From: Ramez Naam (mez@apexnano.com)
Date: Mon Jan 27 2003 - 12:47:19 MST
From: Robert J. Bradbury [mailto:bradbury@aeiveos.com]
> Having *no* fat reserves means your circulating glucose and
> fat levels are going to drop at least some of the time
> meaning you are going to effectively be in a partial CR
> state. Partial CR means less free radicals means less double
> strand breaks means less aging.
The authors of the study note that the mice have far greater glucose
tolerance than controls, which is also a symptom of CR. They
speculate that insulin signaling may be an important underlying
mechanism of the life extension seen in their study and in CR.
Below is the text of the article in Science:
Extended Longevity in Mice Lacking the Insulin Receptor in Adipose
Tissue
Matthias Blüher,1 Barbara B. Kahn,2 C. Ronald Kahn1*
Caloric restriction has been shown to increase longevity in organisms
ranging from yeast to mammals. In some organisms, this has been
associated with a decreased fat mass and alterations in
insulin/insulin-like growth factor 1 (IGF-1) pathways. To further
explore these associations with enhanced longevity, we studied mice
with a fat-specific insulin receptor knockout (FIRKO). These animals
have reduced fat mass and are protected against age-related obesity
and its subsequent metabolic abnormalities, although their food intake
is normal. Both male and female FIRKO mice were found to have an
increase in mean life-span of ~134 days (18%), with parallel increases
in median and maximum life-spans. Thus, a reduction of fat mass
without caloric restriction can be associated with increased longevity
in mice, possibly through effects on insulin signaling.
1 Joslin Diabetes Center and Department of Medicine, Harvard Medical
School, One Joslin Place, Boston, MA, 02215 USA.
2 Department of Medicine, Beth Israel Deaconess Medical Center and
Harvard Medical School, Boston, MA, 02215 USA.
* To whom correspondence should be addressed. E-mail:
c.ronald.kahn@joslin.harvard.edu
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Longevity is dependent on many factors including genetics (1, 2),
hormonal and growth factor signaling (3, 4), body weight (5), body fat
content, and environmental factors (4, 6). Food restriction is the
most potent environmental variable and has been shown to increase
longevity in diverse organisms (6). The effect of restricted feeding
on life-span has been studied in rodents for more than 60 years
(7-10), and although some studies have suggested that reduced food
intake is more important than adiposity (8, 9), it is difficult to
separate the beneficial effect of caloric restriction from that of
leanness and the various biochemical correlates of leanness.
To investigate this question, we evaluated the life-span of the
fat-specific insulin receptor knockout (FIRKO) mouse. These animals
were derived by crossing insulin receptor IR (lox/+) mice, in which
exon 4 of the insulin receptor is flanked by loxP sites (11), with IR
(lox/+) mice that also express the Cre recombinase under the control
of the aP2 promoter/enhancer (12). This breeding strategy also
generated three littermate control groups: wild-type (WT), IR
(lox/lox), and aP2-Cre mice, which were indistinguishable with regard
to physiologic and metabolic parameters and have the same mixed
genetic background as the FIRKO mice. For the aging experiments, 250
animals were housed under the same conditions in a virus-free facility
on a 12-hour light/dark cycle and were given a standard rodent feed
and water ad libitum.
Growth curves were normal in male and female FIRKO mice from birth to
8 weeks of age. Starting at 3 months of age, FIRKO mice maintained 15
to 25% lower body weights and a 50 to 70% reduction in fat mass
throughout life (Fig. 1A). The reduction in adiposity was estimated by
perigonadal fat pad weight but was apparent in all fat depots and was
also reflected by a reduction of ~25% in total-body triglyceride
content (13). FIRKO mice are healthy, lack any of the metabolic
abnormalities associated with lipodystrophy, and are protected against
age-related deterioration in glucose tolerance, which is observed in
all control strains (13). FIRKO mice maintained low body fat, despite
normal food intake (Fig. 1B). Indeed, because FIRKO mice were leaner,
the food intake of FIRKO mice expressed per gram of body weight
actually exceeded that of controls by an average of 55% (Fig. 1C).
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Fig. 1. Age-related changes in fat pad mass per gram body weight (A),
food intake (B), and food intake per gram body weight in FIRKO mice
(C) (initial cohort, n = 40) and control littermates (initial cohort,
n = 20 per genotype). (A) We determined fat pad mass in animals killed
at each age by directly weighing perigonadal fat pads. There was no
difference in body weight or fat pad mass among the three control
genotypes [WT, IR (lox/lox), and aP2-Cre]. After the mice reached the
age of 3 months, the differences in fat pad mass per gram of body
weight were significant for all data points between FIRKO mice
(diamonds) and all three controls (squares) (P < 0.05). (B) In mice
caged singly, we determined food intake (gram per mouse per day) daily
over 5 days by using at least five FIRKO (white bars) and four control
mice (black bars) per genotype (n = 12). Data of the control genotypes
[WT, IR (lox/lox), and aP2-Cre] are plotted together in the black
bars, because there were no differences in daily food intake among
them. (C) Food intake per gram body weight--calculated from the food
intake and body weight data--was significantly increased in FIRKO mice
(white bars) as compared with controls (black bars) (P < 0.05). [View
Larger Version of this Image (21K GIF file)]
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The median life-span of most laboratory mice, such as BALB/c-nu (5) or
C57BL/6J (14), is 30 months. Consistent with this, we found that 45 to
54% of the mice in the control groups lived to 30 months of age. By
contrast, about 80% of the FIRKO mice were alive at this age (Fig.
2A). The increased survival of FIRKO mice was seen in both males and
females and was confirmed in two independent lines of mice. Complete
survival curves revealed that the mean life-span was increased by 134
days (from 753 to 887) or 18% (Fig. 2B). The median life-span in FIRKO
mice was also increased by 3.5 months (from 30 ± 0.6 months to 33.5
months), and the maximum life-span was extended by ~5 months. At 36
months, all mice in the control groups had died, whereas ~25% of the
FIRKO mice were still alive. The longest lived FIRKO mice died at the
age of 41 months. Further analysis of the survival plots (Fig. 2B)
with previously described mathematical models (15) revealed that
extended longevity in FIRKO mice is associated with both a shift in
the age at which the "age-dependent increase in mortality risk"
becomes appreciable and a decreased rate of age-related mortality,
especially after 36 months of age.
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Fig. 2. Extended life-span in FIRKO mice. (A) Percentage of mice
alive at 30 months of age. The median life-span of the three control
genotypes [WT, IR (lox/lox), aP2-Cre] was ~30 months. For this
analysis, the fraction of mice alive at 30 months from founder line 1
[WT (n = 34), IR (lox/lox) (n = 35), aP2-Cre (n = 30), and FIRKO (n =
32)] and from line 2 [WT (n = 33), IR (lox/lox) (n = 31), aP2-Cre (n =
27), and FIRKO (n = 28)] were pooled. Data for males and females were
also pooled, because they were similar in each of the groups. **P <
0.05. (B) Pooled survival curves for FIRKO mice derived from two
different aP2-Cre founder lines. We performed pair-wise comparisons
among genotypes for age-specific survival by log-rank test with
significance corrected for multiple tests. Median life-span in line 1
(n = 131) was FIRKO, 33.5 months; WT, 30.3 months; IR (lox/lox), 28.7
months; and aP2-Cre, 30.7 months. Among the control groups WT, IR
(lox/lox), and aP2-Cre, survival did not differ (P = 0.31), whereas
survival of FIRKO mice was significantly increased (P < 0.001). Median
life-span in line 2 (n = 119) was FIRKO, 33.4 months; WT, 29.8 months;
IR (lox/lox), 30.1 months; and aP2-Cre, 29.9 months. The maximum
longevity (average life-span of the 10% longest lived mice) was
significantly increased from 34.7 months in the controls to 39.5
months in FIRKO mice (P < 0.001). Among the control groups WT, IR
(lox/lox), and aP2-Cre, maximum life-span did not differ (P = 0.62).
The curves shown represent the pooled data from both of these lines.
[View Larger Version of this Image (15K GIF file)]
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The FIRKO mouse demonstrates the beneficial effects of reduced
adiposity on the extension of life-span in a setting where food intake
is normal or even increased relative to body weight. Caloric
restriction has been hypothesized to delay aging by decreasing
metabolism and the associated production of damaging oxygen free
radicals (16-19). In the nematode Caenorhabditis elegans (20) and the
fruit fly Drosophila melanogaster (21), slowing down mitochondrial
metabolism and metabolic rate appears to extend life expectancy.
However, in rodents, caloric restriction appears to extend life-span
without decreasing the metabolic rate (22, 23). In FIRKO mice, the
resistance to obesity, despite normal food intake, suggests that
metabolic rate is increased, rather than decreased (13). If free
radical damage is the important factor, then in the FIRKO mouse this
must be derived directly or indirectly from the decreased fat mass
rather than the diet. Another possibility is that the increased
longevity in FIRKO mice is the direct result of altered insulin
signaling. Mutations that reduce signaling through the insulin-like
signaling pathway can increase life expectancy in C. elegans (24-26)
and in Drosophila (27, 28), and these longevity mutations can be
reversed in some cases by additional activating mutations in the
insulin/IGF-1 signaling pathway. In both of these species, reduced
insulin-like signaling can extend life-span by 50% or more (20, 27,
28).
Although decreased insulin-like signaling appears to increase life
expectancy in invertebrates, whether the same is true in mammals or
humans is unclear. At least three genes have been identified (Pit1dw,
Prop1df, Ghr) in which loss-of-function mutations lead to dwarfism
with reduced levels of IGF-1 and insulin. These are associated with
increased longevity in mice (3, 4). On the other hand,
loss-of-function mutations in the insulin receptor, which lead to
severe insulin resistance (29-31), or even milder forms of insulin
resistance associated with diabetes and obesity (32, 33), result in
shortened life-span in both humans and mice. FIRKO mice have a
selective loss of insulin signaling in adipose tissue only, and this
is not associated with diabetes or glucose intolerance. Moreover,
FIRKO mice have normal to somewhat supernormal glucose tolerance and,
thus, may in some ways mimic caloric restriction, which is known to
extend life-span in rodents (10). Indeed, the phenotype of aging FIRKO
mice shows similarities with the phenotype of food-restricted mice,
such as reduced adiposity, trend to lower insulin levels, and
protection from decreased insulin sensitivity (13).
In summary, the results of our studies with FIRKO mice are consistent
with the view that leanness, not food restriction, is a key
contributor to extended longevity. The exact mechanism underlying this
effect requires further analysis.
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