
determining lifespan is
not the rate of free-radical production, but the cells'
ability to resist
short-term fluctuations in critical metabolites caused by
environmental
stresses, so protecting those cells from damage.

Long haul
Demetrius believes this is determined by a creature's
evolutionary history.
Rodents are opportunistic species that experience periods of
plenty
punctuated by periods of scarcity. When there is lots of
food they reproduce
like crazy; when there isn't, they sit tight. They reach
sexual maturity
early, have a narrow reproductive window and large litters.
Humans, and
larger-bodied animals in general, mature late, have fewer
offspring and a
wider reproductive window. They are more able to move from
resource-poor
regions to resource-rich ones, and are more stable in the
face of
environmental perturbations4.

Demetrius's theory predicts that calorie restriction would
extend lifespan
in opportunistic species, giving them a chance to breed once
conditions
improve, but barely affect lifespan in more stable species.
Some evidence
supports this. As Linda Partridge of University College
London's Centre for
Research on Ageing notes: "Extension of lifespan by dietary
restriction has
been seen particularly clearly in animals with high
reproductive rates -
rodents, worms, flies." In contrast, experiments in rhesus
monkeys have yet
to show that calorie restriction increases lifespan5.

Longevity island: Oto Yara, one of Okinawa's unusually large
number of
centenarians.

Believers in calorie restriction claim this is a
methodological problem:
monkeys live longer than rats, so the experiments take
longer. Studies with
rhesus monkeys begun in the United States in the late 1980s
will not produce
robust data for another 25 years, and human studies such as
CALERIE will
take even longer. In the meantime, they argue, the data from
studies such as
CALERIE support the idea that it could indeed work in people.

Such optimism means that the development of drugs aiming to
mimic calorie
restriction is well advanced, with some compounds already in
clinical
trials6. These drugs are designed to slow ageing and
possibly extend life by
triggering metabolic adaptation without the need for
semi-starvation.
Whether or not calorie restriction increases longevity, it
does seem to ward
off certain age-related diseases. For example,
epidemiological studies have
shown that low-calorie diets are associated with lower
incidences of
age-related ailments such as cancer and neurodegenerative
diseases7.

D. HULSHIZER/AP Weighty issue: separating the benefits of
calorie
restriction from the dangers of obesity is tricky.

The field grew out of a change in thinking about ageing.
Until about 15
years ago, ageing was thought to be an unregulated process
resulting from
the accumulation of cellular damage. Then genetic studies,
particularly in
the nematode worm Caenorhabditis elegans, showed that
manipulating single
genes could increase or decrease lifespan dramatically8. Later,
lifespan-extending mutations were found in other organisms,
including the
fruitfly Drosophila and rodents.

Many genes have been identified that are thought to play a
part in
determining lifespan, such as those involved in insulin
signalling and
stress resistance. One family of enzymes currently in the
limelight is the
sirtuins. The gene SIR2, after which the family is named,
was one of the
first longevity genes to be identified. Species from yeast
to humans carry
variants of it, and extra copies increase lifespan in yeast,
worms and
flies9.

Sirtuin something
Nobody knows how sirtuins might extend lifespan, but David
Sinclair, who
studies ageing at Harvard Medical School in Boston believes
that they
stabilize DNA and counteract the reduced fidelity of
DNA-copying mechanisms
in old cells. The Sir2 protein seems to work with a small
molecule called
NAD, which is involved in metabolism9, so the two together
potentially
explain the association between calorie restriction and ageing.

In 2003, Sinclair's team described 19 plant-derived
molecules that activate
sirtuins in yeast10. One of these, resveratrol, found in
grape skins, has
been reported to have anticancer and neuroprotective
effects. The chemical's
presence in wine has been touted as the explanation of the
'French
paradox' - the low incidence of heart disease in southern
Europe, despite a
fatty diet. Sinclair and others believe it may also extend life.

Working with Rafael de Cabo, Donald Ingram and others at the
NIA's
Laboratory of Experimental Gerontology in Baltimore,
Sinclair is studying
the effects of resveratrol in non-obese mice. The study's
results are not
yet published, but de Cabo claims they look promising. There
is already
published evidence that resveratrol extends life in another
vertebrate. In
February this year, Alessandro Cellerino and his colleagues
at the Scuola
Normale Superiore in Pisa, Italy, revealed that the chemical
not only
extends the maximum lifespan of a short-lived fish called
Nothobranchius
furzeri by 60%, but also seems to protect the fish from
neurodegeneration11.

S. FRANKLIN/MAGNUM PHOTOS Good vintage: a compound found in
red wine called
resveratrol might explain why the French have fatty diets
but long lives.

Cynthia Kenyon, a researcher in ageing at the University of
California, San
Francisco, is "very impressed" with the resveratrol results,
but, she points
out, there is confusion over what it actually does. "In
animals, at least in
some cases, it looks like the effects you see are dependent
on Sir2," she
says. On the other hand, she says, resveratrol has so far
shown no effect on
Sir2 function in human cells in culture. This makes it
unlikely that the
chemical acts directly on the Sir2 protein, although it
might target other
biochemical processes that interact with Sir2.

How it works may not matter in the end, she says. But in the
absence of any
conclusive evidence that sirtuins extend life in mammals, or
that
resveratrol activates sirtuins in human cells, Sirtris
Pharmaceuticals, a
company co-founded by Sinclair and based in Cambridge,
Massachusetts, has
screened half a million compounds and found some that
activate human
sirtuins in the test tube.

Natural experiments
According to Sinclair, Sirtris has unpublished animal data
showing that some
of these sirtuin activators affect markers of longevity in
the same way that
calorie restriction does in rodents and in the humans in the
CALERIE study -
for example, by reducing insulin levels. One of the
molecules is already in
clinical trials, although Sinclair warns it will be several
years before
Sirtris can show that this is an effective way to treat
age-related disease,
let alone extend life.

Kenyon is co-founder of another Cambridge-based company
pursuing anti-ageing
drugs, Elixir Pharmaceuticals. Elixir is interested in
sirtuins, but is
taking a broader approach. Kenyon's group discovered that
activity in
biochemical processes controlled by insulin and another
hormone called
insulin-like growth factor 1 controls ageing. That work has
led them to test
molecules that affect those mechanisms, which control the
body's use of
glucose. The team is also investigating drugs that block the
effects of
ghrelin, another hormone that controls the body's glucose
balance.

"The way we are thinking about getting drugs approved is not
of course for
ageing, but instead for beneficial effects on age-related
disease," says
Kenyon. She envisages that people will start taking them
once they have been
approved for the latter - probably within the next five to
ten years - and a
huge natural experiment will be launched. "If they really
are drugs against
ageing, two things should happen," she says. "One, they
should have efficacy
in additional disease settings, and two, after a while you
might start
noticing that people taking the drugs seem younger."

We are thinking about getting drugs approved not for ageing,
but for
beneficial effects on age-related diseases. [Says] Cynthia
Kenyon

Just such an experiment is underway with the drug metformin,
which enhances
insulin action and was approved for treating type 2 diabetes
in 1995. Since
then, studies in rodents have shown that metformin can
reduce tumour load,
and reduce fasting insulin level and body temperature
without significantly
affecting body weight or food intake. But some researchers
are doubtful
about its usefulness as an anti-ageing drug, because it has
side effects
such as a small risk of a build-up of lactic acid in the
body which, rarely,
can be fatal.

We may never be sure whether calorie restriction extends
human lifespan,
says Ingram. He argues that it is unlikely that a test of
the effects of
lifelong restriction in humans under controlled conditions
will ever be
done, for reasons of cost and practicality.

In the meantime, some believe that researchers into ageing
must follow any
lead, because of the social and economic issues posed by a
rapidly ageing
population. A group of experts led by demographer Jay
Olshansky of the
University of Illinois, Chicago, is calling on the US
government to increase
its funding of basic ageing research, with the initial goal
of delaying all
age-related diseases by about seven years - a goal they
regard as realizable
for generations living today.