Passage adapted from Nikhil Swaminathan, “Eat (Less) to Live (Longer),” ©2007 by Scientific American.
Scientists have known for more than 70 years that the one
surefire way to extend the lives of animals was to cut calories
by an average of 30 to 40 percent. The question was: Why?
Now a new study begins to unravel the mystery and the
mechanism by which reducing food intake protects cells
against aging and age-related diseases.
Researchers report in the journal Cell that the phenomenon
is likely linked to two enzymes—SIRT3 and SIRT4—in
mitochondria (the cell’s powerhouse that, among other tasks,
converts nutrients to energy). They found that a cascade of
reactions triggered by lower caloric intake raises the levels of
these enzymes, leading to an increase in the strength and
efficiency of the cellular batteries. By invigorating the
mitochondria, SIRT3 and SIRT4 extend the life of cells, by
preventing flagging mitochondria from developing tiny holes
(or pores) in their membranes that allow proteins that trigger
apoptosis, or cell death, to seep out into the rest of the cell.
“We didn’t expect that the most important part of this
pathway was in the mitochondria,” says David Sinclair, an
assistant professor of pathology at Harvard Medical School and
a study co-author. “We think that we’ve possibly found
regulators of aging.”
In 2003 Sinclair’s lab published a paper in Nature that
described the discovery of a gene that switched on in the yeast
cell in response to calorie restriction, which Sinclair calls a
“master regulator in aging.” Since then, his team has been
searching for an analogous gene that plays a similar role in the
mammalian cell.
The researchers determined from cultures of human
embryonic kidney cells that lower caloric intake sends a signal
that activates a gene inside cells that codes for the enzyme
NAMPT (nicotinamide phosphoribosyltransferase). The two-
to four-fold surge in NAMPT in turn triggers the production of
a molecule called NAD (nicotinamide adenine dinucleotide),
which plays a key role in cellular metabolism and signaling.
The uptick in NAD levels activates the SIRT3 and SIRT4
genes, increasing levels of their corresponding SIRT3 and
SIRT4 enzymes, which then flood the interior of the
mitochondria. Sinclair says he’s not sure exactly how SIRT3
and SIRT4 beef up the mitochondria’s energy output, but that
events leading to cell death are at the very least delayed when
there are vast quantities of the enzymes.
SIRT3 and SIRT4 are part of a family called sirtuins
(SIRT1, which helps extend cell life by modulating the number
of repair proteins fixing DNA damage both inside and outside
the cell’s nucleus, is also a member). SIRT is short for sir-2
homologue—a well-studied protein that is known to extend
yeast cell longevity. According to Sinclair, all of the mammalian
SIRT genes (and their proteins) are possible drug
targets for therapies aimed at extending life, as well as staving
off age-related illnesses, such as Alzheimer’s disease, cancers
and metabolic disorders, like diabetes.
“I think SIRT3 is the next most interesting sirtuin from a
drug development standpoint,” Sinclair says. “It does protect
cells, but there’s growing evidence that it may mediate the
benefits of exercise as well.”
Sinclair’s lab is now working on developing what he calls a
possible “supermouse” with elevated levels of NAMPT to see
if it lives longer and is more disease-resistant than normal
mice.
Matt Kaeberlein, a pathologist at the University of
Washington in Seattle, says that Sinclair’s team has an
interesting hypothesis connecting the mitochondria to
longevity, but that it needs to be more directly tested in the
context of dietary restriction. “If the NAMPT-overexpressing
mice are long-lived and disease resistant, that will provide
more support for this idea.”
Scientists have known for more than 70 years that the one
surefire way to extend the lives of animals was to cut calories
by an average of 30 to 40 percent. The question was: Why?
Now a new study begins to unravel the mystery and the
mechanism by which reducing food intake protects cells
against aging and age-related diseases.
Researchers report in the journal Cell that the phenomenon
is likely linked to two enzymes—SIRT3 and SIRT4—in
mitochondria (the cell’s powerhouse that, among other tasks,
converts nutrients to energy). They found that a cascade of
reactions triggered by lower caloric intake raises the levels of
these enzymes, leading to an increase in the strength and
efficiency of the cellular batteries. By invigorating the
mitochondria, SIRT3 and SIRT4 extend the life of cells, by
preventing flagging mitochondria from developing tiny holes
(or pores) in their membranes that allow proteins that trigger
apoptosis, or cell death, to seep out into the rest of the cell.
“We didn’t expect that the most important part of this
pathway was in the mitochondria,” says David Sinclair, an
assistant professor of pathology at Harvard Medical School and
a study co-author. “We think that we’ve possibly found
regulators of aging.”
In 2003 Sinclair’s lab published a paper in Nature that
described the discovery of a gene that switched on in the yeast
cell in response to calorie restriction, which Sinclair calls a
“master regulator in aging.” Since then, his team has been
searching for an analogous gene that plays a similar role in the
mammalian cell.
The researchers determined from cultures of human
embryonic kidney cells that lower caloric intake sends a signal
that activates a gene inside cells that codes for the enzyme
NAMPT (nicotinamide phosphoribosyltransferase). The two-
to four-fold surge in NAMPT in turn triggers the production of
a molecule called NAD (nicotinamide adenine dinucleotide),
which plays a key role in cellular metabolism and signaling.
The uptick in NAD levels activates the SIRT3 and SIRT4
genes, increasing levels of their corresponding SIRT3 and
SIRT4 enzymes, which then flood the interior of the
mitochondria. Sinclair says he’s not sure exactly how SIRT3
and SIRT4 beef up the mitochondria’s energy output, but that
events leading to cell death are at the very least delayed when
there are vast quantities of the enzymes.
SIRT3 and SIRT4 are part of a family called sirtuins
(SIRT1, which helps extend cell life by modulating the number
of repair proteins fixing DNA damage both inside and outside
the cell’s nucleus, is also a member). SIRT is short for sir-2
homologue—a well-studied protein that is known to extend
yeast cell longevity. According to Sinclair, all of the mammalian
SIRT genes (and their proteins) are possible drug
targets for therapies aimed at extending life, as well as staving
off age-related illnesses, such as Alzheimer’s disease, cancers
and metabolic disorders, like diabetes.
“I think SIRT3 is the next most interesting sirtuin from a
drug development standpoint,” Sinclair says. “It does protect
cells, but there’s growing evidence that it may mediate the
benefits of exercise as well.”
Sinclair’s lab is now working on developing what he calls a
possible “supermouse” with elevated levels of NAMPT to see
if it lives longer and is more disease-resistant than normal
mice.
Matt Kaeberlein, a pathologist at the University of
Washington in Seattle, says that Sinclair’s team has an
interesting hypothesis connecting the mitochondria to
longevity, but that it needs to be more directly tested in the
context of dietary restriction. “If the NAMPT-overexpressing
mice are long-lived and disease resistant, that will provide
more support for this idea.”