know whether any of the compounds will
work at all, much less work safely.
Interestingly, the race to put time in a
bottle has not been deterred by the fact
that the mechanism of growing old is still
largely a mystery. So too is the way that a
drastic drop in calories pushes the slow-motion button.
“I’ve been in the field 15 years now,
and it’s amazing how theories come and
go very quickly. There isn’t a central
agreed theory about what aging is at the
moment. But I think in the next decade
we’ll know,” says David Gems, a biologist at the Institute of Healthy Aging at
University College London. When it
comes to caloric restriction, “the thing
you have to understand is that we don’t
really know how it works.” Much of the
research is housed at universities and
government research labs, but a small
antiaging biotech industry (populated
largely by current and former academics) has also sprung up.
When food is scarce
Many leaps into the antiaging market
seek to mimic biochemical reactions
that occur naturally in cells when eating
slows way down. While the script remains
incomplete, research has uncovered some
key molecular players — such as the family of enzymes known as sirtuins, which
are the target of resveratrol. When food
intake plummets, emergency alarms go
off inside a cell. “There are energy sensors
somewhere that turn on some genes and
turn off other genes,” says George Roth,
formerly at the National Institute on
Aging and now the CEO at GeroScience,
a Maryland-based biotech firm trying to
develop an antiaging drug. This genetic
fire drill appears to protect tissues from
normal wear and tear. To scientists, each
gene switched off or on offers a possible
“A lot of compounds have come down
the pike,” says Ingram, who helped
found GeroScience. Some approaches
have already lost favor, such as the idea
of short-circuiting aging solely through
antioxidants, chemicals that neutralize
damaging molecules called free radicals.
Many “were built around the antioxidant
hypothesis, and just have gone nowhere.”
The antioxidant approach probably
didn’t pay off because it was too simple
an answer for a complex problem. The
body ages for many reasons, and more
than one are tied to calorie intake. During times of plenty, the body doesn’t
seem to protect itself as much from the
harmful by-products shed during the
business of daily living. When food is
scarce, protection matters most.
Overeating probably also fuels disease
in indirect ways, by inciting inflammation or raising insulin levels, which in
turn helps stoke energy-hungry tumors.
Ingram and Roth wrote in the February-March Experimental Gerontology that any
antiaging drug must have a global impact
on chemical reactions in the body, just as
calorie restriction does. “Our perspective has always been that aging operates
on multiple mechanisms,” Ingram says.
The GeroScience research focuses
on the processing of glucose, the body’s
source of energy. Of special interest is
mannoheptulose, a compound which
occurs naturally in avocados, though Roth
says it degrades quickly once the fruit
ripens. Mannoheptulose partially turns
off hexokinase, an enzyme that ignites a
series of chemical reactions, known as the
glycolytic pathway, when glucose enters
a cell. Starving a cell of hexokinase is like
sending a chemical memo that less energy
is coming in. At a meeting in 2009, Roth
reported unpublished data showing that
mice fed mannoheptulose lived about
30 percent longer on average than normal
mice, even though the groups consumed
the same number of calories.
Organism On caloric restriction Using drugs or genetic modi;cations
Yeast Lives three times as long
Inhibiting the TOR nutrient-sensing pathway by deleting TOR and related genes produces a several-fold
increase in life span.
Fruit ;y Reducing activity of the insulin/insulin-like growth
factor signaling (IIS) pathway through genetic dele-
tions extends life. So does using rapamycin, a drug
that acts via the TOR pathway.
Mouse Lives 30 to 50 percent as
long as normal.
Mutations that reduce activity of the IIS pathway or
the TOR pathway, called m TOR in mammals, increase
life span. So do rapamycin and the diabetes drug
metformin. Mannoheptulose, which slows metabolism of glucose, may extend life by 30 percent.
Monkey No published results of experimental drugs.
Longer life for all Drastically reducing daily calorie intake has successfully slowed
aging in many organisms. Now scientists are ;nding out whether drugs and genetic
tweaks that mimic this dietary restriction have similar life span–extending potential.
Lives two times as long
Less age-related disease
and lowered age-related
mortality after 15–20 years.
Human Long-term study of 25 percent reduction in calories
Not yet determined. Some researchers have hopes
for rapamycin and mannoheptulose, among others.
Studies of resveratrol and SIRT1 activators, which
both stimulate sirtuins, and metformin are ongoing.