 |
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: |
| |
|
| |
|
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.
|
|
|
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.
|
|
|
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.
|
|
|
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.
|
|
|
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.
|
|
|
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.
|
|
|
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.
|
|
| |
|
