Breakthrough
suggests way to protect cells from damage caused by chronic disease.
SAN
FRANCISCO, CA—December 6, 2012—Scientists at the Gladstone Institutes have
identified a novel mechanism by which a type of low-carb, low-calorie
diet—called a "ketogenic diet"—could delay the effects of aging. This
fundamental discovery reveals how such a diet could slow the aging process and
may one day allow scientists to better treat or prevent age-related diseases,
including heart disease, Alzheimer's disease and many forms of cancer.
As the
aging population continues to grow, age-related illnesses have become
increasingly common. Already in the United States, nearly one in six people are
over the age of 65. Heart disease continues to be the nation's number one
killer, with cancer and Alzheimer's close behind. Such diseases place
tremendous strain on patients, families and our healthcare system. But today,
researchers in the laboratory of Gladstone Senior Investigator Eric Verdin, MD,
have identified the role that a chemical compound in the human body plays in
the aging process—and which may be key to new therapies for treating or
preventing a variety of age-related diseases.
In the
latest issue of the journal Science, available online today, Dr. Verdin and his
team examined the role of the compound β-hydroxybutyrate (βOHB), a so-called
"ketone body" that is produced during a prolonged low-calorie or
ketogenic diet. While ketone bodies such as βOHB can be toxic when present at
very high concentrations in people with diseases such as Type I diabetes, Dr.
Verdin and colleagues found that at lower concentrations, βOHB helps protect
cells from "oxidative stress"—which occurs as certain molecules build
to toxic levels in the body and contributes to the aging process.
"Over
the years, studies have found that restricting calories slows aging and
increases longevity—however the mechanism of this effect has remained
elusive" Dr. Verdin said. Dr. Verdin, the paper's senior author, directs
the Center for HIV & Aging at Gladstone and is also a professor at the University
of California, San Francisco, with which Gladstone is affiliated. "Here,
we find that βOHB—the body's major source of energy during exercise or
fasting—blocks a class of enzymes that would otherwise promote oxidative
stress, thus protecting cells from aging."
Oxidative
stress occurs as cells use oxygen to produce energy, but this activity also
releases other potentially toxic molecules, known as free radicals. As cells
age, they become less effective in clearing these free radicals—leading to cell
damage, oxidative stress and the effects of aging.
However,
Dr. Verdin and his team found that βOHB might actually help delay this process.
In a series of laboratory experiments—first in human cells in a dish and then
in tissues taken from mice—the team monitored the biochemical changes that
occur when βOHB is administered during a chronic calorie-restricted diet. The
researchers found that calorie restriction spurs βOHB production, which blocked
the activity of a class of enzymes called histone deacetylases, or HDACs.
Normally
HDACs keep a pair of genes, called Foxo3a and Mt2, switched off. But increased
levels of βOHB block the HDACs from doing so, which by default activates the
two genes. Once activated, these genes kick-start a process that helps cells
resist oxidative stress. This discovery not only identifies a novel signaling
role for βOHB, but it could also represent a way to slow the detrimental
effects of aging in all cells of the body.
"This
breakthrough also greatly advances our understanding of the underlying
mechanism behind HDACs, which had already been known to be involved in aging
and neurological disease," said Gladstone Investigator Katerina
Akassoglou, PhD, an expert in neurological diseases and one of the paper's
co-authors. "The findings could be relevant for a wide range of
neurological conditions, such as Alzheimer's, Parkinson's, autism and traumatic
brain injury—diseases that afflict millions and for which there are few
treatment options."
"Identifying
βOHB as a link between caloric restriction and protection from oxidative stress
opens up a variety of new avenues to researchers for combating disease,"
said Tadahiro Shimazu, a Gladstone postdoctoral fellow and the paper's lead
author. "In the future, we will continue to explore the role of βOHB—especially
how it affects the body's other organs, such as the heart or brain—to confirm
whether the compound's protective effects can be applied throughout the
body."
###
Matthew
Hirschey, PhD; John Newman, MD, PhD; Wenjuan He, PhD; Kotaro Shirakawa, PhD;
Natacha Le Moan, PhD; Carrie Grueter, PhD; Hyungwook Lim, PhD; Laura Saunders,
PhD; Robert V. Farese, Jr., MD; and Katerina Akassoglou, PhD, also participated
in this research at Gladstone. This research was supported by the Gladstone
Institutes.
About
the Gladstone Institutes
Gladstone
is an independent and nonprofit biomedical-research organization dedicated to
accelerating the pace of scientific discovery and innovation to prevent, treat
and cure cardiovascular, viral and neurological diseases. Gladstone is
affiliated with the University of California, San Francisco.
Graham
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