Questions 1-11 are based on the following
passage.
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
5 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,
10 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
15 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
20 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
25 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.
30 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
35 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
40 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
45 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
50 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,
55 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
60 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.
65 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-
70 overexpressing mice are long-lived and disease resistant,
that will provide more support for this idea."