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Evidence From the Biological Mechanisms of Aging. Evolutionary Models Suggest
There Are Specific Interventions that Make It Possible to Extend Human Longevity. |
E-Newsletter No. 46
RESTRICTION of CALORIC INTAKE (CR)
CR extends longevity in organisms from yeast to mice, and postpones or prevents a
remarkable array of diseases and age-dependent deterioration, without causing irreversible
developmental or reproductive defects [(Sohal, Weindruch, Science 273, 59 (1996)].
By combining our knowledge of the molecular pathways that regulate longevity and CR, we
can begin to develop a novel strategy to prevent diseases such as cancer, Alzheimer's, and
vascular diseases.
The molecular pathways involved in the regulation of chronological life span were
identified at about the same time in yeast and worms. Similar to the life span of higher
eukaryotes, the yeast chronological life span is determined by measuring survival time.
However, aging in the unicellular yeast is also studied by measuring the number of buds
generated by an individual mother cell (replicative life span).
GENE SILENCING
The down regulation of glucose-dependent signaling by mutations in the RAS2, CYR1/PKA, or
SCH9 genes extends the yeast chronological life-span up to 300% and increases resistance
to oxidative stress and heat shock.
The down regulation of the CYR1/PKA pathways also extends the yeast replicative life span
by a mechanism dependent on the silencing protein SIR2. Chronological life-span extension
in yeast is mediated by stress-resistance transcription factors Msn 2 and Msn 4 and
mitochondrial superoxide dismutase.
In the worm, C. elegans, the down-regulation of the pathways that include DAF-2, AGE-1,
and AKT-1/AKT-2 proteins extends survival up to 300% and increases thermotolerance and
antioxidant defenses through stress resistance transcription factor DAF-16.
These yeast and worm "longevity pathways" share several homologous proteins,
including superoxide dismutase, catalase, heat shock proteins, and the serine threonine
kinases SCH9 (yeast) and AKT-1/AKT-2 (worm).
The conserved function of longevity genes is also supported by the role of a gene
homologous to yeast SIR2 in extending longevity in worms. Thus chronological longevity in
yeast and worms is extended by inactivation of pathways that promote growth and, by an
increase in protection against oxidative damage, and other forms of stress.
CONTROL, REPAIR And REPLACE OXIDATIVE DAMAGE
Systems that repair and replace damaged DNA, proteins, and lipids are also likely to play
a major role in extending survival.
Conserved genes also regulate longevity in fruit flies. Mutations that decrease the
activity of the fly insulin/IGF-I-like pathway cause dwarfism, but nearly doubles
longevity.
These mutations also increase the expression of SOD and the storage of nutrients.
The similarities between the yeast, worm and fly longevity regulatory pathways suggest
that portions of these pathways have evolved from common ancestors.
DOWN REGULATION OF INSULIN/IGF-I SIGNALING PATHWAYS
Because glucose and insulin/IGF-I signaling pathways are down-regulated in the absence of
nutrients, mutations in these pathways may simulate starvation conditions.
A decrease in IGF-I signaling may also extend longevity in mice. Mice homozygous for
mutations in the Prop-1 or Pit-1 genes are dwarfs, but live 25 to 65% longer than
wild-type. Prop-1or Pit-1 homozygotes are deficient in serum growth hormone, thyroid
stimulating hormone, and prolactin as well as for IGF-I, which is secreted by liver cells
upon stimulation with GH. The plasma GH deficiency appears to mediate the effects of
Prop-1 and Pit-1 mutations on longevity, because the mice that cannot release GH in
response to growth hormone releasing hormone also live longer.
Furthermore, dwarf mice with high plasma GH but a 90% lower IGF-1 [GH receptor binding
protein (GHR/BP) null mice] live longer than the wild-type mice.
Taken together, these studies suggest that the reduction in plasma IGF-1 is responsible
for a major portion of the life-span increase in dwarf, GH-deficient, and GHR/BP null
mice.
ENHANCE ADAPTATIONS TO STRESS
Mammals also exhibit an association between stress resistance and reduced IGF-1 signaling.
The activities of antioxidant enzymes such as superoxide dismutase and catalase are
decreased in murine hepatocytes exposed to GH or IGF-1 and in transgenic mice overexposing
GH.
In rats, IGF-1 attenuates cellular stress response and the expression of stress response
proteins heat shock protein 72 and homoxygenase.
The storage of fat or glycogen is another aspect of the stress response. In yeast, the
down-regulation of the RAS2/CYR1/PKA pathway (where PKA is protein kinase A) results in
the accumulation of glycogen, which is the major carbon source catabolized during periods
of starvation.
By contrast, in worms, flies and mice, the down-regulation of the insulin/IGF-1-like
pathways results in the accumulation of fat.
Dwarf mutations cause fat accumulation, which is reversed by administration of GH.
IGF-1 deficiency also increases fat accumulation in humans. (see "Human GH/IGF-1
Deficiency Diseases" section). In mammals, fat is the major carbon source during long
periods of starvation (hibernation), whereas glycogen provides glucose only during short
period of fasting.
Therefore, the switch between glycogen storage in yeast and fat storage in metazoans is
consistent with the role of longevity regulatory pathways in inducing accumulation of the
carbon source that would maximize long-term survival during period of starvation.
GH/IGF-1 and DISEASES in RODENTS
The ability of GH and IGF-1 to lower antioxidant defenses in hepatocytes, as described
above, indicates that IGF-1 can promote cellular damage and disease in mammals.
Thirty years ago, Silberberg [Patho.Microbiol. 38, 417 (1972)] showed that Pit-1 dwarf
mice, which are deficient in plasma GH and IGF-1, had less osteoarthritis than wild-type
mice.
Since then, high levels of IGF-1 have been associated with increased risk of several human
diseases including breast, lung, colorectum, and prostate cancer. IGF-1 appears to also
promote cancer in mice, as tumors in Pit-1 or Prop-1 dwarf mice are either reduced or
delayed.
Mice with elevated GH and IGF-1, instead exhibit severe kidney lesions and a much shorter
life span. Liver adenomas and carcinomas, as well as heart lesions, are common in older
mice that overexpress GH (although the GH levels are supraphysiological). The reduction of
plasma GH and IGF-1 may also have beneficial therapeutic effects in diabetic neuropathy.
The role of GH and IGF-I in age-dependent cognitive decline is unclear. Infusion of IGF-1
into the brains of old rats for 4 weeks partially reverses the age-dependent decline in
memory, but has no effect on sensory motor skills.
By contrast, Prop-1 dwarf mice show improved cognitive function compared with age-matched
normal mice. Further studies are needed on the role of plasma IGF-1 in cognitive decline
and neurodegenerative diseases.
HUMAN GH/IGF-1 and DISEASES
Diseases that result in either overproduction or reduction of plasma GH and/or IGF-1 can
be informative for developing therapies that prevent multiple are related diseases. Human
somatotroph adenomas of the pituitary gland can cause chronic secretion of excessive GH,
resulting in acromegaly, which is associated with a major life-shortening from
cardiovascular diseases and cancer.
Treatment of acromegaly with somatostatin analogues decreases GH and IGF-1, resulting in
clinical improvements. Although these studies imply a role for GH and IGF-1 in diseases of
aging, the abnormally high GH levels in acromegaly patients provide limited information on
the role of normal levels of GH in cancer and cardiovascular diseases.
The dwarf phenotype of long-lived yeast, flies, and mice suggest that it will be difficult
to extend human longevity without causing side effects. In fact, GH deficiency in humans
can lead to reduced life expectancy and is associated with increased fat mass, reduced
muscle and bone mass, behavioral problems, increased prevalence of hypertension, insulin
resistance, and premature atherosclerosis. Thus the changes that accompany fat
accumulation may counteract the putative beneficial effects of GH/IGF-1 deficiency in
humans.
The increased mortality is observed in GH deficient hypopituitary patients that, in most
cases, also lack adrenocorticotrophic hormone (ACTH). By contrast, human mutations
analogous to the Prop-1 mutations that extend longevity in rodents cause defects including
dwarfism, wrinkled skin, and intellectual deficiency, but do not appear to shorten life
span.
Among the rare Prop-1 patients for whom life-span data are available, several surpassed
the average life span, and one survived to age 91. Unlike most patients with GH
deficiency, humans with Prop-1 mutations do not lack ACTH, raising the possibility that
the increased mortality observed in hypopituitary patients is caused by ACTH and not GH
deficiency.
The human Laron Syndrome (LS) is caused by a deficit in the GH receptor and resembles GH
deficiency clinically and biochemically. Laron Syndrome is characterized by high GH, but
very low plasma IGF-1, very short stature, obesity, and impairments in physical and
intellectual development. Later in life, LS causes hypercholesterolemia and glucose
intolerance [Laron, J. Clin. Endocrinol. Metab. 84, 4397(1999)].
In summary, GH and IGF-1 deficiency in humans are associated with major defects and
diseases. However, the normal (and possibly longer) life-span of a few individuals with
mutations analogous to those that extend longevity in mice suggest that it may be possible
to extend human longevity by reducing plasma GH and IGF-1 levels.
Although studies in rodent models point to GH and IGF-1 as promoters of aging and
age-related diseases, GH is prescribed extensively as an antiaging hormone. GH treatment
can increase body mass and decrease adipose tissue in 61 to 81-year-old men with low
plasma IGF-1 concentration, and long-term GH replacement therapy causes some improvement
in patients with GH deficiencies. However, the "antiaging" effects of GH therapy
are typically observed after short-term treatment of patients with low plasma GH.
By contrast, chronically high GH levels increase the incidence of diseases, including
cancer and kidney diseases in rodents, and increased cardiovascular diseases and cancer in
human acromegaly patients. GH administration also increases the development of diabetes
and glucose intolerance in healthy older women and men [Blackman, JAMA 288, 2282(2002)],
and increases morbidity and mortality in patients that are clinically ill, even after
short-term treatment. It is clear that a major and chronic increase in plasma GH/IGF-1
levels increases morbidity and mortality.
DRUG TARGETS
These data summarized here suggest that three categories of drugs may have the potential
to prevent or postpone multiple age-related diseases; drugs that:
1. Simulate dwarf mutations and therefore decrease GH production by pituitary cells,
2. Prevent IGF-1 release from the liver, or
3. Decrease IGF-1 signaling by acting on either extracellular or intracellular targets.
The well-characterized yeast and worm "longevity"
pathways should provide templates for the identification of genes and drugs that regulate
longevity and diseases in mammals.
Concept diagram illustrates a path from basic genome data to a more detailed understanding of complex molecular and cellular systems, and the need to develop new computational analysis, and modeling and simulation capabilities to meet this goal. The points on the plot are very approximate, depending greatly on how each problem is abstracted and represented computationally. Research is under way to create the mathematics, algorithms, and computer architectures required to understand each level of biological complexity. |
MOLECULAR GENETICS IN CLINICAL PRACTICE
| Mechanistically based diagnostic criteria |
| Predisposition testing and screening |
| Rapid molecular diagnostic testing of pathogens |
| Pharmacogenetics |
| Identification of new drug targets |
| Tools for molecular medicine (for example, recombinant DNA methodology) |
| Gene therapy |
SCHEMATIC REPRESENTATION OF THE ACTION OF LIFE-SPAN-DETERMINING GENES ON MITOCHONDRIAL FUNCTION AND ROS FORMATION.
The dotted arrows represent actions that are likely but that have
not yet been formally demonstrated. |
Recent progress in the science of aging is driven largely by the use
of model systems, ranging from yeast and nematodes to mice. |
Evolutionary theory correctly asserts that aging is not an
adaptive trait, but that many organismal functions are bound to fail with time, because
none could have evolved to last indefinitely. However, the mechanisms of aging are
nonetheless more specific than previously thought.
The findings on life-span determination in C. elegans suggest that ROS (reactive oxygen
species) which are an inevitable consequence of life in an oxygen-rich world, are a
leading proximal cause of aging.
The results with SIR2 genes to silence the expression of other regulatory genes promotes
longevity by reducing toxic overproduction of ribosomal DNA repeats. This silencing
reduces gene expression and genomic instability in the nucleus. The results with SIR2
indicate that organisms have evolved ways to endure times of environmental stress, and so
have developed regulator processes that implement survival strategies.
Because organisms are not designed to last forever, and genetic changes are needed for
natural selection, is it possible that normal aging is caused, in part, by inadequately
repaired DNA damage? Genomic maintenance is necessary imperfect. Mutations in one or a few
of the possible hundreds of genes involved may increase its imperfect nature in a
tissue-specific manner, but might never completely mimic normal aging. Hence, the
accelerated aging symptoms in humans and mice with genetic defects in genome maintenance
strongly suggest that genomic instability, driven by oxidative damage further supports the
hypothesis of ROS damaging by-products being the primary cause of normal aging. Thus,
facilitating genetic or pharmacologic interventions that reduce oxidative damage to DNA,
promote DNA repair, or optimize the cellular responses to DNA damage appear to be the most
effective pathway to prolong healthy life ("health-span") and delay aging.
The physiological changes that allow for survival must impinge on the processes limiting
life span, in particular ROS production and detoxification. Life span, therefore, appears
to be regulated in these situations in spite of the fact that it is not the feature shaped
adaptively by natural selection.
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