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Several gene manipulations
can influence the lifespan (longevity). In some
rare cases such tricks with genes may increase
the longevity of the organism. But much more
often gene manipulation in fact decreases longevity.
We describe below some of the favorable cases
in which longevity is increased.
HGH acts mainly on the liver to generate IGF-1
(insulin-like growth factor, termed also somatomedin
C). And in turn IGH-1 acts on a variety of tissues
to stimulate proportional body growth.
Laron syndrome is a disorder
characterized by HGH-gene mutations in humans.
These individuals are stunted in growth (dwarfs)
because of their resistance to HGH action. A
similar "Laron syndrome" can be experimentally
demonstrated in mice.
First longevity model: After
disrupting the HGH gene in mice, Okada and Kopchick
(2001) showed that these animals have normal
birth weights. However, their growth rate lags
after a few days. By the age of three months,
these mice are approximately half the size of
their siblings. But, surprisingly, researchers
have found that these dwarf mice live significantly
longer than control mice (Cischigano et al.,
2000).
Second longevity model: This
result is similar to that found by Bartke et
al., (2000) who have shown that reduced HGH
levels promote longevity.
Based on these results, it
seems worthwhile to test HGH-antagonists as
an anti-aging drug. The most well-known antagonist
of the HGH receptors is Pegvisomant; others
are Trovert and Somavert.
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2005
Departamento de
Fisiologia, Facultad de Medicina, Valencia,
Spain.
Females live longer
than males in many mammalian species,
including humans. Mitochondria from
females produce approximately half the
amount of H(2)O(2) than males. We have
found that females behave as double
transgenics overexpressing both superoxide
dismutase and glutathione peroxidase.
This is due to oestrogens that act by
binding to the estrogen receptors and
subsequently activating the mitogen
activated protein (MAP) kinase and nuclear
factor kappa B (NF-kappaB) signalling
pathways. Phytoestrogens mimic the protective
effect of oestradiol using the same
signalling pathway. The critical importance
of upregulating antioxidant genes, by
hormonal and dietary manipulations,
in order to increase longevity is discussed.
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Program in Developmental
Biology, Baylor College of Medicine, Houston,
TX 77030, USA.
Fertility disorders
affect approximately 15% of individuals
worldwide. With the imminent completion
of the human and mouse genome sequence,
it will be more feasible to identify
the relevant genes underlying many fertility
disorders. Already, the mouse has been
utilized extensively as a genetic tool
for the dissection of gene function,
often providing significant insights
into the relationship between gene and
disease. In fact, there are over 200
mouse models that display reproductive
defects. However, the available mouse
mutant resources provide functional
information for a mere 10% of the total
number of genes in the mouse or human
genomes at best. The improvement of
available genome annotations together
with more powerful techniques to manipulate
the mouse genome provide substantial
improvements in our ability to identify
genes involved in reproduction, and
in the future will likely benefit patients
with fertility problems.
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2001
Department of Physiology,
School of Medicine, Southern Illinois
University, Carbondale, Illinois 62901,
USA.
National Institute on Aging, NIH Animal
Center, 16701 Elmer School Road, Poolesville,
Maryland 20837, USA.
University of Michigan, 1500 East Medical
Center Drive, Ann Arbor, Michigan 48109,
USA.
Gerontology Research Center, 5600 Nathan
Shock Drive, Baltimore, Maryland 21224,
USA.
Ames dwarf mice are
mutant mice that live about 50% longer
than their normal siblings because they
carry a 'longevity' gene, Prop1df, and
in some phenotypic respects they resemble
normal mice whose lifespan has been
extended by restricted food intake.
Here we investigate whether these factors
influence lifespan by similar or independent
mechanisms, by deliberately reducing
the number of calories consumed by Ames
dwarf mice. We show that calorie restriction
confers a further lifespan increase
in the dwarfs, indicating that the two
factors may act through different pathways.
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Department of Physiology,
Southern Illinois University School of
Medicine, Carbondale, IL 62901-6512, USA.
Mutant mice with a
combined deficiency of growth hormone
(GH), prolactin, and thyrotropin, and
knockout mice with GH resistance, live
longer than their normal siblings. The
extension of life span in these animals
is very large (up to 65%), reproducible,
and not limited to any particular genetic
background or husbandry conditions.
In addition to demonstrating that genes
control aging in mammals, these findings
suggest that GH actions, growth, and
body size may have important roles in
the determination of life span. We describe
the key phenotypic characteristics of
long-living mutant and knockout mice,
with an emphasis on those characteristics
that may be related to delayed aging
in these animals. We also address the
broader topic of the relationship between
GH, growth, maturation, body size, and
aging, and we attempt to reconcile the
well-publicized antiaging action of
GH with the evidence that suppression
of GH release or action can prolong
life.
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1998
Center on Aging,
National Opinion Research Center, University
of Chicago, IL 60637, USA.
The evolutionary theory of aging predicts
that the equilibrium gene frequency
for deleterious mutations should increase
with age at onset of mutation action
because of weaker (postponed) selection
against later-acting mutations. According
to this mutation accumulation hypothesis,
one would expect the genetic variability
for survival (additive genetic variance)
to increase with age. The ratio of additive
genetic variance to the observed phenotypic
variance (the heritability of longevity)
can be estimated most reliably as the
doubled slope of the regression line
for offspring life span on paternal
age at death. Thus, if longevity is
indeed determined by late-acting deleterious
mutations, one would expect this slope
to become steeper at higher paternal
ages. To test this prediction of evolutionary
theory of aging, we computerized and
analyzed the most reliable and accurate
genealogical data on longevity in European
royal and noble families. Offspring
longevity for each sex (8409 records
for males and 3741 records for females)
was considered as a dependent variable
in the multiple regression model and
as a function of three independent predictors:
paternal age at death (for estimation
of heritability of life span), paternal
age at reproduction (control for parental
age effects), and cohort life expectancy
(control for cohort and secular trends
and fluctuations). We found that the
regression slope for offspring longevity
as a function of paternal longevity
increases with paternal longevity, as
predicted by the evolutionary theory
of aging and by the mutation accumulation
hypothesis in particular.
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