Prolonged longevity of hypopituitary dwarf mice


Bartke, A.; Brown Borg, H.; Mattison, J.; Kinney, B.; Hauck, S.; Wright, C.

Experimental Gerontology 36(1): 21-28

2001


In two types of mutant dwarf mice, congenital deficiencies in pituitary function are associated with remarkably increased life expectancy. In this review, we will describe the key phenotypic characteristics of these animals, the evidence that they exhibit delayed aging, and the mechanisms that are suspected to account for their prolonged longevity.

Experimental
Gerontology
ELSEVIER
Experimental
Gerontology
36
(2001)
21-28
Mini-Review
www.elsevier.nl/locate/expgero
Prolonged
longevity
of
hypopituitary
dwarf
mice
A.
Bartke",
H.
Brown-Borg
b
,
J.
Mattison',
B.
Kinney
a
,
S.
Hauck
a
,
C.
Wright
a
'Department
of
Physiology,
Southern
Illinois
University
School
of
Medicine,
Carbondale,
IL
62901-6512,
USA
b
Department
of
Physiology,
University
of
North
Dakota
School
of
Medicine,
Edwin James
Research
Center,
501
N.
Columbia
Road,
Grand
Forks,
ND
58202-9037,
USA
`National
Institute
on
Aging,
NIH
Animal
Center,
Building
103,
1B06,
16701
Elmer
School
Road,
Poolesville,
MD
20837,
USA
Received
24
July
2000;
accepted
22
September
2000
Abstract
In
two
types
of
mutant
dwarf
mice,
congenital
deficiencies
in
pituitary
function
are
associated
with
remarkably
increased
life
expectancy.
In
this
review,
we
will
describe
the
key
phenotypic
characteristics
of
these
animals,
the
evidence
that
they
exhibit
delayed
aging,
and
the
mechanisms
that
are
suspected
to
account
for
their
prolonged
longevity.
©
2001
Elsevier
Science
Inc.
All
rights
reserved.
1.
Original
description,
mode
of
inheritance
and
key
endocrine
characteristics
In
1929,
Snell
reported
the
discovery
of
a
recessive
mutation
that
caused
hereditary
dwarfism
in
the
mouse
(Snell,
1929).
This
mutation
was
named
dwarf,
symbol
dw,
and
subsequently
became
known
as
Snell
dwarf.
The
affected
animals,
homozygous
for
this
mutation
(dw/dw),
were
of
normal
size
at
birth
but
grew
slowly
and
reached
only
a
fraction
(approximately
1/3
by
weight)
of
normal
adult
body
size.
Subsequent
studies
by
many
investigators
provided
evidence
that
the
anterior pituitary
of
Snell
dwarf
mice
is
under-
developed
and
devoid
of
cells
producing
the
growth
hormone
(GH),
prolactin
(PRL)
and
thyroid
stimulating
hormone
(TSH)
(reviews
in
Grtineberg,
1952;
Bartke,
1979a,b).
By
performing
reciprocal
transplants
of
pituitaries
between
normal
and
Snell
dwarf
mice,
Carsner
and
Rennels
(1960)
succeeded
in
demonstrating
that
absence
of
GH
secretion
in
the
Snell
dwarf
mice
was
due
to
a
primary
pituitary
defect
rather
than
hypothalamic
dysfunction.
Studies
in
the
laboratories
of
Karin
(Theill
and
Karin,
1993)
and
Rosenfeld
(Li
et
al.,
1990)
led
to
the
identification
of
a
homeotic
gene,
pituitary-1
(pit-1),
which
is
*
Corresponding
author.
Tel.:
+1-618-453-1512;
fax:
+1-618-453-1517.
E-mail
address:
abartke@som.siu.edu
(A.
Bartke).
0531-5565/01/$
-
see
front
matter
©
2001
Elsevier
Science
Inc.
All
rights
reserved.
P11:
S0531-5565(00)00205-9
22
A.
Bartke
et
al.
/Experimental
Gerontology
36
(2001)
21-28
responsible
for
differentiation
of
somatotrophs,
lactotrophs
and
thyrotrophs
(cells
produ-
cing
GH,
PRL
and
TSH,
respectively)
during
fetal
development
of
the
pituitary
and
to
the
demonstration
that
the
Snell
dwarfism
is
due
to
a
mutation
at
the
pit-1
locus.
Failure
to
produce
pit-1
protein
in
dw/dw
mice
is
responsible
for
defects
of
endocrine
function
in
these
animals
(Li
et
al.,
1990).
In
1961,
Schaible
and
Gowen
reported
discovery
of
another
recessive
mutant
causing
hereditary
dwarfism
in
the
mouse
and
named
it
Ames
dwarf,
symbol
df
(Schaible
and
Gowen,
1961).
This
mutation
is
located
on
a
different
chromosome
than
Snell
dwarfism
(chromosome
11
rather
than
16),
but
apparently
produces
the
same
defects
in
pituitary
development
and
thus
an
identical
phenotype.
Some
differences
between
the
Ames
and
Snell
dwarf
mice
in
the
cytology
of
their
pituitaries
have
been
described
(Gage
et
al.,
1996),
but
both
mutants
appear
to
exhibit
complete
GH,
PRL
and
TSH
deficiency.
In
1996,
Sornson
et
al.
reported
that
the
Ames
dwarfism
is
due
to
mutation
of
a
gene
that,
in
the
course
of
the
normal
development
of
mouse
pituitary,
is
expressed
approximately
one
day
earlier
than
pit-1
and
is
responsible
for
development
of
pit-1
positive
cells.
This
gene
was
named
Prophet
of
pit-1,
Prop-1,
and
thus
the
Ames
dwarfs
are
homozygous
mutants
at
the
Prop-1
locus
(Sornson
et
al.,
1996).
2.
Breeding
and
husbandry
of
dwarf
mice
Homozygous
Snell
(dw/dw)
and
Ames
(df/df)
dwarf
mice
are
usually
infertile
(details
below),
but
can
be
readily
produced
by
mating
heterozygous
carriers
of
these
genes.
According
to
the
Mendelian
recessive
inheritance,
mating
of
two
heterozygotes
(e.g.
df/+
x
df/+)
produces
25%
of
homozygous
(df/df)
animals
among
the
progeny.
The
remaining
animals
are
phenotypically
normal
but
2
out
of
3
are
heterozygous
for
the
df
gene.
Female
dwarfs
(both
dw/dw
and
df/df)
are
infertile
due
to
PRL
deficiency
and
the
resulting
failure
of
luteal
function,
and
can
reproduce
only
when
PRL
replacement
is
provided
by
means
of
daily
injections
or
transplants
of
normal
pituitaries
under
the
kidney
capsule
(review
in
Bartke,
1979b,
2000).
Most
of
the
male
dwarfs
are
also
infertile,
although,
depending
on
their
genetic
background,
an
occasional
male
can
sire
a
few
litters.
Fertility
in
male
dwarfs
can
be
induced
by
treatment
with
GH,
PRL
or
thyroxine.
When
fertile
dwarf
males
are
mated
with
heterozygous
females,
half
of
the
progeny
is
dwarf.
All-dwarf
litters
can
be
produced
by
mating
hormone-treated
male
and
female
dwarfs
(reviewed
in
Bartke,
1979b,
2000).
As
was
mentioned
earlier
in
this
review,
dwarf
mice
appear
normal
at
birth,
but
soon
afterwards
their
growth
rate
begins
to
be
reduced
and
between
the
ages
of
10-14
days
they
can
be
distinguished
from
their
normal
siblings
by
smaller
size,
delayed
eye
opening
and
altered
head
shape.
The
Snell
and
Ames
dwarf
mice
do
not
require
any
special
housing
or
husbandry
conditions
with
the
following
exceptions:
first,
they may
not
thrive
if
weaned
at
the
age
of
21
days
(the
usual
age
of
weaning
normal
mice)
and
thus
should
remain
with
the
dam
for
a
longer
period.
This
is
particularly
helpful
if
the
dam
had
mated
during
postpartum
estrus
and
the
dwarfs
can
remain
with
her
for
the
second
lactation.
Second,
these
tiny
animals
appear
to
benefit
from
being
group
rather
than
single
housed
and
it
is
A.
Bartke
et
al.
/Experimental
Gerontology
36
(2001)
21-28
23
recommended
to
place
them
after
weaning
or
with
normal
female
animals
or
with
other
dwarfs.
3.
Longevity
of
dwarf
mice
As
was
mentioned
at
the
onset
of
this
chapter,
the
life
span
of
the
Ames
and
Snell
dwarf
mice
is
substantially
longer
than
the
life
span
of
their
phenotypically
normal
(homozygous
+/+,
or
heterozygous
+/df
or
+/dw)
siblings.
Prolonged
survival
of
the
Ames
dwarf
mice
was
reported
by
Brown-Borg
and
her
colleagues
in
1996
(Brown-Borg
et
al.,
1996).
The
longevity
of
Snell
dwarf
mice
was
a
subject
of
some
early
controversy
(reviewed
in
Bartke,
2000),
but
increased
life
span
of
these
animals
was
mentioned
as
early
as
1972
(Silberberg,
1972)
and
was
recently
demonstrated
conclusively
(Miller,
1999;
Flurkey
and
Harrison,
personal
communication).
The
mean
age
at
death
of
dwarf
mice
exceeds
the
corresponding
value
in
the
normal
controls
by
40-65%,
depending
primarily
on
gender
and
genetic
background
(Brown-Borg
et
al.,
1996;
Miller,
1999).
Both
the
average
and
the
maximal
life
span
are
significantly
greater
in
dwarfs
than
in
normal
mice,
and
the
slopes
of
survival
curves
are
parallel
in
dwarf
and
normal
mice
(Brown-Borg
et
al.,
1996;
Miller,
1999;
Fig.
1).
Therefore,
it
can
be
concluded
that
the
extension
of
life
span
in
dwarf
mice
is
associated
with,
and
most
likely,
due
to
delayed
aging.
Additional
support
for
this
conclusion
is
provided
by
results
of
longitudinal
studies
of
various
physiological
and
behavioral
characteristics
of
these
animals
(Mattison
et
al.,
2000;
Kinney
and
Bartke,
unpublished
observations).
It
is
of
interest
to
point
out
that
the
magnitude
of
the
exten-
sion
of
life
in
dwarf
as
compared
to
normal
mice
is
at
least as
great
as
the
maximal
life
extension
that
can
be
achieved
in
genetically
normal
animals
by
caloric
restriction.
Caloric
restriction
is
the
only
well-documented
method
of
delaying
aging
and
prolonging
life
span
in
mammals
and
thus
has
become
the
"gold
standard"
of
gerontological
research.
1.0
0.8
0.6
0.4
--‘
1
4
0.0
0.2
--e—
dvildw
1
I
---
Controls
0
10
20
30
40
50
60
Months
of
Age
to
0.4
0.2
—a—
Control
dfldf
0.0
0
5
10
15
20
25
30
35
40
45
50
55
Age
(Months)
Fig.
1.
Survival
plots
of
dwarf
mice.
Left
panel:
Snell
dwarf
mice
and
normal
controls
(reproduced
with
permission
from
Miller,
1999);
Right
panel:
Ames
dwarf
mice
and
normal
controls
(recalculated
from
data
published
by
Brown-Borg
et
al.,
1996).
The
graphs
show
proportion
of
animals
remaining
alive
(survival)
within
the
group
calculated
after
death
of
individual
animals.
24
A.
Bartke
et
al.
/Experimental
Gerontology
36
(2001)
21-28
4.
Phenotypic
characteristics
As
can
be
expected
from
the
multitude
of
important
physiological
actions
of
GH,
PRL
and
thyroid
hormones,
combined
deficiency
of
GH,
PRL
and
TSH
produces
profound
alterations
of
the
phenotype.
Phenotypic
characteristics
of
dwarf
mice
that
have
been
proposed
or
can
be
suspected
to
contributed
to
their
prolonged
longevity
are
listed
below.
4.1.
Anti-oxidant
enzymes
Activity
of
catalase
(CAT)
are
significantly
elevated
in
the
liver
and
kidney
of
Ames
dwarf
mice
as
compared
to
age-
and
sex-matched
normal
animals
from
the
same
strain
(Bartke
et
al.,
1998;
Brown-Borg
and
Rakoczy,
2000).
Moreover,
hypothalamic
activity
of
CAT
and
Cu/Zn
superoxide
dismutase
(SOD)
are
elevated
in
Ames
dwarf
compared
to
normal
mice
(Hauck
and
Bartke,
2000).
In
as
much
as
damage
of
cellular
components
by
reactive
oxygen
species
(ROS)
are
believed
to
be
an
important
and
perhaps
a
key
mechan-
ism
of
aging,
increased
activity
of
CAT
and
SOD,
which
are
involved
in
removing
ROS,
stand
out
as
a
very
likely
mechanism
of
prolonged
longevity
of
dwarf
mice.
In
support
of
this
possibility,
there
is
some
evidence
for
reduced
oxidative
damage
in
the
Ames
dwarf
vs.
normal
mice
(Bartke
et
al.,
1998;
Carlson
et
al.,
1999;
Brown-Borg
and
Rakoczy,
2000).
To
address
the
functional
significance
of
enhanced
activity
of
anti-oxidant
enzymes
in
the
Ames
dwarf
mice,
we
have
examined
their
ability
to
survive
exposure
to
Paraquat,
a
herbicide
producing
toxicity
due
to
oxidative
stress.
After
receiving
a
single
intraperito-
neal
dose
of
75
mg
of
Paraquat
per
kg
body
weight,
Ames
dwarfs
survived
significantly
longer
than
normal
mice
(Bartke,
Hauck
and
Wright,
unpublished
observations).
4.2.
Body
temperature
and
metabolic
rate
Twenty-four
hour
telemetric
recording
of
body
core
temperature
(T
c
.)
in
the
Ames
dwarf
and
normal
mice
equipped
with
implantable
transmitters
revealed
that
T
is
markedly
reduced
in
the
dwarfs
(Hunter
et
al.,
1999).
The
difference
between
the
dwarfs
and
normal
mice
averaged
1.5°C
and
persisted
under
conditions
known
to
reduce
or
increase
T
eo
(Hunter
et
al.,
1999).
Metabolic
rate
in
Snell
dwarf
mice
was
measured
and
was
found
to
be
significantly
reduced
(Griineberg,
1952).
Reduction
of
T
and
metabolic
rate
in
dwarf
mice
is
consistent
with
primary
TSH
deficiency
and
the
resulting
hypothyr-
oidism.
Deficiency
of
GH
could
also
contributes
to
these
findings
because
GH
exerts
both
anabolic
and
calorigenic
effects.
However,
food
consumption
of
the
Ames
dwarf
mice,
adjusted
per
gram
of
body
weight,
is
increased
rather
than
reduced
(Mattison
et
al.,
2000).
This
apparent
discrepancy
could
be
due
to
increased
heat
loss
due
to
larger
surface
mass
ratio
of
these
tiny
animals
or
to
reduced
efficiency
of
food
utilization
in
dwarf
vs.
normal
mice.
Although
there
is
no
clear
or
consistent
relationship
between
metabolic
rate
and
aging
in
homeothermic
("warm-blooded")
animals,
reduced
metabolism
of
dwarf
mice
can
contri-
bute
to
their
longevity
by
reducing
production
of
ROS
or
by
other
mechanisms.
A.
Bartke
et
al.
/Experimental
Gerontology
36
(2001)
21-28
25
4.3.
Regulation
of
plasma
glucose
levels
Plasma
glucose
levels
are
significantly
lower
in
the
Ames
dwarf
than
in
the
normal
mice
(Borg
et
al.,
1995).
This
was
observed
in
animals
with
unrestricted
access
to
food
(Borg
et
al.,
1995)
and
also
after
overnight
fast
(Turyn
and
Bartke,
unpublished).
Plasma
insulin
levels
are
reduced
in
fasted
Ames
dwarf
mice
(Turyn
and
Bartke,
unpublished)
and
in
ad
libitium
fed
male
dwarfs
(Borg
et
al.,
1995).
Concomitant
reduction
in
peripheral
levels
of
glucose
and
insulin
implied enhanced
insulin
sensitivity
and,
indeed,
the
suppressive
effect
of
a
single
large
dose
of
insulin
on
plasma
glucose
levels
was
significantly
greater
in
dwarf
than
in
normal
mice
(Mattison,
Pazo
and
Bartke,
unpublished).
We
believe
that
increased
sensitivity
of
Ames
dwarf
mice
to
insulin
is
primarily
due
to
deficiency
of
GH
because
animals
with
isolated
GH
resistance
due
to
targeted
disruption
("knock-out")
of
the
GH
receptor/GH
binding
protein
gene
are
extremely
insulin
sensitive
(Coschigano
et
al.,
2000,
and
personal
communication),
while
transgenic
mice
overexpressing
GH
are
insulin
resis-
tant
(Dominici
et
al.,
1999).
Increased
insulin
sensitivity
and
reduced
plasma
glucose
levels
in
Ames
dwarf
mice
are
probably
not
related
to
alterations
in
glucocorticoid
or
leptin
signaling.
Basal
plasma
corticosterone
levels
are
not
altered
in
females
and
increased
in
males
(Borg
et
al.,
1995),
and
we
did
not
detect
alterations
in
plasma
leptin
levels
except
for
a
reduction
in
middle-aged
female
dwarfs
in
comparison
to
age-matched
normal
females
(Mattison
and
Bartke,
unpublished).
Reduced
plasma
glucose
levels
in
Ames
dwarf
mice
are
very
likely
to
contribute
to
delayed
aging
and
prolonged
longevity
of
these
animals.
Nonenzymatic
glycation
of
proteins
is
believed
to
represent
an
important
mechanism
of
aging,
and
association
of
hyperglycemia
with
reduced
life
expectancy
is
very
well
documented.
4.4.
Growth
hormone
deficiency
The
most
striking
phenotypic
characteristics
of
the
Ames
and
Snell
dwarf
mice
include
suppression
of
postnatal
growth
and
adult
body
size
consequent
to
primary
deficiency
of
GH
and
reduced
peripheral
levels
of
IGF-I
(Holder
et
al.,
1980;
Chandrashekar
and
Bartke,
1993).
We
believe
that
absence
of
GH
signaling
in
dwarf
mice
is
a
major,
and
most
likely
the
key
reason
for
extension
of
their
life
span.
In
support
of
this
possibility,
significant
extension
of
life
span
was
recently
reported
in
mice
with
targeted
disruption
of
the
GH
receptor/GH
binding
protein
gene,
which
leads
to
GH
resistance,
suppression
of
plasma
IGF-I
levels,
and
approximately
50%
reduction
in
adult
body
size
(Coschigano
et
al.,
2000).
In
these
GH
receptor
"knock-out"
(GH-R-KO)
mice,
deficiency
of
GH
signaling
is
the
only
primary
genetic
defect,
prolactin
levels
are
increased
rather
than
reduced
(Chandrashekar
et
al.,
1999;
and
unpublished
observations),
both
females
and
males
are
fertile,
and
hypothyroidism
is
mild
(Hauck
and
Bartke,
unpublished),
and
presumably
secondary
to
GH/IGF-I
deficiency.
Thus,
findings
in
GH-R-KO
mice
indicate
that
disrup-
tion
of
GH
signaling
is
sufficient
to
delay
aging
(Kinney
and
Bartke,
unpublished
obser-
vations)
and
prolong
life.
In
further
support
of
the
inverse
relationship
between
GH
signaling
and
life
span,
transgenic
mice
overexpressing
GH
live
shorter
than
normal
26
A.
Bartke
et
al.
/Experimental
Gerontology
36
(2001)
21-28
mice
and
exhibit
numerous
symptoms
of
premature
aging
(reviewed
in
Bartke
et
al.,
1998).
Mechanisms
linking
suppression
of
GH
signaling
and
delayed
aging
remain
to
be
elucidated.
They
are
likely
to
include
increased
sensitivity
of
plasma
glucose
levels
to
insulin,
which
was
discussed
earlier
in
this
chapter,
reduced
number
of
cell
divisions
(Winick
and
Grant,
1968),
which
presumably
decreases
the
opportunities
for
ROS-
induced
damage
and
somatic
mutations,
and
reduced
risk
of
developing
neoplastic
lesions.
The
important
role
of
IGF-I
in
tumorigenesis
and
stimulation
of
tumor
growth
is
suggested
by
both
epidemiological
and
in
vitro
studies.
Small
body
size
correlates
with
increased
life
expectancy
in
mice
(review
in
Bartke
et
al.,
1998),
dogs
(Patronek
et
al.,
1997),
and
other
species,
apparently
including
the
human
(Samaras
et
al.,
1999).
One
of
the
suggested
mechanisms
for
this
association
is
improved
efficiency
of
the
cardiovascular
system
and
reduced
cardiac
work
load
in
small
individuals
(Samaras
et
al.,
1999).
Thus,
diminutive
size
of
dwarf
mice
may
confer
longevity
advantage
in
these
animals.
5.
Other
potential
mechanisms
of
delayed
aging
in
hypopituitary
dwarf
mice
In
addition
to
the
mechanisms
already
mentioned,
hypopthyroidism,
hypoprolactin-
emia,
delayed
sexual
maturation
and
hypogonadism
may
contribute
to
delayed
aging
of
the
Ames
and
Snell
dwarf
mice.
However,
prolonged
longevity
of
GH-R-KO
mice,
which
are
mildly
hyper-
rather
than
hypoprolactinemic,
fertile,
and
only
mildly
hypothyroid
(details
and
references
earlier
in
this
chapter),
suggests
that
the
role
of
these
phenotypic
characteristics
of
dwarf
mice
is
probably
minor.
We
are
currently
using
microarray
tech-
nology
to
identify
genes
with
altered
levels
of
expression
in
the
Ames
dwarf
as
compared
to
normal
mice.
6.
Conclusions
The
impressive
extension
of
life
span
in
the
mouse
by
a
loss-of-function
mutation
at
a
single
locus
provides
novel
models
for
the
study
of
mechanisms
of
aging
in
mammals.
The
results
available
to
date
suggest
that
alterations
in
hormonal signaling
mediate
genetic
effects
of
the
corresponding
genes
on
longevity
and
thus
are
likely
to
be
involved
in
genetic
programming
of
aging
and
life
span.
Preliminary
evidence
of
prolonged
long-
evity
in
humans
with
hypopituitarism
caused
by
a
mutation
at
the
Prop-1
locus,
the
same
locus
which
is
mutated
in
the
Ames
dwarf
mice
(Krzisnik
et
al.,
1999),
suggests
that
results
obtained
in
hereditary
dwarf
mice
may
apply
to
man
and
other
species.
The
association
of
reduced
growth,
maturation,
and
fertility
with
prolonged
longevity
appears
counterintuitive
but
is
consistent
with
findings
in
calorically
restricted
animals
and
with
data
derived
from
animals
selected
for
differences
in
body
size
(reviewed
in
Bartke
et
al.,
1998;
Bartke,
2000).
It
would
appear
that
the
normal
rates
of
growth
and
sexual
maturation,
as
well
as
attainment
of
normal
stature
and
reproductive
potential
may
incur
significant
"costs"
in
terms
of
aging
and
life
expectancy.
Consequently,
suppression
of
growth
and
maturation
by
genetic
mutations,
gene
knock-out,
or
caloric
restriction
can
A.
Bartke
et
al.
I
Experimental
Gerontology
36
(2001)
21-28
27
prolong
life,
while
acceleration
of
these
processes
by
overexpression
of
GH and
probably
also
by
excessive
nutrition
can
shorten
life.
Acknowledgements
Our
studies
were
supported
by
NIH,
by
the
Illinois
Council
for
Food
and
Agricultural
Research,
by
the
Fraternal
Order
of
the
Eagles,
and
by
institutional
funds.
We
apologize
to
those
whose
work
pertinent
to
this
topic
was
not
cited
due
to
limitations
imposed
by
the
format
of
this
Mini
Review
or
to
inadvertent
omissions.
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