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Intrinsic skin aging: The role of oxidative stress
Borut Poljšak1, Raja G. Dahmane1, Aleskandar Godic2 ✉
1Faculty of Health Studies, University of Ljubljana, Zdravstvena pot 5, SI-1000 Ljubljana, Slovenia. 2Faculty of Medicine, University of Ljubljana, Vrazov
trg 2, SI-1000 Ljubljana, Slovenia. ✉ Corresponding author: aleksandar.godic@mf.uni-lj.si
1
2012;21:1-4
doi: 10.2478/v10162-012-0012-5
Introduction
Human skin, like all other organs, undergoes changes due to ag-
ing. Skin aging appears to be the result of two types of aging, “in-
trinsic” and “extrinsic”. “Intrinsic” structural changes occur as
a consequence of physiological aging and are genetically deter-
mined. However, it is very dicult, if not impossible, to separate
“intrinsic” aging from a variety of other factors clearly contribut-
ing to aging, such as smoking, sun exposure, alcohol consump-
tion, dietary habits, and other environmental and lifestyle factors
(1, 2). Hereditary genetic inuences are actually believed to con-
tribute no more than 3% to aging, making epigenetic and post-
translational mechanisms the most important pathways of aging
(3, 4). Consequently, the rate of aging is signicantly dierent
among dierent populations and even among dierent anatomi-
cal sites in a single individual.
Many theories have tried to explain the aging process, but the
most plausible of these concentrate on DNA damage and the con-
comitant repair process, which induce genome-wide epigenetic
changes leading to cell senescence, loss of proper cell function,
and genomic aberrations (5). Whether many post-translational
mechanisms of skin aging are independent pathways or a con-
sequence of DNA damage and the resulting epigenetic changes
remains to be established.
“Intrinsic” (genetically determined) and “extrinsic” (UV- and
toxic exposure–mediated) skin aging processes overlap and are
strongly related to increased generation of free radicals in the
skin. The underlying mechanism of both processes is increased
oxidative stress, which is probably the single most harmful con-
tributor to skin aging, leading to loss of cells and the extracellular
matrix as the most prominent features of chronologically aged
skin (6). Oxidative stress is the imbalance between ROS produc-
tion and antioxidative defense (Table 1).
The clinical manifestations of intrinsic aging are ne wrin-
kles, thin and transparent skin, loss of underlying fat leading to
hollowed cheeks and eye sockets, dry and itchy skin, inability to
perspire suciently, hair graying, hair loss or hirsutism, and thin-
ning of nail plates (7).
Most studies of intrinsic skin aging are derived from obser-
vations of tissues other than skin. The mechanisms of intrinsic
aging apply more or less to all proliferating and terminally dif-
ferentiated cells (8). It is widely accepted that intrinsic aging is
primarily caused by accumulated damage due to free radical re-
actions and by reactive oxygen species (ROS)–induced damage to
critical cellular macromolecules (6).
Generation of reactive oxygen species and oxidative
stress
Free radicals are a vital part of the metabolism and are essential
for life, playing roles such as killing microbes in macrophages.
Intrinsic aging depends on the homeostasis between free radical
production and the eectiveness of defense and repair systems.
In order to understand the basic principles of intrinsic skin aging,
the biochemistry of free radical formation is briey presented.
There is no doubt that oxygen (O2) is essential for life (9). Humans
and other aerobes need O2 because they have evolved electron
transport chains (ETC) and other enzyme systems utilizing O2 and
can tolerate its toxic byproducts through antioxidant defense.
The predecessors of the anaerobic bacteria that exist today fol-
lowed a “blind” evolutionary path of restricting themselves to
environments devoid of O2. It could be argued that the evolution
of multi-cellular aerobes and antioxidant defense mechanisms
are intimately related (10). Even present-day aerobes suer oxi-
dative damage. Free radicals important for living organisms in-
clude hydroxyl (OH•), superoxide (O2
−), nitric oxide (NO•), thyl
(RS•), and peroxyl (RO2
•).14 Peroxynitrite (ONOO−), hypochlorous
acid (HOCl), hydrogen peroxide (H2O2), singlet oxygen (1O2), and
ozone (O3) are not free radicals but can easily lead to free radical
reactions.
The term reactive oxygen species (ROS) is oen used to include
not only free radicals but also the non-radicals (1O2, ONOO−, H2O2,
O3). Reactive oxygen species are reactive molecules that contain
an oxygen atom (11). The essence of metabolic energy production
is in food oxidation: electrons in the respiratory chain are accepted
by electron carriers, such as nicotinamide dinucleotide (NAD+)
and avins (avin mononucleotide/FMN and avin adenine di-
nucleotide/FAD). The resulting reduced nicotinamide adenine di-
nucleotide (NADH) and reduced avins (FMNH2 and FADH2) can
be re-oxidized in mitochondria, producing large amounts of ATP
Abstract
Skin aging appears to be the result of two overlapping processes, intrinsic and extrinsic. It is well accepted that oxidative stress
contributes signicantly to extrinsic skin aging, although ndings point towards reactive oxygen species (ROS) as one of the major
causes of and single most important contributor; not only does ROS production increase with age, but human skin cells’ ability to
repair DNA damage steadily decreases over the years. We extrapolated mechanisms of intrinsic oxidative stress in tissues other
than skin to the skin cells in order to provide eective anti-aging strategies and reviewed the literature on intrinsic skin aging and
the role of oxidative stress.
Acta Dermatovenerologica
Alpina, Pannonica et Adriatica
Acta Dermatovenerol APA
Received: 21 February 2012 | Returned for modication: 27 February 2012 | Accepted: 25 May 2012
2
Acta Dermatovenerol APA | 2012;21:1-4B. Poljšak et al.
(12). Generation of ROS in mitochondria is therefore a byproduct
of cell respiration, due to electron leakage in the electron trans-
port chain (ETC) during oxidative phosphorylation (13) (Fig. 1).
O2 + e− → O2
•− superoxide anion (1)
O2
• − + e− + 2H+ → H2O2 hydrogen peroxide (2)
H2O2 + e− + H+ → H2O + OH• hydroxyl radical (3)
OH• + e− + H+ → H2O water (4)
Sum:
O2 + 4e− + 4H+ → 2H2O (5)
There are two main sources of ROS: a mitochondrial source
(which plays the principal role in aging) and a non-mitochondrial
source (which has a dierent, sometimes specic role, especially
in the pathogenesis of age-related diseases). Most studies suggest
that the majority of intracellular ROS production is derived from
mitochondria (14). However, some authors are skeptical due to
the lack of rm experimental evidence (15). At least in the liver,
peroxisomes and the endoplasmic reticulum have a greater ca-
pacity to produce ROS (15).
The mitochondrial source of ROS is represented by the elec-
tron transport chain and the nitric oxide synthase reaction (16).
The rate of mitochondrial respiration is responsible for the rate of
generation of ROS: the higher the metabolic rate, the shorter the
maximum lifespan of cells, with some exceptions to this rule (17).
A Fenton reaction is an example of the non-mitochondrial source
of ROS and involves H2O2 degradation, which is catalyzed by free
bivalent iron ions and leads to the generation of OH•.
(Fenton reaction) (Reaction 6)
(Haber–Weiss reaction) (Reaction 7)
Superoxide, ascorbic acid, and α-tocopherol also play impor-
tant roles as reducing agents in Reaction 6, in which the metal
ions are recycled. Reaction 7 is the Haber–Weiss reaction, which
supports the notion that transition metals play an important role
in the formation of hydroxyl radicals. It should be borne in mind
that the body’s iron content increases with age (18, 19). Sources
of H2O2 are mitochondria (superoxide dismutase reaction), per-
oxisomes (acyl-CoA oxidase reaction), and amyloid β of senile
plaques (superoxide dismutase-like reactions) (16, 20). Sources
of superoxide (O2
•−) are mitochondria, microsomes that contain
cytochrome P450 enzymes, a respiratory burst of phagocytic cells,
and others.
The production of mitochondrial superoxide radicals occurs
primarily at two enzymatic complexes in the electron transport
chain: complex I (NADH dehydrogenase) and complex III (ubiqui-
none–cytochrome c reductase) (16). Under normal metabolic con-
ditions, complex III is the main site of ROS production (21). With
respect to human aging, the weak point of this otherwise elegant
system lies in the formation of free radical semiquinone anion
species (•Q−), which occurs as an intermediate in the regenera-
tion of coenzyme Q (16). Once formed, •Q− can readily and non-
enzymatically transfer electrons to molecular oxygen with the
subsequent generation of a superoxide radical. The generation
of ROS therefore becomes predominantly a function of metabolic
rate and, as such, this rate can be indirectly correlated with the
corresponding rate of oxidative stress (22). Analyses of the con-
trol of oxidative phosphorylation-electron transport chain activ-
ity suggest that the system appears to be primarily pull-regulated
rather than push-regulated: putting in more NADH at the begin-
ning of the respiratory chain does not drive up respiration, but
shuts it down by restricting the availability of ADP (23). When
there is an abundant, non-limiting amount of ADP available, mi-
tochondria are said to be operating in state 3 respiration. When
ADP is absent, there is no ATP production and the proton trans-
duction mechanism becomes backed up, which is called state 4
respiration. Because the proton-motive force declines in state 3
compared to state 4, free-radical production would be expected
to be considerably elevated in state 4 compared to state 3. This
eect is interesting because it is actually the exact opposite of the
postulated link between energy metabolism and free-radical pro-
duction (aging) (23). The ux through the electron transport chain
is relevant to the aging process because it is related to the rate of
production of ROS. Small reductions in metabolic ux through the
electron transport chain occur at the cost of increased upstream
substrate levels (24). This increased concentration of reduced up-
Figure | Endogenous sources of ROS production: stepwise reduction of molecular
oxygen via one-electron transfer in mitochondria.
Increased free-radical production Decreased antioxidative defense
Endogenous Exogenous
• increasedmitochondrialleakage • environment(UVRexposure,pollution,pesti-
cides, radiation, etc.)
• increased3O2 concentration
• mutationorreducedactivityofenzymes(cata-
lase, SOD, glutathione peroxidase)
• reducedbiokineticsofantioxidantmetabolism
• reducedintakeofantioxidantsfromfood
• reducedbioabsorbtionofantioxidantsfrom
food
• others
• increasedrespiration • lifestyle
• elevationinO2 concentration • strenuousexercise:increasedphysicalactivity
of an untrained individual
• inflammation • smoking
• others • increasedintakeofdietarycompoundsprone
to increase initiation rates:
- increased metal ion intake (e.g., Fe, Cu, Cr)
- polyunsaturated lipids
- easily peroxidized amino acids (e.g., lysine)
• diseasesandchronicillnesses
• chronicinflammation
• psychologicalandemotionalstress
• others
Table | The (im)balance between ROS production and antioxidative defense.
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Acta Dermatovenrol APA | 2012;21:1-4 Intrinsic skin aging: The role of oxidative stress
stream substrates allows a larger generation of ROS (16). Aerobic
metabolism requires the constant removal of excess electrons
through the reduction of oxygen (25). The need for oxygen as
an electron acceptor is the sole purpose of breathing. Inevitable
byproducts of this process are O2
−•, H2O2, and HO•. This happens
mainly by complexes I and III (23, 24) of the electron transport
chain, the most important sources of endogenous free radicals.
About 10 oxygen molecules are processed by each human cell
daily and the leakage of partially reduced oxygen molecules is
about 1 to 5%, yielding about 2×10 superoxide and hydrogen per-
oxide molecules per cell per day (10, 12, 26). Based on the amount
of oxygen damaged and altered nucleotides detected in human
urine, it has been estimated that approximately 2×104 oxidative
DNA lesions occur per human genome every day (27). Assuming
that the repair of each excised adduct involves replacing one to
ve nucleotides, then oxygen-induced damage to DNA results in
the replacement of 2×105 nucleotides per human cell per day (28).
Each human cell receives 10,000 ROS hits per day, which equals 7
trillion insults per second per person.
Estimates of oxygen consumption in direct reactions to generate
free radicals vary (23). However, typically cited values are around
1.5 to 5% of the total consumed oxygen (29, 30). These estimates
have been questioned by Hansford et al. (30) and Staniek and
Nohl (31, 32), who suggested that H2O2 production rates are less
than 1% of consumed O2. However, even if we accept a conserva-
tive value of 0.15%, this still represents a substantial amount of
free radicals (23). As mentioned above, the rate of generation of
H2O2 depends on the state of the mitochondria as determined by
the concentration of ADP, substrates, and oxygen (33, 34).
A steep increase in electron-transfer chain activity produces a
linear increase in ATP production but an exponential increase in
ROS formation. Cells can produce the same amount of ATP for less
ROS by having a larger number of mitochondria running at a low-
er rate of electron-transfer chain activity. Heart cells, for example,
have thousands of mitochondria, whereas skin cells have fewer
mitochondria per cell. Whether skin cells suer more ROS-in-
duced damage is to the best of our knowledge not yet established.
Oxidative damage and intrinsic skin aging
Skin cells are constantly exposed to ROS and oxidative stress from
exogenous and endogenous sources. The dierence between the
two skin types is decay in the capacity of lipid membrane turnover
of chronologically older skin (35, 36). Not only does ROS produc-
tion increase with age but human skin cells’ ability to repair DNA
damage steadily decreases over the years (37). Reducing free radi-
cal production in the rst place is far more ecient than trying
to neutralize free radicals aer they have been produced (Fig. 2).
The energy required by skin cells comes from three sources:
mitochondrial oxidative phosphorylation, glycolysis, and the
creatine/phosphocreatine system. All three major energy sources
are aected by intrinsic and extrinsic skin aging and oer poten-
tial entry points for intervention strategies to decelerate the skin
aging process (8). Due to impaired mitochondria with age, less
energy is produced by mitochondrial oxidative phosphorylation,
although the number of mitochondria does not change with age.
Higher energy demand needs higher energy production via non-
mitochondrial pathways, such as glycolysis. With advancing age,
energy production is mostly anaerobic. Primary keratinocytes
derived from elderly donors show higher glucose uptake and in-
creased lactate production, which indicates suboptimal utiliza-
tion of glucose and a shi in metabolism towards increased gly-
colysis (8).
Figure | Cellular generation of reactive oxygen species and antioxidant defense
system.
Normal human dermal broblasts have a limited lifespan in
vitro and cease proliferating aer a xed number of cell divisions.
This process by which cells stop proliferation is called cellular se-
nescence (38). Senescence is also characterized by a decrease in
total cell numbers. It is not yet clear whether aging causes mito-
chondrial damage or vice versa. A loss of mitochondrial functions
can cause premature senescence of the skin cells. This has been
demonstrated in a reduction in the level of oxidative phosphoryl-
ation in human broblasts, which caused a reduction in cell pro-
liferation and premature senescence (39). In addition to the well-
established inuence of ROS on proliferation and senescence, a
reduction in the level of oxidative phosphorylation is causally re-
lated to reduced cell proliferation and the induction of premature
senescence. Changes that occur with senescence can eect mito-
chondrial respiration. Using a human broblast model of in vitro
senescence, Zwerschke et al. analyzed age-dependent changes in
the cellular carbohydrate metabolism (40). The authors showed
that senescent broblasts enter into metabolic imbalance as-
sociated with a strong reduction in the levels of ribonucleotide
triphosphates, including ATP, which are required for nucleotide
biosynthesis and hence proliferation. ATP depletion in senescent
broblasts is due to dysregulation of glycolytic enzymes and ulti-
mately leads to a drastic increase in cellular AMP, which is shown
to induce premature senescence (40). With increasing passage
number, senescent broblasts show a loss of membrane potential
and a decline in ATP production (40, 41). A signicant decrease
in mitochondrial membrane potential in ex vivo samples of hu-
man dermal broblasts from elderly donors was recently found,
accompanied by a signicant increase in ROS levels. Respiratory
activity was not signicantly altered with donor age, probably re-
ecting genetic variation (42). It seems that long-term exposure of
cells to ROS initiates a vicious cycle resulting in a reduced capac-
ity of stress response, a reduction in ATP synthesis, and a further
increase of ROS production in the aected cells (43).
Skin tissues engage in and derive energy mostly using aerobic
glycolysis. Despite the presence of oxygen, there is preferential
conversion of glucose to lactate (44). This results in the produc-
tion of substantial amounts of lactate, which is carried to the liver
by the bloodstream and converted back to glucose (the Cory cy-
cle). Skin has a strong preference for the metabolism of glucose
rather than fatty acids or ketone bodies, although alternative cit-
ric acid cycle intermediates such as glutamine are also actively
utilized (45). Interestingly, of the relatively small amount of oxy-
gen that is metabolized by the skin, the majority is supplied to the
epidermis and upper dermis by diusion from the atmosphere.
4
Acta Dermatovenerol APA | 2012;21:1-4B. Poljšak et al.
Because the majority of ATP in the skin is generated by glycolysis,
mitochondria may be less important for ATP generation, although
they may still have a pivotal role in aging (46, 47).
In conclusion, excess production of ROS and reduced antioxi-
dant activity with advanced age signicantly contribute to chron-
ological aging. Oxidative damage is the major cause and single
most important contributor to skin aging.
Acknowledgment
Parts of this manuscript were published in the paper Dahmane R,
Poljšak B. Free radicals and intrinsic skin aging: basic principles.
Health Med. 2011;5:1647-54.
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