[biomed] [tt] Brain Growth Receptors Control Lifespan

[Christian Weisgerber]

Brain Growth Receptors Control Lifespan

Richard Robinson

Citation: Robinson R (2008) Brain Growth Receptors Control Lifespan.
PLoS Biol 6(10): e274 doi:10.1371/journal.pbio.0060274

Published: October 28, 2008
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When resources are short, growing organisms face an existential choice:
should you ignore the shortage and hope for better times soon, or scale
back and live within your limited means? And if you do scale back, will
there be any payoff later in life? For animals, these choices are
played out hormonally, with environmental fluctuations leading to
internal rearrangements in endocrine signal and response throughout the
growing body.

In mammals, two principal hormones--growth hormone (GH) and
insulin-like growth factor 1 (IGF-1)--promote growth. Remarkably,
inhibiting one or both of these two not only retards growth, but also
extends lifespan, not just in lab animals, but possibly also in people:
mutations that reduce the function of the IGF-1 receptor have recently
been discovered in centenarians (who are also short). Growth occurs
throughout the body, and receptors for IGF-1 are found in every organ
on virtually every cell. But Laurent Kappeler et al. now show that it
is the IGF-1 receptors in the brain that set the pattern for growth and
lifespan.

The authors were led to the brain by the hierarchy of the endocrine
system itself. While the pituitary gland, which sits just beneath the
cranium, is often called the "master gland," it is really more of a
first mate, taking its orders directly from the brain's hypothalamus.
The hypothalamus controls differentiation and daily function of the
pituitary, sending it instructions in the form of "releasing hormones,"
including growth hormone releasing hormone (GHRH). The pituitary, in
turn, releases its own corresponding hormones into the blood stream,
including growth hormone, which travels to the liver, triggering the
production of IGF-1. Collectively, this cascade is known as the
"somatotropic axis," and the authors reasoned that if the axis is
ultimately controlled from the brain, then its ability to respond to
resource fluctuations might be found there as well.

To test this, they selectively knocked out IGF-1 receptors in the
brains of mice, leaving peripheral receptors (including those in the
pituitary) alone. While homozygous knockouts--missing both gene copies,
and producing no brain receptors--had significant developmental
defects, the heterozygotes, which had one normal and one missing copy,
were healthy and behaved normally. But by 20 days after birth, the
knockout mice lagged in growth, and by 90 days, had fallen behind by
10% in body weight and 5% in length compared with their normal
littermates.

Despite normal levels of IGF-1 receptors on the pituitary, the size of
the gland was reduced, and its ability to produce GH was
correspondingly smaller. In the hypothalamus, production of GHRH was
diminished, although somatostatin, a hormone with opposite effects,
continued to be produced normally. While most organs were smaller than
normal, fat tissue was increased, likely as a consequence of reduced
GH. The effects of IGF-1 receptor knockout did not extend to other
hormonal control axes--both gonadal and thyroidal functions remained
normal, emphasizing the specificity of reduced IGF-1 stimulation.

Mean lifespan was also increased in the knockout mice, by about 10%.
The effect on lifespan was curious, however. While the mean was
extended, the maximum was not--more knockout mice lived longer, but the
oldest knockout mouse lived no longer than the oldest normal mouse. The
increased mean lifespan can be explained by low peripheral GH and
IGF-I, which is itself a consequence of reduced central IGF
sensitivity, in keeping with previous studies that have shown that
reduced peripheral IGF-I and GH extend lifespan. The reason for the
second effect (unchanged maximum lifespan) is unclear and will require
more investigation.

These results suggest that IGF-1 feedback onto the hypothalamus during
development plays a key role in determining the set-point of the
somatotropic axis throughout life. While previous experiments have
implicated IGF-1 suppression in lifespan extension, this study shows
that central, rather than peripheral, suppression is sufficient to
trigger the effect. Longer lifespan can also be the consequence of
caloric restriction, and these results may indicate one mechanism that
mediates that phenomenon. They also open the door to a multitude of
experiments to further explore the interplay of environment and
endocrine control in setting the trajectory of metabolism, growth, and
longevity.


[ For the research article referenced by the above synopsis, see:

Kappeler L, De Magalhaes Filho C, Dupont J, Leneuve P, Cervera P,
et al. (2008)
Brain IGF-1 Receptors Control Mammalian Growth and Lifespan through
a Neuroendocrine Mechanism.
PLoS Biol 6(10): e254 doi:10.1371/journal.pbio.0060254 ]
-- 
Christian "naddy" Weisgerber                          naddy at mips.inka.de
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