Aging and Reactive oxygen Species

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• Aging and Reactive oxygen Species

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Aging What is it?

• Aging, has been termed generally as a progressive
  decline in the ability of a physiological process
  after the reproductive phase of life.

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Theories of aging

• Genetic theories
• Claim that aging is genetically determined
• Damage-accumulating theories
• Claim that aging is a result of accumulating
  cellular damage to proteins, membranes
• A possible cause of cellular damage could be
  reactive oxygen species.

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Genetic theories
Genetic theories of aging propose that aging is a
continuation of the process of development and
differentiation, and is a sequence of events
encoded into the genome. Some genes that alter
or regulate life span (age-1, LAG1, RAS1 and
RAS2) were identified in worm (C. elegans), fly
(Drosophila) and fungi (yeast and
Neurospora). Human disorders of premature aging
(e.g., Werners syndrome) were linked to specific
genes encoding, for example, enzymes such as
helicase. Aging was linked to the length of
telomeres and to telomerase activity in aging
cells. We will not discuss further the theory
of genetic aging in this presentation.
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Damage-accumulating theories
Damage-accumulating theories propose that aging
is caused by progressive accumulation of cellular
damage (different theories propose different
damages, see table below). The accumulation of
damaged molecules in cells is thought to result
over time due to failure of repair and
maintenance systems.
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Basis for The Free Radical Theory Pearl 1920s

• Pearl proposed The rate of living hypothesis.
• This hypothesis directly links the metabolic rate
  with the life expectancy of an organism.
• It suggested that there was a precise mechanism
  that linked metabolism with life span.
• The hypothesis stated that there is a vital
  cellular element that was somehow consumed at the
  same rate as the overall metabolic rate. When
  this unknown, vital element was exhausted death
  occurred.

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Many experimental evidences support the
metabolic-life span theory. The graph below shows
an example of an experiment performed with
housefly.
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Free Radical Theory of Aging Harman 1956

• Normal aging results from random deleterious
  damage to tissues by free radicals.
• Because many ROS are not radicals, the theory
  should be named The Oxidative Damage Theory of
  Aging

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• Oxidative damage A common link between all aging
  theories
• ROS are produced during normal metabolism.
  Studies have shown accumulated damage to DNA,
  protein and membrane.
• Enhanced ROS production may be a consequence of
  genes selected because they confer benefits in
  early life, however, would cause enhanced ROS
  production during aging.
• Deterioration of tissues with age may lead to
  increaser ROS production.
• Link to metabolic activity. Large animals consume
  less oxygen per unit of body mass than small
  animals and they live longer.
• Insects consume much more oxygen when flying than
  at rest and resting insects live longer (see
  Figure 1).
• Continue in next slide

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6. Most oxygen consumed by aerobic eukaryotes is
used in the mitochondria. Mitochondrial DNA
rapidly accumulates mutations with age. 7. Longer
lived organisms were found to contain more
efficient ROS scavenging systems (see correlation
table below).
Continue in next slide
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8. In certain species with similar metabolic
rates, but with different lifespans, the rate of
mitochondrial ROS production correlates with
longevity (decreased rate in longer lifespan
species). 9. Senescence can be induced by ROS
application to cells. 10. Caloric restriction in
rodents is associated with decreased level of
oxidative damage to DNA.
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Mitochondrial ROS generation appears to be a
common link in aging of different organisms
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Potential targets of ROS within cells that may
determine the rate of aging.
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Testing the hypothesis One way to test the
oxidative damage theory of aging is to apply
antioxidants. In lower organisms a positive
effect was found (see Figure below), however in
mammals the effects of antioxidants on aging are
very small or zero.
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Testing the hypothesis Another way to test the
hypothesis is to use transgenic
organisms. Experiments with transgenic organisms
are ongoing. Some evidance from Drosophila has
shown that overexpression of SOD and catalase
together improved lifespan by 30-40 and
decreased oxidative damage. Interestingly,
overexpression of SOD or catalase did not improve
lifespan. Extended lifespan mutants of C. elegans
show high tolerance to ROS. One of these mutants
(age-1) also shows enahnced expression of SOD and
catalase. It is possible that the extended life
mutations cause activation of ROS scavenging
mechanisms.
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Many different factors could affect ROS
metabolism. These could change due to genetic
alterations and could be linked to aging (see
table below).
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Conclusions The oxidative damage theory seems to
link all other aging theories. It holds for
now. The only experimentally proven treatment
that can improve lifespan in mammals (and most
likely humans) is restricted calorie intake!!!
This presentation is based on the following
book Halliwell B, Gutteridge JMC (1999) Free
radicals in biology and medicine. 3rd
Edition. Oxford University Press.