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It appears that mouse deletion mutants of
http://en.wikipedia.org/wiki/Agouti-related_protein (AgRP)
were longer
lived, although obese, subjects. In Fig. 3, although not
significant, the AgRP^-/- mice expended 35% more energy and
had 50% more food intake than the wild type mice.

Redmann SM Jr, Argyropoulos G.
AgRP-deficiency could lead to increased lifespan.
Biochem Biophys Res Commun. 2006 Nov 2; [Epub ahead of print]
PMID: 17097059

The Agouti-related protein (AgRP) is a central orexigenic
peptide leading to
increased food intake when ubiquitously overexpressed.
AgRP-deficient
(AgRP(-/-)) mice have either no phenotype or present an
age-related
leanness. In this study, AgRP(-/-) mice were fed alternate
high fat or low
fat diets in an effort to determine whether AgRP is a
mediating factor for
the effects of dietary fat on metabolic parameters. There
were no striking
metabolic differences between AgRP(-/-) and the equally
obese wild type
littermates but AgRP(-/-) mice displayed a significantly
longer lifespan.
The point estimate of median survival for the AgRP(-/-)
group was 9.8%
greater while the significantly low hazard ratio (0.494)
suggests that
mortality incidence of AgRP(-/-) mice is less than one-half
that of the wild
type reference population. It is concluded that although
AgRP(-/-) mice
become morbidly obese consuming a high fat diet (a landmark
feature for a
shortened lifespan), they seem to overcome obesity- and
age-related
pathologies and live significantly longer than their
metabolically similar
wild type littermates.

... Studies in humans have shown that single nucleotide
polymorphisms (SNPs)
impairing AgRP expression or protein function are associated
with reduced
BMI, lower incidence of type 2 diabetes, prevention of
late-onset obesity,
and macronutrient selection [12], [13] and [14].

... high fat (HF) or low fat (LF) diets ... The effect of
AgRP-deficiency
appears to resemble that of calorie restriction while
ameliorating to a
degree the effects of long-term HF feeding on lifespan [15]
and [16]. ...
metabolic similarities between AgRP^-/- mice and their wild
type littermates
that experienced the anticipated shorter lifespan under the
same nutritional
paradigm.

... regular chow diet (12.1% fat ... High fat (60 kcal%,
D12492) and low fat
(10 kcal%, D12450B) diets ... Mice consumed alternate diets
as follows: at 3
weeks of age chow; at 16 weeks HF diet; at 21 weeks LF diet;
at 41 weeks
chow; at week 42 HF diet until death. ...

... Overexpression or intracerebroventricular administration
of AgRP leads
to hyperphagia and the development of obesity. An earlier
publication
surprisingly showed that AgRP-deficient mice did not present
an anticipated
phenotype such as increased metabolic rate or reduced food
intake [10]. A
more recent report however showed that AgRP^-/- mice exhibit
increased
metabolic rate and increased body temperature but in an
age-dependent
fashion [11]. The mice described here were derived from
those reported
earlier [10]. Mice were backcrossed three times to C57BL/6J
and homozygous
AgRP^-/- were compared to WT littermates. Mice were placed
on alternate HF
and LF diets in order to examine whether dietary fat content
could reveal a
metabolic phenotype (e.g., leanness) in this AgRP knockout
strain.

The body weight of male AgRP^-/- did not differ
significantly from that of
the WT littermates and, in contrast to expectations,
AgRP^-/- males weighed
more but in an age-dependent fashion (35 weeks of age
onwards but not always
at statistically significant levels Fig. 1). A heavier
phenotype by the male
AgRP^-/- was also reported earlier [10]. Muscle mass was
higher while fat
mass was lower in the male AgRP^-/- mice but again not
always at
statistically significant levels. The higher muscle mass
could perhaps
explain the marginally higher body weight of these mice.
There were no
significant differences between AgRP^-/- and WT littermates
in any other
metabolic parameter measured (24-h energy expenditure and
diurnal food
intake).

The female AgRP^-/- mice exhibited a leaner phenotype from
WT littermates
(Fig. 2) but it was statistically significant only between
the ages of 12-30
weeks, a period during which all mice consumed LF diet.
Female AgRP^-/- mice
had higher energy expenditure and seemed to be eating more
food than WT
littermates (which is inconsistent with the anticipated
effect of
AgRP-deficiency) but not at statistically significant levels
(Fig. 2). Of
interest was an apparent cold-sensitivity by the AgRP^-/-
females (p < 0.05)
when placed at 4 °C but after 4 h they recovered
sufficiently to match the
WT littermates (data not shown).

The most striking phenotype of the AgRP^-/- mice was their
extended
lifespan. Survival of the AgRP^-/- mice was found to differ
significantly
from that of the wild type population, based on a stratified
log-rank test
(p = 0.045). The point estimate of median survival for the
AgRP^-/- mice
(101 weeks) exceeded that of their counterparts by 9.8%.
Furthermore, the
estimated hazard ratio of 0.494 for the AgRP^-/- animals
relative to wild
type indicates that AgRP-deficiency is associated with an
approximately
2-fold reduction in mortality incidence. These findings
imply a considerable
extension to lifespan associated with AgRP-deficiency,
especially
considering that these mice consumed a mandatory HF diet
from 7.7 months of
age and up to their death. Moreover, these mice gained
significant amount of
weight (reaching up to 78 g) that did not differ from the
weight gained by
WT littermates. It is noteworthy that the longest lived
AgRP^-/- mouse was a
male that reached 2 years and 9 months of age. This mouse
weighed from 55 to
68 g between the ages of 12-24 months with its weight
gradually declining to
39.5 g by the age of 2 years and 7 months old (Table 1).

Table 1. Summary of mice, genotypes, gender, and
statistical analyses of
survival curves
==========================================================
Genotype N Events Median survival (95% CL) Chi^2 log-rank
Hazard ratio
==========================================================
WT 16 (12M, 4F) 100% (16) 92 (75-97) 4.02 0.494
AgRP^-/- 21 (14M, 7F) 100% (21) 101 (88-108) p: 0.045* p: 0.049*
==========================================================
* Significant at p < 0.05.

Lifespans of mouse strains are known to differ. C57BL/6J
mice, in general,
live longer than A/J, BALB/cJ, and DBA/2J mice [17] but
mutations and
obesity in mice of C57BL/6J genetic background shortened the
lifespan [18].
Wild strain alleles tend to extend maximum lifespans [19]
while big mice die
young with early life body weight being a predictor of
longevity [20].
Gerontological data show that C57BL/6J males and females
live on average 878
and 794 days, respectively, while consuming regular chow
[21]. The mice
presented here were of a mixed genetic background (a
theoretical 87.5% of
C57BL/6J genotype) living on average 707 days for the
AgRP^-/- and 644 days
for the WT mice, consuming an HF diet from the age of 7.7
months. It is
unlikely that the genetic background itself played a
significant role to the
differences in lifespan between the AgRP^-/- and WT mice
because they were
all littermates. Similarly, there were no striking metabolic
differences
between AgRP-deficient and WT mice and therefore it is
likely that a
different type of factor may be responsible for the extended
lifespan of the
AgRP^-/- mice. The growth hormone and insulin growth factor
have been shown
to play significant roles in the aging process [22] and [23]
but neither was
assessed in the AgRP^-/- mice since the prolonged lifespan
was an unexpected
phenotype.

In humans, lower adiposity and caloric restriction leads to
longevity [16],
while obesity is a significant factor contributing to a
decreased lifespan
[15]. Carriers of the Ala67Thr SNP in AgRP are less likely
to develop
visceral obesity in later age [13] possibly due to
macronutrient selection
[24], which suggests that AgRP genetic defects may provide a
mechanism for
protecting humans against late onset visceral obesity. The
data presented
here show that AgRP-deficient mice develop an advantage that
enables them to
overcome the negative effects of morbid obesity and live
significantly
longer than their wild type littermates. These data also
suggest that the
involvement of AgRP in the process of aging may be
independent from its role
in feeding behavior. This study was not originally designed
to be a
longevity study and therefore additional experiments using
larger sample
sizes would need to be conducted to confirm the findings
presented here.