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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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