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More and more researchers
have come to the conclusion that oxidative stress
caused by free radicals (the modern term is "Reactive
oxygen species", ROS) may be the main and primary
cause of aging. This idea was first suggested by
Denham Harman in 1956, and research on the concept
was comprehensively reviewed by him more recently
(Harman, 1986). Currently this theory is being researched
by numerous workers; see for the example the papers
by Beckman and Ames (1998), Sohal and Weindruch
(1996). Internally produced ROS have been found
to damage macromolecules like DNA, proteins, and
lipids inside cells. These damaged macromolecules
may in some cases be subsequently removed by the
action of anti-aging forces, or they may irreversibly
accumulate (thus constituting aging forces). Reactive
oxygen species (ROS) are molecules that are more
reactive than ground-state molecular oxygen. These
species include true radicals such as superoxide
anion radical (*O-O--*), hydroxyl radical (*OH),
hydroxy-oxyl radical (HO-O*), nitric oxide (*N=O),
lipid peroxyl radical (L-O-O*), and non-radical
molecules such as singlet oxygen (O-O*) and various
hydro-peroxides (ROOH, LOOH, H2H2). ROS formation
is attributed to many vital cellular processes.
The mitochondrion is the main endogenous source
of these free radicals. About 90% of the oxygen
consumed in a cell is consumed in the mitochondria,
and about 2% of that oxygen is converted to superoxide
anion radical (*O-O--*) in the electron-transport
system in the mitochondrial inner membrane (Chance
et al., 1979). Scientists believe that the mitochondria
and the mitochondrial genome are the main targets
for damage by ROS (Beckman and Ames, 1998, Miquel
1991, Wallace 1992). Many scientists consider that
the gradual weakening of body functions as we get
old, known as aging, is a result of the slow but
insidious work of these "little enemies".
What are these "free radicals", and where
do they come from? They are in fact very simple
compounds of oxygen, in which the originally harmless
molecule has acquired an extra electron. Unfortunately,
the formation of free radicals is a natural process,
which will continue to occur as long as one breaths
oxygen. But the formation of free radicals is accelerated
by several factors, such as environmental pollutants,
UV light, and nuclear radiation. Free radicals are
very reactive particles and they aggressively attack
all the surrounding molecules within the cell. The
attacked molecules become oxidized, making them
structurally damaged and even toxic for the body.
Free radicals are rather indiscriminate in what
they their attack, so everything that they come
in contact with - such as DNA molecules, proteins,
or lipids (the scientific name for fats) - becomes
oxidized. The initial damage caused by free radicals
can lead to further alteration of cellular function.
It is known that our cells have the potential to
divide quickly and to grow much faster than they
do normally. The normal growth and regular development
of the human body requires very complex interactions
between hundreds of genes within the fragile DNA
molecule. Cells in which the "genetic messenger"
DNA is damaged by free radicals sooner or later
lose the ability to control their own division;
and uncontrolled growth leads to the appearance
of malignant tumors (cancer). Other consequences
of free radical activities are cardiovascular disorders
such as atherosclerosis. In this case lipids (fats)
oxidized by free radicals play the major role. The
oxidized lipids are toxic for the organism and they
induce chronic inflammatory reactions within the
walls of the blood vessels. This gradually leads
to the blockage of the vessels, which thus constrict
the blood-supply; and so their ability to supply
blood to the organs is lost. The arteries of the
heart are most frequently affected, thus giving
rise to heart disease and later to myocardial infarction
(heart attack). In the case of the brain, the blockage
of blood-vessels leads to a "stroke",
often causing permanent brain damage, partial paralysis,
etc. Due to the high incidence of atherosclerosis
in the population, the oxidation of lipids has attracted
much attention from scientists. In the laboratory
it is easy to observe that the lipids from blood
(normally light yellow) are quickly converted into
brown oxidation products. Outside the laboratory
a similar process can be easily observed if butter
(which consists mostly of saturated lipids) is kept
without refrigeration for a long time. The results
are even more visible on hot summer days when the
temperatures are closer to the 37°C (98°F)
of our body. Talking about foods and oxidation it
is interesting to consider vegetable oils, which
are highly recommended as a healthy substitute for
saturated animal fats like butter. Every housewife
knows that unlike butter, vegetable oils stay fresh
for months without refrigeration. The same is happening
inside our bodies - unsaturated vegetable fats successfully
resist the attacks of free radicals and (if they
are present in appropriate quantities) provide a
powerful protection against atherosclerosis.
Selected references
on
Oxidative stress, reactive oxygen species (ROS),
faulty anti-oxidation system: |
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Cardiology Division, Department
of Medicine, The Johns Hopkins Hospital, 720 Rutland
Avenue, Baltimore, MD 21205, USA.
The long-standing free radical
theory of aging, which attributes cellular pathology
to the relentless accumulation of reactive oxygen
species (ROS), remains attractive but controversial.
Emerging insights into the molecular interactions
between ROS and reactive nitrogen species (RNS)
such as nitric oxide suggest that, in biological
systems, one effect of increased ROS is the disruption
of protein S-nitrosylation, a ubiquitous posttranslational
modification system. In this way, ROS may not only
damage cells but also disrupt widespread signaling
pathways. Here, we discuss this phenomenon in the
context of the cardiovascular system and propose
that ideas regarding oxidative stress and aging
need to be reevaluated to take account of the balance
between oxidative and nitrosative stress.
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Department of Pathophysiology,
Medical University, ul. Jaczewskiego 8, 20-090 Lublin,
Poland.
Recent studies suggest that
adipose tissue hormone, leptin, is involved in the
pathogenesis of arterial hypertension. However,
the mechanism of hypertensive effect of leptin is
incompletely understood. We investigated whether
antioxidant treatment could prevent leptin-induced
hypertension. Hyperleptinemia was induced in male
Wistar rats by administration of exogenous leptin
(0.25 mg/kg twice daily s.c. for 7 days) and separate
groups were simultaneously treated with superoxide
scavenger, tempol, or NAD(P)H oxidase inhibitor,
apocynin (2 mM in the drinking water). After 7 days,
systolic blood pressure was 20.6% higher in leptin-treated
than in control animals. Both tempol and apocynin
prevented leptin-induced increase in blood pressure.
Plasma concentration and urinary excretion of 8-isoprostanes
increased in leptin-treated rats by 66.9% and 67.7%,
respectively. The level of lipid peroxidation products,
malonyldialdehyde + 4-hydroxyalkenals (MDA+4-HNE),
was 60.3% higher in the renal cortex and 48.1% higher
in the renal medulla of leptin-treated animals.
Aconitase activity decreased in these regions of
the kidney following leptin administration by 44.8%
and 45.1%, respectively. Leptin increased nitrotyrosine
concentration in plasma and renal tissue. Urinary
excretion of nitric oxide metabolites (NO(x)) was
57.4% lower and cyclic GMP excretion was 32.0% lower
in leptin-treated than in control group. Leptin
decreased absolute and fractional sodium excretion
by 44.5% and 44.7%, respectively. Co-treatment with
either tempol or apocynin normalized 8-isoprostanes,
MDA+4-HNE, aconitase activity, nitrotyrosine, as
well as urinary excretion of NO(x), cGMP and sodium
in rats receiving leptin. These results indicate
that oxidative stress-induced NO deficiency is involved
in the pathogenesis of leptin-induced hypertension.
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Department of Physiology, University
of Texas Health Science Center, Mail code 7756,
7703 Floyd Curl Drive, San Antonio, TX 78229-3900,
USA.
In attempt to meet tissue
demands for proper blood flow, the vasculature alters
its structure, simultaneously responding to both
physical and chemical stresses. Substantial information
has emerged in this field of study, particularly
concerning the roles of the endothelium and smooth
muscle cells in relation to signaling pathways for
mechanotransduction. As a first line of defense
upon exposure to various stressors, the endothelium
and smooth muscle cells respond with adaptive cellular
modifications. One prime example of these modifications
is the cellular response to oxidative stress as
evidenced by accumulated data. A recent proposal
of the inflammatory hypothesis of vascular aging
emphasized that stress-induced vascular aging may
be the primary event that underlies the general
aging phenomenon of systemic dysfunction.
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Department of Pharmacology,
Physiology and Therapeutics, University of North
Dakota School of Medicine and Health Sciences, Grand
Forks, ND 58203-2817, USA.
The physiological decline
that occurs with aging is thought to result, in
part, from accumulation of oxidative damage produced
by reactive oxygen species (ROS) generated during
normal metabolism. Two genetic mouse models of aging,
the Ames dwarf and growth hormone (GH) transgenic,
suggest that hormone levels may play a role in antioxidative
defense and aging. To explore this possibility,
catalase (CAT), an enzyme involved in elimination
of ROS, was evaluated in long-lived dwarf and short-lived
transgenic mice. Catalase activity and/or protein
was significantly elevated in livers from dwarf
mice at 3, 6, 13-15, and 24 months of age when compared
to age-matched wild type mice. In contrast, a 50
and 38% reduction (P<0.05) in CAT protein was
observed in 3 and 10 to 12 month old GH transgenics
respectively, when compared to wild type mice. Kidneys
from old dwarf mice exhibited significantly increased
CAT activity (22%), protein (16%) and mRNA expression
(59%) compared to wild type mice. Conversely, kidneys
from GH transgenic mice showed reductions in CAT
activity. The results of this study suggest that
hormonal status modulates antioxidative mechanisms
and that CAT is important in overall defense capacity
with respect to lifespan in both decelerated (dwarf)
and accelerated (transgenic) mammalian models of
aging.
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Buck Institute for Age Research,
Novato, CA 94949, USA.
We tested the theory that
reactive oxygen species cause aging. We augmented
the natural antioxidant systems of Caenorhabditis
elegans with small synthetic superoxide dismutase/catalase
mimetics. Treatment of wild-type worms increased
their mean life-span by a mean of 44 percent, and
treatment of prematurely aging worms resulted in
normalization of their life-span (a 67 percent increase).
It appears that oxidative stress is a major determinant
of life-span and that it can be counteracted by
pharmacological intervention.
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Human Nutrition Research Center
on Aging at Tufts University, Boston, MA 02111,
USA.
Several methods have been developed
to measure the total antioxidant capacity of a
biological sample. The use of peroxyl or hydroxyl
radicals as pro-oxidants in the oxygen radical
absorbance capacity (ORAC) assay makes it different
and unique from the assays that involve oxidants
that are not necessarily pro-oxidants. An improvement
in quantitation is achieved in the ORAC assay
by taking the reaction between substrate and free
radicals to completion and using an area-under-curve
technique for quantitation compared to the assays
that measure a lag phase. The interpretation of
the changes in plasma or serum antioxidant capacity
becomes complicated by the different methods used
in detecting these changes. The interpretation
also depends upon the conditions under which the
antioxidant capacity is determined because the
measurement reflects outcomes in a dynamic system.
An increased antioxidant capacity in plasma or
serum may not necessarily be a desirable condition
if it reflects a response to increased oxidative
stress. Similarly, a decrease in plasma or serum
antioxidant capacity may not necessarily be an
undesirable condition if the measurement reflects
decreased production of reactive species. Because
of these complications, no single measurement
of antioxidant status is going to be sufficient,
but a "battery" of measurements, many
of which will be described in Forum articles,
will be necessary to adequately assess oxidative
stress in biological systems.
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Division of Biology, California
Institute of Technology, Pasadena, CA 91125, USA.
Toward a genetic dissection
of the processes involved in aging, a screen for
gene mutations that extend life-span in Drosophila
melanogaster was performed. The mutant line Methuselah
(mth) displayed approximately 35 percent increase
in average life-span and enhanced resistance to
various forms of stress, including starvation, high
temperature, and dietary paraquat, a free-radical
generator. The mth gene predicted a protein with
homology to several guanosine triphosphate-binding
protein-coupled seven-transmembrane domain receptors.
Thus, the organism may use signal transduction pathways
to modulate stress response and life-span.
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