Write your abstract here.Reducing insulin
signaling in the brain can prolong
lifespan.
One
route to a long
and healthy life may be establishing the right balance
in
insulin signaling between the brain and the rest of the body,
according to new research from Children’s Hospital Boston. The study,
published in the July 20 issue of Science, not only reinforces the
value of exercising and eating in moderation, but also helps explain a
paradox in longevity research.
Insulin
sends a vital signal throughout the body telling cells to use sugar
from the blood. But when cells become less sensitive to insulin, which
often happens as we age and gain weight, the body must make more
insulin to keep sugar under control and avoid type 2 diabetes. For a
long time, clinicians and scientists thought that “more insulin was a
good thing,” says Morris White, PhD, a Howard Hughes Medical Institute
investigator in Children’s Division of Endocrinology, who led the new
study. “But the increased insulin also gets into the brain, where it
can be detrimental.”
Studies
in the worm C. elegans and in fruit flies show that reducing insulin
signaling lengthens lifespan. But in humans and rodents, reducing
insulin signaling often causes diabetes. The view that insulin could
reduce lifespan is difficult to reconcile with decades of clinical
practice and scientific investigation to treat diabetes.
White
suspected that the key to explaining this paradox—and to maximizing
both health and longevity—is to reduce insulin signaling only in the
brain. To test this idea, White’s team measured longevity and other
characteristics in several groups of mice. In one group, they used a
genetic trick to cut in half the amount of Irs2, a protein that carries
the insulin signal inside the cell, in every cell of the body. Two
other groups of mice were genetically engineered to have half, or
nearly all, Irs2 removed only from the brain cells. Another group of
normal mice served as controls.
“To
our surprise, all of the engineered mice lived longer,” says Akiko
Taguchi, PhD, first author of the study. Even more surprising, the mice
lacking Irs2 only in the brain lived almost half a year longer than the
normal mice – an 18 percent increase in lifespan – despite being
overweight and having higher blood insulin levels, changes that usually
reduce lifespan. These long-lived mice were more active in old age,
retained youthful metabolic cycles (burning sugar by day and fat by
night) and retained protective levels of anti-oxidant enzymes such as
superoxide dismutase, which protect against oxidative stress, or
“biological rusting,” in the brain and body.
The
mice with normal brain Irs2 levels aged less gracefully – they lost the
metabolic rhythms of youth, became more sedentary, and had reduced
anti-oxidant enzymes after meals, leaving them vulnerable to cellular
damage. Such damage correlates with a host of age-related diseases such
as atherosclerosis, Alzheimer’s disease and cancer, notes White.
White
believes the study findings suggest a new approach to preventing
diseases that shorten lifespan. “The engineered mice live longer
because the diseases that kill them – cancer, cardiovascular disease
and others – are being postponed by reducing insulin-like signaling in
the brain,” he says, “regardless of how much insulin there is in the
rest of the body.”
Drugs
that regulate Irs2 signaling in the brain (but not elsewhere in the
body) are one possible preventive strategy, but no such drug has yet
been found. Targeted drugs will be important because Irs2 is needed in
other tissues, particularly the pancreatic beta cells that produce
insulin.
“The
easiest way to keep insulin levels low in the brain,” White says, “is
old-fashioned diet and exercise.” Although obesity and sedentary
lifestyles tune down the body’s sensitivity to insulin, exercise can
bring it back and reduce blood insulin levels. Eating smaller meals
keeps insulin low in the bloodstream, ensuring that less reaches the
brain. The new drugs designed to fight insulin resistance and type 2
diabetes might have a similar effect.
“This
study provides a new explanation of why it’s good to exercise and not
eat too much,” says White. “It has less to do with how we look, and
more to do with a healthy brain, especially in old age.”
The
study also calls into question the long-term effects of insulin therapy
for diabetes, White adds. “High insulin should be the short term
solution to insulin resistance, because it might damage the brain in
the long run,” he says. Better treatments for diabetes and healthy
aging, he suggests, should concentrate on sensitizing the body’s cells
to low amounts of insulin.
Source: Children’s Hospital Boston