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| Increasing endogenous hydrogen sulfide production during dietary restriction plays a major role in delivering the benefits of longevity and stress resistance. |
A new study led by Harvard School of Public Health (HSPH) researchers
identifies a key molecular mechanism behind the health benefits of
dietary restriction, or reduced food intake without malnutrition. Also
known as calorie restriction, dietary restriction is best known for its
ability to slow aging in laboratory animals. The findings here show that
restricting two amino acids, methionine and cysteine, results in
increased hydrogen sulfide (H2S) production and protection against
ischemia reperfusion injury, damage to tissue that occurs following the
interruption of blood flow as during organ transplantation and stroke.
Increased H2S production upon dietary restriction was also associated
with lifespan extension in worms, flies, and yeast.
Although H2S gas is extremely toxic in high amounts, low levels
present in naturally occurring sulfur springs have long been associated
with health benefits. Mammalian cells also produce low levels of H2S,
but this is the first time that this molecule has been linked directly
to the health benefits of dietary restriction.
"This finding suggests that H2S is one of the key molecules
responsible for the benefits of dietary restriction in mammals and lower
organisms as well," said senior author James Mitchell, associate
professor of genetics and complex diseases. "While more experiments are
required to understand how H2S exerts its beneficial effects, it does
give us a new perspective on which molecular players to target
therapeutically in our efforts to combat human disease and aging."
The study appears online December 23, 2014 in Cell.
Dietary restriction is a type of intervention that can include
reduced overall food intake, decreased consumption of particular
macronutrients such as protein, or intermittent bouts of fasting. It is
known to have beneficial health effects, including protection from
tissue injury and improved metabolism. It has also been shown to extend
the lifespan of multiple model organisms, ranging from yeast to
primates. The molecular explanations for these effects are not
completely understood, but were thought to require protective
antioxidant responses activated by the mild oxidative stress caused by
dietary restriction itself.
First author Christopher Hine, research fellow in the Department of
Genetics and Complex Diseases, and colleagues demonstrated that one week
of dietary restriction increased antioxidant responses and protected
mice from liver ischemia reperfusion injury, but surprisingly, this
protective effect was intact even in animals that could not mount such
an antioxidant response. Instead, the researchers found that the
protection required increased production of H2S, which occurred upon
reduction of dietary intake of the two sulfur-containing amino acids,
methionine and cysteine. When the diet was supplemented with these two
amino acids, increased H2S production and dietary restriction benefits
were both lost.
The investigators also found that genes involved in H2S production
were also required for longevity benefits of dietary restriction in
other organisms, including yeast, worms, and flies.
"These findings give us a better understanding of how dietary
interventions extend lifespan and protect against injury. More
immediately, they could have important implications for what to eat and
not to eat before a planned acute stress like surgery, when the risk of
ischemic injury can be relatively high," said Hine.
