From: matus [matus@snet.net]
Sent: Monday, August 26, 2002 12:21 AM
To: matus@snet.net
Subject: MFD List - The Serious Search for an Anti-Aging Pill

(An excellent article from Scientific American on the search for a pill that
mimics the effects of a caloric restriction diet. - Mike)

The Serious Search for an Anti-Aging Pill

from -
http://www.sciam.com/article.cfm?articleID=000BC08E-5B8C-1D2B-97CA809EC588EE
DF&catID=2

In government laboratories and elsewhere, scientists are seeking a drug able
to prolong life and youthful vigor. Studies of caloric restriction are
showing the way

By Mark A. Lane, Donald K. Ingram and George S. Roth

STUART BRADFORD

CALORIC-RESTRICTION MIMETIC would, if successful, enable humans to derive
many of the health and life-extending benefits seen in animals on restricted
diets--without requiring people to go hungry.

As researchers on aging noted in a position statement this past May, no
treatment on the market today has been proved to slow human aging--the
buildup of molecular and cellular damage that increases vulnerability to
infirmity as we grow older. But one intervention, consumption of a
low-calorie yet nutritionally balanced diet, works incredibly well in a
broad range of animals, increasing longevity and prolonging good health.
Those findings suggest that caloric restriction could delay aging in humans,
too.

Unfortunately, for maximum benefit, people would probably have to reduce
their caloric intake by roughly 30 percent, equivalent to dropping from
2,500 calories a day to 1,750. Few mortals could stick to that harsh a
regimen, especially for years on end. But what if someone could create a
pill that mimicked the physiological effects of eating less without actually
forcing people to go hungry? Could such a caloric-restriction mimetic, as we
call it, enable people to stay healthy longer, postponing age-related
disorders (such as diabetes, atherosclerosis, heart disease and cancer)
until very late in life?

We first posed this question in the mid-1990s, after we came upon a chemical
agent that, in rodents, seemed to reproduce many of caloric restriction's
benefits. Since then, we and others have been searching for a compound that
would safely achieve the same feat in people. We have not succeeded yet, but
our failures have been informative and have fanned hope that
caloric-restriction, or CR, mimetics can indeed be developed eventually.

The Benefits of Caloric Restriction

Our hunt for cr mimetics grew out of our desire to better understand caloric
restriction's many effects on the body. Scientists first recognized the
value of the practice more than 60 years ago, when they found that rats fed
a low-calorie diet lived longer on average than free-feeding rats and had a
reduced incidence of conditions that become increasingly common in old age.
What is more, some of the treated animals survived longer than the
oldest-living animals in the control group, which means that the maximum
life span (the oldest attainable age), not merely the average life span,
increased. Various interventions, such as infection-fighting drugs, can
increase a population's average survival time, but only approaches that slow
the body's rate of aging will increase the maximum life span.
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Click here for a sidebar on how a prototype caloric-restriction mimetic
works.

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The rat findings have been replicated many times and extended to creatures
ranging from yeast to fruit flies, worms, fish, spiders, mice and hamsters.
Until fairly recently, the studies were limited to short-lived creatures
genetically distant from humans. But long-term projects under way in two
species more closely related to humans--rhesus and squirrel monkeys--suggest
that primates respond to caloric restriction almost identically to rodents,
which makes us more optimistic than ever that CR mimetics could help people.


The monkey projects--initiated by our group at the National Institute on
Aging in the late 1980s and by a separate team at the University of
Wisconsin- Madison in the early 1990s--demonstrate that, compared with
control animals that eat normally, caloric-restricted monkeys have lower
body temperatures and levels of the pancreatic hormone insulin, and they
retain more youthful levels of certain hormones (such as DHEAS, or
dehydroepiandrosterone sulfate) that tend to fall with age.

The animals also look better on indicators of risk for age-related diseases.
For example, they have lower blood pressure and triglyceride levels
(signifying a decreased likelihood of heart disease), and they have more
normal blood glucose levels (pointing to a reduced risk for diabetes, which
is marked by unusually high blood glucose levels). Further, we have recently
shown that rhesus monkeys kept on caloric restriction for an extended time
(nearly 15 years) have less chronic disease, just as the risk data
suggested. They and the other monkeys must be followed still longer,
however, before we will know whether low food intake can increase both
average and maximum life spans in monkeys: rhesus monkeys typically live
about 24 years and sometimes up to 40; squirrel monkeys typically live about
19 years but may live for 28.

The Journey Starts

By 1995 we wanted to know how the many physiological and biochemical changes
induced by caloric restriction led to delaying aging in mammals. For a
number of reasons, we suspected that changes in cellular metabolism would be
key. By "metabolism" we mean the uptake of nutrients from the blood and
their conversion to energy usable for cellular activities. We focused on
metabolism in part because the benefits of caloric restriction clearly
depend on reducing the overall amount of fuel coming into the body for
processing. Also, caloric restriction affects the aging of a wide variety of
tissues, which implies that it alters biological processes carried out by
all cells. Few processes are more fundamental than metabolism.

We specifically wondered whether changes related to metabolism of the sugar
glucose would account for the benefits of caloric restriction. Glucose,
which forms when the body digests carbohydrates, is the primary source of
energy in the body--that is, it is the main material used by cells for
making ATP, or adenosine triphosphate, the molecule that directly powers
most cellular activities. We also wanted to know whether alterations in the
secretion and activity of insulin, which influences glucose use by cells,
would be important. Insulin is secreted as glucose levels in the blood rise
after a meal, and it serves as the key that opens cell "doors" to the sugar.
We concentrated on glucose and insulin because reductions in their levels
and increases in cellular sensitivity to insulin are among the most
consistent hallmarks of caloric restriction in both rodents and primates,
occurring very soon after restriction is begun.

Shortly after we decided to test the hypothesis that caloric restriction
retards aging by altering metabolism, others began publishing data showing
that metabolic processes involving glucose and insulin influence life span.
Such findings encouraged our belief that we were on the right track. For
instance, a number of investigati
STUART BRADFORD; NATIONAL INSTITUTE ON AGING (photographs)


SIDEBAR: Caloric Restriction's Varied Effects
ons achieved remarkable extensions of life span in nematode worms by
mutating genes similar to those involved in molecular responses to insulin
in mammals. More recently researchers have found that lowered intake of
glucose or disruption of glucose processing can extend life span in yeast.
And in fruit flies, genes involved in metabolism, such as INDY (I'm Not Dead
Yet), have been implicated in life-span control.

An "Aha!" Moment

around the time the nematode work came out, we began to scour the scientific
literature for ways to manipulate insulin secretion and sensitivity without
causing diabetes or its opposite, hypoglycemia. Our search turned up studies
from the 1940s and 1950s mentioning a compound called 2-deoxy-D-glucose
(2DG) that was being tested in rodents for treating cancer but that also
reportedly lowered insulin levels in the blood. As we perused the literature
further, we had a true "aha!" moment.

The compound apparently reproduced many classic responses to caloric
restriction--among them reduced tumor growth (a response only slightly less
robust than the well-known extension of life span), lowered temperature,
elevated levels of glucocorticoid hormones and reduced numbers of
reproductive cycles. If 2DG really could mimic many aspects of caloric
restriction in animals, we thought, perhaps it would do the same for people.


While we were planning our first studies of 2DG, we scanned the literature
for details of how it works at the molecular level, learning that it
disrupts the functioning of a key enzyme involved in processing glucose in
cells. The compound structurally resembles glucose, so it enters cells
readily. It is also altered by an enzyme that usually acts on glucose
itself. But the enzyme that completes the next of several steps involved in
glucose processing essentially chokes on the intermediate produced from 2DG.
When it tries to act on this intermediate, it fails; in addition, its
ability to act on the normal glucose intermediate becomes impaired.

The net result is that cells make smaller amounts of glucose's by-products,
just as occurs when caloric restriction limits the amount of glucose going
into cells. Certain of these products serve as the raw material for the
ATP-making machinery, which is composed of a series of protein complexes
located in intracellular compartments called mitochondria. Deprived of this
raw material, the machinery makes less ATP. In essence, 2DG tricks the cell
into a metabolic state similar to that seen during caloric restriction, even
though the body is taking in normal amounts of food. As long as the amount
of ATP made meets the minimum requirements of cells, this diminished
operation of the ATP-making machinery is apparently beneficial.

Why might reduced functioning of the ATP-producing machinery help combat
aging? We can't say with certainty, but we have some ideas. A long-standing
theory of aging blames the production of molecules called free radicals. The
lion's share of free radicals in the body are emitted as the ATP-making
machinery operates. Over time these highly reactive molecules are thought to
cause permanent damage to various parts of cells, including the protein
complexes responsible for generating ATP. Perhaps by reducing the rate of
ATP production, 2DG and caloric restriction slow the rate at which free
radicals form and disrupt cells.

The lack of glucose's by-products might retard aging in another way as well.
Certain of those substances help to induce cells in the pancreas to secrete
insulin after an organism eats. Reductions in the amount of those
by-products would presumably limit insulin secretion and thereby minimize
insulin's unwanted actions in the body. Aside from indirectly promoting
excessive operation of the ATP-making machinery and thus boosting
free-radical production, insulin can contribute to heart disease and to
undesirable cell proliferation.

We also suspect that cells interpret reduced levels of raw materials for the
ATP-making machinery as a signal that food supplies are scarce. Cells may
well respond to that message by switching to a self-protective mode,
inhibiting activities not needed for cell maintenance and repair--such as
reproduction--and pouring most of their energy into preserving the integrity
of their parts. If that idea is correct, it could explain why caloric
restriction has been shown to increase production of substances that protect
cells from excess heat and other stresses.

This adoption of a self-preservation mode would mirror changes that have
been proposed to occur on an organismic level in times of food scarcity. In
the generally accepted "disposable soma" theory of aging, Thomas Kirkwood of
the University of Newcastle in England has proposed that organisms balance
the need to procreate against the need to maintain the body, or soma. When
resources are plentiful, organisms can afford both to maintain themselves
and to grow and reproduce. But when food is limited, the body invokes
processes that inhibit growth and reproduction and takes extra care to
preserve the soma.

Testing Begins

In our first experiments devoted to examining 2DG's effectiveness, we
delivered low doses to rats by adding it to their feed for six months. The
treatment moderately reduced fasting blood glucose levels (levels measured
after food was removed for 12 hours), body weight and temperature, and
robustly reduced fasting insulin levels--findings consistent with the
actions of caloric restriction itself. Interestingly, after an initial
adjustment to the novel diet, the 2DG group did not eat significantly less
food than the controls. Thus, these exciting preliminary analyses revealed
that it was possible to mimic at least some sequelae of caloric restriction
without reducing food intake.

Shortly after we published these results, in 1998, other groups began
identifying more ways that 2DG imitates caloric restriction. For example,
Mark P. Mattson, then at the University of Kentucky, and his colleagues had
reported earlier that caloric restriction could attenuate damage to nerve
cells and limit behavioral deficits in rodents treated with compounds toxic
to brain cells. When they then treated rodents with 2DG instead of caloric
restriction, they observed the same neuronal protection.

At this writing, we are in the midst of conducting long-term rodent trials
of 2DG. Results from the first year of this endeavor confirm our previous
findings that 2DG slightly reduces blood glucose and body temperature. We
are also examining whether 2DG reduces the incidence of cancer and increases
life span when fed to animals at low doses from the time they are weaned
until they die.

The work so far clearly provides a "proof of concept" that inhibiting
glucose metabolism can re-create many effects of caloric restriction.
Regrettably, however, 2DG has a fatal flaw preventing it from being the
"magic pill" we were hoping for. Though safe at certain low levels, it
apparently becomes toxic for some animals when the amount delivered is
raised just a bit or given over long periods. The narrowness of the safety
zone separating helpful and toxic doses would bar it from human use. We hope
this is not a general feature of CR mimetics.

Moving On

Assuming our long-term studies confirm that inhibiting metabolism can retard
aging, the task becomes finding other substances that yield 2DG's benefits
but are safer over a broader range of doses and delivery schedules. Several
candidates seem promising in early studies, including iodoacetate, being
investigated by Mattson's group, now at the NIA's Laboratory of
Neurosciences. In animals this agent appears to protect brain cells from
assaults by toxic substances, just as 2DG and caloric restriction do.
Treatment with antidiabetic medications that enhance cellular sensitivity to
insulin might be helpful as well, as long as the amounts given do not cause
blood glucose levels to fall too low.

A great deal of research implicates glucose metabolism in regulating life
span, yet other aspects of metabolism can also change in reaction to caloric
restriction. When the body cannot extract enough energy from glucose in
food, it can switch to obtaining energy in alternative ways. For example, it
may shift to breaking down protein and fat. Pharmaceuticals that targeted
these processes might serve as CR mimetics, either alone or in combination
with drugs that intervene in glucose metabolism. Some compounds that act in
those pathways have already been identified, although researchers have not
yet assessed their potential as CR mimetics. Drugs that replicate only
selected effects of caloric restriction could have a role to play as well.
In theory, antioxidant vitamins might fit that bill. Research conducted to
date, however, indicates that this particular intervention probably will not
extend longevity.

Unlike the multitude of elixirs being touted as the latest anti-aging cure,
CR mimetics would alter fundamental processes that underlie aging. We aim to
develop compounds that fool cells into activating maintenance and repair
activities that lead to greater health and longevity of the organism. That
job is difficult but no longer seems impossible. If scientists can develop
agents that offer the benefits of 2DG without its drawbacks, they will
finally enable people to have their cake--a longer, healthier life--and eat
it, too.

- The Serious Search for an Anti-Aging Pill: How a Prototype
Caloric-Restriction Mimetic Works -

The best-studied candidate for a caloric-restriction mimetic, 2DG
(2-deoxy-D-glucose), works by interfering with the way cells process the
sugar glucose. It has proved toxic at some doses in animals and so cannot be
used in humans. But it has demonstrated that chemicals can replicate the
effects of caloric restriction; the trick is finding the right one.

Cells use the glucose from food to generate ATP (adenosine triphosphate),
the molecule that powers many activities in the body. More specifically,
after glucose enters cells, a series of enzymatic reactions in the cytoplasm
and mitochondria of cells alter the glucose bit by bit, ultimately producing
substances that feed electrons (e-) into the ATP-making machinery. Transfer
of the electrons from one component of the machinery to another, and finally
to oxygen, causes protons (H+)

to flow through a complex named ATP synthase, which responds by generating
ATP. By limiting food intake, caloric restriction minimizes the amount of
glucose entering cells and decreases ATP generation. When 2DG is
administered to animals that eat normally, glucose reaches cells in
abundance, but the drug prevents most of it from being processed and thus
reduces ATP synthesis. Researchers have proposed several explanations for
why interruption of glucose processing and ATP production might retard
aging. One possibility relates to the ATP-making machinery's emission of
free radicals, which are thought to contribute to aging and to such
age-related diseases as cancer by damaging cells. Reduced operation of the
machinery should limit their production and thereby constrain the damage.
Another hypothesis suggests that decreased processing of glucose could
indicate to cells that food is scarce (even if it isn't) and induce them to
shift into an anti-aging mode that emphasizes preservation of the organism
over such "luxuries" as growth and reproduction. --M.A.L., D.K.I. and G.S.R.

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