Science News
Week of Dec. 13, 2003; Vol. 164, No. 24

Ketones to the Rescue

Fashioning therapies from an adaptation to starvation
Ben Harder

In times of plenty, both the mind and the body thrive. But deprived of basic
sustenance, the mind perishes before the body does. That's not New Age
philosophy; it's basic metabolic chemistry. While most of the body manages food

shortages with relative ease, the tissues of the brain are vulnerable during
periods of scarcity. So when blood sugar dips, the brain must fall back on
special
biochemistry to meet its energy needs. From studying that metabolic back-up
system, a coterie of scientists has drawn inspiration that could lead to a new
treatment for conditions as diverse as epilepsy, diabetes, Alzheimer's disease,

and heart failure.

Most of the time, the body makes its fundamental fuel, glucose, from ingested
carbohydrates. With each meal, the bloodstream gets replenished with glucose
to replace the blood sugar that hungry cells have consumed to satisfy their
metabolic needs. The body can't store glucose well, yet cells must be fed
continually. So the body puts away extra energy in the form of fat, which it
can
break down into energy-supplying fatty acids when needed. A starving animal or
a
person with normal fat stores can thus sustain most of the body's cells for
weeks or months without eating.

But brain cells, even hungry ones, can't avail themselves of these emergency
stores. A physiological barrier that blocks toxins in the bloodstream so they
can't enter the delicate brain also keeps out fat and fatty acids. As a
consequence, when glucose in the blood runs low, brain cells can run into
trouble.

People are uniquely vulnerable to such glucose starvation because of their
disproportionate braininess. Although the brain makes up about 2 percent of a
normal adult's weight, it commands roughly 20 percent of the body's resting
metabolic budget.

A condition found only in people and a few ruminants can protect against this
Achilles' heel. The state, known to followers of the popular Atkins diet, is
called ketosis. When blood-glucose concentrations get low, the liver converts
a portion of fatty acids into acids called ketone bodies or ketones. These
substances can substitute for glucose and fatty acids as cellular fuel.
However,
unlike fatty acids, ketones can penetrate the blood-brain barrier.

While ketosis may guard the brain in times of starvation, Richard L. Veech
has additional applications in mind. Veech, who works at the National
Institutes
of Health in Rockville, Md., argues that ketones might be therapeutic any
time cells are threatened by energy deprivation. Such threats could arise both
from a lack of fuels and from cells' failure to properly metabolize the fuels
at
their disposal. The latter category covers a broad array of diseases.

Veech and others have been suggesting for several years that ketosis could
help treat, among other conditions, Alzheimer's and Parkinson's diseases,
certain insulin disorders such as type 1 diabetes, and several metabolic
disorders
caused by rare mutations.

"These diseases appear wildly different," Veech says. Treating "all these
different things with some magic substance sounds improbable," he adds. Yet
across a wide range of specialties, doctors who've dabbled with ketone-based
therapies are warming to that seemingly outlandish idea, and a vanguard of
research
on ketone therapies is appearing in scientific journals. At NIH earlier this
fall, Veech hosted a gathering of researchers who have studied ketones.

Ketone cuisine

There is one medical condition in which ketones find proven, if limited,
application. Since the 1920s, a ketosis-inducing diet has been used to treat
some
cases of severe childhood epilepsy. This high-fat, low-protein, low-carb
regimen shifts the body's main fuel supply from glucose to ketones and fatty
acids.
This ketogenic diet is more extreme than the high-protein Atkins diet, which
produces ketones in urine but not necessarily in the blood, says Veech.

Whereas most people consume less than a third of their calories in the form
of fat and the rest as carbohydrates or protein, people on the medical
ketogenic diet obtain at least two-thirds of their calories from fat.

"It's a hideous diet," says Kieran Clarke of the University of Oxford in
England, who attended Veech's summit. "Think of eating pounds of butter at a
time,
and eating cream on top of that," she says. Not surprisingly, many children
find the diet unpalatable. In studies, refusal to eat has been a primary cause
for the treatment's failure. Implementing the diet, furthermore, usually
requires a hospital stay and the involvement of numerous dietitians and
pediatricians. Enforcing it requires parents to weigh foods and calculate
ratios of
calories from different sources.

With the widespread introduction in the 1960s of more effective drugs for
epilepsy, the unwieldy diet's use declined. Its reputation has recently enjoyed
a
resurgence, however, because some seizures that had been resistant to the
drugs were observed to stop during ketosis. The well-publicized case of one
boy,
whom doctors at Johns Hopkins Medical Institutions in Baltimore successfully
treated with the ketogenic diet, inspired the 1997 movie First Do No Harm.

Even so, no more than a few hundred people in the United States are on the
medical ketogenic diet at any one time, estimates Eileen P.G. Vining, a
pediatric neurologist at Johns Hopkins. For one thing, she says, it's
prescribed
almost exclusively for children because doctors are concerned about the heart
attack risk that adults might face from chowing down on so much fat.

To get a feel for how serious the side effects of the ketogenic diet might
be, Vining, Peter O. Kwiterovich, and their colleagues studied 141 epileptic
children they'd treated for at least 6 months at Johns Hopkins since 1994. The
children's blood concentrations of total cholesterol, triglycerides, and other
markers associated with cardiovascular disease had jumped by as much as 60
percent during the ketogenic treatment. Meanwhile, blood concentrations of
high-density lipoproteins, or good cholesterol, fell by an average of 13
percent, the
researchers reported in the Aug. 20 Journal of the American Medical
Association.

Even if those numbers translate into a health risk for children on a
ketogenic diet, which is far from certain, "it's a price worth paying" when
children
are wracked by drug-resistant seizures, Vining contends.

Nevertheless, there could be a better way. Studies suggest that certain
ketones are directly involved in inhibiting seizures. That raises the
possibility
of supplanting the ketogenic diet with pure ketones as drugs.

Rescue mission

Limited quantities of ketones are produced for research purposes, but they
are expensive and difficult to test because the body breaks them down quickly.
Nevertheless, neurologist Serge Przedborski of Columbia University is
experimenting with ketones. Przedborski's main research interest is Parkinson's
disease
(SN: 5/3/03, p. 285: Available to subscribers at
http://www.sciencenews.org/20030503/note10.asp), the symptoms of which include
tremors, muscle stiffness,
and loss of balance and coordination. The physiological hallmark of
Parkinson's is the loss of certain neurons that respond to the brain chemical
dopamine.

The degeneration of those neurons and of similar brain cells in Alzheimer's
disease has been linked to defects in the cells' energy-producing machinery, or

mitochondria. In both diseases, mitochondria in some neurons are inefficient
at metabolizing glucose. But the process by which mitochondria metabolize
ketones isn't necessarily impaired in the two diseases.

Veech, Clarke, and four of their colleagues from Japan demonstrated 3 years
ago that, in test tubes, the ketone D-beta-hydroxybutyrate protects neurons
that have the mitochondrial defects associated with Parkinson's and
Alzheimer's.

To test the effectiveness of the approach in animals, Przedborski and his
colleagues implanted into some laboratory mice a pump that gradually released
D-beta-hydroxybutyrate, and into other mice a dummy pump. A day later, the
researchers gave the animals a neurotoxin that inhibits glucose metabolism in
the
critical neurons. That procedure is commonly used in the lab to induce a
condition similar to Parkinson's disease.

After a week, the researchers counted surviving neurons. While mice given
dummy pumps had lost about two-thirds of a certain neuron type associated wit

Parkinson's, mice treated with 160 milligrams of D-beta-hydroxybutyrate per
kilogram of body weight per day appeared to have lost only one-third of those
cells. Mice receiving lower doses of the ketone didn't fare noticeably better
than
the animals that had gotten the dummy pumps.

"It's not a dramatic effect," Przedborski acknowledges. "But, sure enough, we
were able to recover some of the function of the mitochondria." Most
important, the scientists report in the September Journal of Clinical
Investigation,
the high dose of the ketone prevented the mice from developing Parkinson's-like

movement problems.

To confirm that defective mitochondria use ketones to detour around their
obstructed metabolic pathway, Przedborski's team administered a second toxin,
which interferes with ketone metabolism. In mice with both metabolic pathways
blocked, the ketone therapy didn't rescue any neurons.

The Columbia researchers' findings support the idea that ketones could help
people with Parkinson's disease, says Theodore B. VanItallie of St.
Luke's-Roosevelt Hospital Center in New York City. "There's enough evidence
available now
to encourage people to test the hypothesis," he says. "There's at least a
reasonable possibility that these things [ketones] will work."

VanItallie and his colleagues recently put several people with Parkinson's
disease on a ketogenic diet, but the researchers haven't yet gathered enough
data to draw conclusions. VanItallie is looking for funding to mount a
full-size
trial.

Diabetes, too, can affect the brain. Children with type-1 diabetes lose some
mental acuity when their glucose metabolism slows, says Jullie W. Pan of the
Albert Einstein College of Medicine in New York. That can eventually affect
their academic performance.

In type 1 diabetes, the body doesn't have enough insulin to do its normal job
of transporting glucose into cells that would metabolize it. In fact, ketosis
is a symptom of diabetic shock because it arises when glucose metabolism is
suppressed. Insulin injections can boost glucose metabolism, but blood insulin
can vary considerably between injections.

Pan is now studying the effect of ketone infusions in diabetic children to
see whether the therapy might compensate for the effects of glucose-metabolism
fluctuations on the brain.

Putting heart into it

Brain effects of low glucose availability aren't the only problems that
ketones could conceivably fight. An international team of doctors recently
reported
successes in using ketones to treat three children with the rare genetic
disease known as multiple acyl-CoA dehydrogenase deficiency, or MADD. The
metabolic defect renders the body unable to process certain fatty acids. A
low-fat
diet and other interventions sometimes help affected children, but weakened
muscles, particularly heart muscles, and damage to other tissues can lead to
early
death.

The first child the researchers treated with ketones was a 2-year-old boy
receiving standard treatment for MADD who suddenly developed quadriplegia and
could no longer speak. To supply energy to poorly functioning cells, doctors
gave
the boy oral doses of ketones every 4 hours. The boy recovered gradually
until, after 19 months of the ketone therapy, he could again walk unassisted, a

development that NIH's Veech hails as remarkable.

The researchers subsequently gave the same treatment to two other children
with MADD, both of whom had suffered heart failure. These patients showed
substantial recovery, pediatrician Johan L.K. Van Hove, now at the University
of
Colorado Health Sciences Center in Denver, and his colleagues reported in the
April 26 Lancet.

Oxford's Clarke suggests that ketones could treat heart failure from other
muscle-weakening causes, as well. One hypothesis of heart disease suggests that

a heart can gradually fail after a nonfatal heart attack because the organ's
muscle cells become inefficient at both taking up glucose and metabolizing
fatty acids, says Clarke. Ketones could provide heart muscle with an
alternative
energy source. Clarke is experimenting on failure-prone rat hearts to test this

idea.

If this treatment is ever to be practical, an abundant and reasonably
inexpensive source of purified ketones will be needed, she says. "The only way
now we
can produce ketones in the body is a high-fat diet," she says. "You couldn't
feed a high-fat diet to a heart-failure patient. That would be a disaster."

Even in the small amounts needed by the children that Van Hove and his
colleagues treated, purified ketones could cost $20,000 per patient per year,
says
Veech. The higher quantity of ketones that an adult would require would lead to

even more expense.

That's only a temporary obstacle, according to Veech. In the lab, scientists
can already use bacteria to manufacture a compound that can be processed into
ketones. If researchers can improve on the current method for refining the
precursor, then ketones could be inexpensively produced, he says, and his
theories about their broad medical effectiveness could be put to the test.

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References and Sources

References:

Kashiwaya, Y. . . . K. Clarke, and R.L. Veech. 2000. D-b-hydroxybutyrate
protects neurons in models of Alzheimer's and Parkinson's disease. Proceedings
of
the National Academy of Sciences 97(May 9):5440-5444. Available at
http://www.pnas.org/cgi/content/full/97/10/5440.

Kwiterovich, P.O., E.P.G. Vining, et al. 2003. Effect of a high-fat ketogenic
diet on plasma levels of lipids, lipoproteins, and apolipoproteins in
children. Journal of the American Medical Association 290(Aug. 20):912-920.
Abstract
available at http://jama.ama-assn.org/cgi/content/abstract/290/7/912.

Tieu, K. . . . and S. Przedborski. 2003. D-b-hydroxybutyrate rescues
mitochondrial respiration and mitigates features of Parkinson disease. Journal
of
Clinical Investigation 112(Sep. 15):892-901. Available at
http://www.jci.org/cgi/content/full/112/6/892.

Van Hove, J.L.K., et al. 2003. D,L-3-hydroxybutyrate treatment of multiple
acyl-CoA dehydrogenase deficiency (MADD). Lancet 361(April 26):1433-1435.
Summary.

VanItallie, T.B., and T.H. Nufert. 2003. Ketones: Metabolism's ugly duckling.
Nutrition Reviews 61(October):327-341. Abstract available at
http://dx.doi.org/10.1301/nr.2003.oct.327-341.

Veech, R.L., et al. 2001. Ketone bodies, potential therapeutic uses. IUBMB
Life 51:241-247. Abstract available at
http://dx.doi.org/10.1080/152165401753311780.

Further Readings:

Seppa, N. 2003. Protein implicated in Parkinson’s disease. Science News
163(May 3):285. Available to subscribers at
http://www.sciencenews.org/20030503/note10.asp.

Sources:

Kieran Clarke
Department of Biochemistry
University of Oxford
Oxford OX1 3QU
United Kingdom

Philippe Demaerel
Department of Radiology
University Hospital Gasthuisberg
Katholieke Universiteit Leuven
B-3000 Leuven
Belgium

Peter O. Kwiterovich
Lipid Research Atherosclerosis Division
Johns Hopkins University
Lipid Clinic
550 North Broadway
Suite 308
Baltimore, MD 21205

Jullie W. Pan
Department of Neurology and Neuroscience
The Gruss Magnetic Resonance Research Center
Room 211
Albert Einstein College of Medicine of Yeshiva University
1300 Morris Park Avenue
Bronx, NY 10461

Serge Przedborski
BB-307
Columbia University
650 West 168th Street
New York, NY 10032

Kim Tieu
Department of Neurology
Columbia University
650 West 168th Street
New York, NY 10032

Johan L.K. Van Hove
Department of Pediatrics
Box C233
University of Colorado Health Sciences Center
4200 East Ninth Avenue
Denver, CO 80262

Theodore B. VanItallie
1678 Jose Gaspar Drive
Boca Grande, FL 33921

Richard L. Veech
Unit on Metabolic Control
Laboratory of Membrane Biochemistry and Biophysics
National Institute of Alcohol Abuse and Alcoholism
12501 Washington Avenue
Rockville, MD 20852

Eileen P.G. Vining
Pediatric Epilepsy Center
Department of Pediatrics
Johns Hopkins Medical Institutions
Baltimore, MD 21205

http://www.sciencenews.org/20031213/bob8.asp

From Science News, Vol. 164, No. 24, Dec. 13, 2003, p. 376.

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