Antioxidants
An
antioxidant is any substance that can delay or prevent the
oxidation of a substrate when it is present in small amounts
relative to the amount of substrate. There may be multiple
mechanisms involved at different levels of the oxidative
sequence, but essentially an antioxidant's role is to intercept
a free radical before it can react with a substrate.
The
most damaging effects of oxygen toxicity is the formation
of free radicals - these cause oxidative stress. Free radicals
are defined as any species capable of independent existence
that contains one or more unpaired electrons. They can also
be formed by loss or gain of an electron.
The
longer we live, the more our cells become damaged by oxygen
toxicity, so the secret to slowing aging must lie with preventing
this process. The human lifespan has increased from 40-75
years over 400 years, but the lifespan potential (LSP) has
not - the longest people live is still about 100 years.
Do our genes predestine us to die at a certain lifespan?
There are two theories which answer this question. The Death
Gene Theory says we are genetically controlled to limit
cell growth. The Homeostatic Theory says that our oxidative
defences break down with age due to the genetically programmed
reduction in synthesis of antioxidants and reduced absorption
of dietary antioxidants.
Reactive
Oxygen Species and Oxidative Damage
Reactive
Oxygen Species (ROS) are produced by reducing molecular
oxygen. They detoxify invading organisms and chemicals.
However, stray ROS initiate lipid peroxidation in healthy
cells leading to Alzheimer's, atherosclerosis, cancer, diabetes
etc. Normal antioxidant defences generally protect against
these occurring, however as the antioxidant defences decrease
with age, oxidation increases, as does the enzyme activity
creating ROS - therefore diseases of old age occur. The
rates of free radical generation also increase with disease,
so antioxidant activity is even more important here.
Measuring
oxidative damage can be done in several ways. It can be
assessed by looking at oxidative DNA damage; levels of antioxidant
enzymes such as catalase, SOD and glutathione peroxidase;
levels of antioxidants and vitamins such as betacarotene,
C, E, flavonoids and phenolics; oxidative damage to lipids
and oxidative damage to proteins. There is an inverse correlation
between oxidative damage and plasma antioxidant levels of
vitamin C and E for example.
Antioxidant
Function
The
correlation between metabolic rate and rate of aging is
measured by the oxidation of products. The rate of oxygen
consumption per unit of body weight is inversely related
to Life Span Potential. Levels of Super Oxide Dismutase,
Gluthathione Peroxidase and vitamin E are potent antioxidants
that correlate with Life Span Potential, and these antioxidants
plus others show an important interdependence in reactions.
SOD removes O 2 - by accelerating it to H 2 O 2, and catalases
convert H 2 O 2 into water and O 2. Glutathione peroxidase
removes H 2 O 2 by using it to oxidize reduced glutathione
to oxidized glutathione - and this is dependent on co-operation
between catalase and glutathione peroxidase. Vitamin E is
considered the best lipid-soluble antioxidant because it
delays lipid peroxidation by reacting with chain propogating
peroxyl radicals faster than these radicals can react with
proteins or fatty acid side chains to produce a less reactive
vitamin E radical. Vitamin C regenerates this radical back
to alpha-tocopherol. Beta-Carotene is another that is known
to improve longevity.
Flavonoids
and phenols in plants scavenge peroxyl radicals, protect
against lipid peroxidation and limit breakdown of membrane
lipids. They also control the release of ROS from macrophages
and neutrophils. The flavonoid content of red wine may explain
the French Paradox, where a high fat intake is associated
with low cardiovascular disease - the flavonoids inhibit
LDL oxidation in the arteries, and may even protect against
the negative effects of a high dairy fat diet. Phenolics
found in fruits and vegetables in the Mediterranean Diet
also support the French Paradox - these antioxidants are
in biochemical equilibrium. Catechins are other antioxidants
found in red wine, chocolate and green tea (EGCG).
Antioxidants
inhibit radical chain oxidation of lipids in several ways.
- They
interrupt lipid oxidation cycles by chain-breaking the
carbon-hydrogen bonds by either donating a hydrogen or
electron from a peroxyl radical, or accepting a hydrogen
or electron from an alkyl radical. The most important
donating antioxidants are alpha-tocopherol and ubiquinol
in lipids and ascorbic acids in serum.
- The
main antioxidant role of ascorbic acid is for regenerating
alpha-tocopherol. In the presence of ascorbic acid, alpha-tocopherol
concentration remains constant. This is why ascorbic acid
is not directly correlated with Lifespan Potential, but
it is depleted under oxidative stress. Ascorbic acid also
detoxifies carcinogenic nitrosamines in cooked meat and
scavenges oxides of nitrogen, ozone, vehicle exhaust and
cigarettes.
- The
initiation of lipid peroxidation is susceptible to inhibition
by preventative antioxidants that remove or prevent formation
of initiating radicals. Singlet oxygen is a highly reactive
ROS, and betacarotene's main role is to quench these.
The most important preventative antioxidants are peroxide-decomposing
enzymes - catalase and glutathione peroxidase which remove
hydrogen peroxide and alkyl hydroperoxides.
- The
synergistic action of antioxidants is important - they
each act by different mechanisms
Lipid
Peroxidation
Lipid
peroxidation occurs in the phospholipids of the cell membrane.
The fatty acids can shift or lose their double-bonds and
oxygen molecules may bind to a different carbon molecule
from the one that lost the hydrogen. A basic summary of
the lipid peroxidation process:
- Initiation
of peroxidation
- Molecular
rearrangement
- Oxygen
- Lipid
peroxy radical
- Oxidation
of cholesterol
- Lipid
hydroperoxide plus a new carbon-centered radical that
continues with this reaction
Why
is lipid peroxidation so bad? It damages the cell membrane
which decreases membrane fluidity. This can increase the
leakiness of the protective membrane, which allows species
to cross the membrane. It also inactivates membrane-bound
enzymes, and the membrane may also rupture and lysozymes
spill out. Lipid peroxidation also inhibits red blood cell's
ability to migrate through capillaries; disrupts mitochondrial
electron transport and activates arachidonic acid metabolism.
Lipid peroxidation is also an important issue for the food
industry, and antioxidants maintain nutritional quality
for shelf life.
Atherogenesis
Once
lipid peroxidation of LDL has occurred in the subendothelial
space, it activates the expression of MCP1 and MCSF. These
allow the entry into the cell and maturation of monocytes
to macrophages. Further LDL oxidation results from these.
Oxidised LDL is recognized by the scavenger receptor of
macrophages and foam cells occur. This results in endothelial
dysfunction and encourages platelets to stick to the arterial
walls - triggering the atherosclerosis process.
Antioxidants
and Cancer
The
human diet contains natural carcinogens and chemoprotective
agents. Most are blocking agents which prevent tumour initiation.
Examples are CYP enzyme inhibitors which prevent conversion
of precarcinogens to carcinogens that damage DNA, protein
and lipids; and Phase II detoxifying enzyme inducers. Suppressing
antioxidants inhibit tumour development from initiated cells.
Flavonoids
are known to inhibit carcinogen-induced cancer of the skin,
lung, stomach oesophagus, duodenum and colon in rodents,
and green tea is protective against a similar variety of
human cancers. The proposed mechanisms of action of flavonoids
for cancer are that they prevent an inflammatory response
in tumours; they form inactive complexes with carcinogens;
they inhibit metabolic activation of carcinogens; they stimulate
immune response; and they have antioxidant free radical
scavenging activity. Flavonoids are highly active and undergo
fast electron transfer to repair DNA radicals, which reduces
strand breaks and base damage. Flavonoids can still act
as antioxidants in low concentrations when vitamin C is
present for redox recycling.
Some
antioxidants and protective herbs have been shown to be
both chemoprotective and carcinogenic and pro-oxidant at
different concentrations. The chemoprotective role is only
effective at certain stages of carcinogenesis and is detrimental
in others. Chemoprotective agents are enzyme modulators,
antioxidants, inhibitors of carcinogen-adduct formation,
inhibitors of oncogene activation and modulators of signaling
cascades. Further research is required to ascertain the
total safety of antioxidants and where the carcinogenic
level is.
The
maintenance of dietary flavonoids may reduce certain cancers.
Antioxidants in apples have been used to treat colon cancer
cell lines and show strong inhibition of tumour proliferation.
This could be due to the phytochemical combination of phenolics
and flavonoids in apples, and eating the whole fruit may
provide the correct balance to quench ROS.
Antioxidant
Supplements
There
is growing evidence that taking antioxidant supplements
may prevent disease, but it is unclear whether it extends
Life Span Potential. Supplementing with single antioxidants
may be counter productive because it may result in less
efficient control of oxidation with an imbalance of nutrients.
Supplements should be a combination of chain-breaking and
preventative antioxidants. Alpha-tocopherol (vitamin E)
is a particularly useful antioxidant as it makes up an integral
part of the lipid bi-layer forming the outer membrane of
the cell, so it can prevent free radical damage before they
enter the cell. Even if it is not possible to extend lifespan,
research should attempt to control oxidative cell damage
to reduce the diseases of old age and improve quality of
life for the elderly.
- Info
summarized from R. Anderson lecture, University of Auckland
Medical School September 2003
- Antioxidants,
the Modern Elixir? Gerald Scott, Chemistry in Britain
Nov 1995
- Eat,
Drink and be Healthy, Okezie Aruoma, Chemistry in Britain
April 1996
- Searching
for the Fountain of Youth, James Wright, Chemistry in
Britain Feb 2003
- Antioxidant
activity of fresh apples, Marian Eberhardt, Nature Vol
405 June 2000
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