Accepted: 7 November 2017

DOI: 10.1111/jocd.12518

REVIEW ARTICLE

Atmospheric skin aging—Contributors and inhibitors

David McDaniel MD, FAAD1,2,3,4 | Patricia Farris MD, FAAD5,6 |

Giuseppe Valacchi PhD7,8

1
McDaniel Laser and Cosmetic Center and
McDaniel Institute of Anti-Aging Research, Summary
Virginia Beach, VA, USA Cutaneous aging is a complex biological process consisting of 2 elements: intrinsic
2
Hampton University Skin of Color
aging, which is primarily determined by genetics, and extrinsic aging, which is largely
Research Institute, Hampton, VA, USA
3
School of Science, Hampton University, caused by atmospheric factors, such as exposure to sunlight and air pollution, and
Hampton, VA, USA lifestyle choices, such as diet and smoking. The role of the solar spectrum, com-
4
Department of Biological Sciences, Old
prised of ultraviolet light, specifically UVB (290-320 nm) and UVA (320-400) in
Dominion University, Norfolk, VA, USA
5
Department of Dermatology at Tulane
causing skin damage, including skin cancers, has been well documented. In recent
University, New Orleans, LA, USA years, the contribution of visible light (400-700 nm) and infrared radiation (above
6
Old Metairie Dermatology, Metairie, LA, 800 nm) in causing skin damage, similar to the photodamage caused by UV light, is
USA
7 also being elucidated. In addition, other atmospheric factors such as air pollution
Plants for Human Health Institute,
Department of Animal Sciences, NC State (smog, ozone, particulate matter, etc.) have been implicated in premature skin aging.
University, Kannapolis, NC, USA
8
The skin damage caused by environmental exposure is largely attributable to a com-
Department of Life Sciences and
Biotechnology, University of Ferrara, plex cascade of reactions inside the skin initiated by the generation of reactive oxy-
Ferrara, Italy gen species (ROS), which causes oxidative damage to cellular components such as
Correspondence proteins, lipids, and nucleic acids. These damaged skin cells initiate inflammatory
David McDaniel, McDaniel Laser and responses leading to the eventual damage manifested in chronically exposed skin.
Cosmetic Center and McDaniel Institute of
Anti-Aging Research, Virginia Beach, VA, Novel therapeutic strategies to combat ROS species generation are being developed
USA. to prevent the skin damage caused by atmospheric factors. In addition to protecting
Email: research@drmcdaniel.com
skin from solar radiation using sunscreens, other approaches using topically applied
Funding information ingredients, particularly antioxidants that penetrate the skin and protect the skin
SkinCeuticals, NY
from within, have also been well documented. This review summarizes current
knowledge of atmospheric aggressors, including UVA, UVB, visible light, infrared
radiation (IR), and ozone on skin damage, and proposes new avenues for future
research in the prevention and treatment of premature skin aging caused by such
atmospheric factors. New therapeutic modalities currently being developed are also
discussed.

KEYWORDS
antioxidants, atmospheric skin aging, oxidative stress, ozone, solar radiation

1 | INTRODUCTION exposures to which an individual is subjected from conception to

death. It includes both external and internal factors as well as the
Solar exposure coupled with living in an oxygen-rich atmosphere can human body’s response to these factors.2 Photodamage caused by
cause unwanted and deleterious stress on the skin.1 It has been pre- sunlight can lead to wrinkling, scaling, dryness, and mottled pigment
viously described in the literature that aging entails the totality of abnormalities (hypo- and hyperpigmentation). The extreme

124 | © 2018 Wiley Periodicals, Inc. wileyonlinelibrary.com/journal/jocd J Cosmet Dermatol. 2018;17:124–137.

MCDANIEL ET AL.
consequence of photodamage is skin cancer. The UV portion of sun-
light is absorbed by chromophores present in the skin, resulting in
the generation of reactive oxygen species (ROS) within the skin.
These ROS cause damaging oxidation of DNA, including oxidation of
nucleic acids, proteins, lipids, and other cellular organelles such as
mitochondria, resulting in photodamage and visible tissue aging.3
Many chromophores (chemicals capable of absorbing UV radia-
tion and generating damaging reactive oxygen species) exist within
the skin.4 DNA absorbs UVB light, inducing changes between adja-
cent pyrimidine bases. These damaged DNA molecules can stimulate
repair mechanisms that are known to cause inflammatory responses
within the skin. Other chromophores within the skin absorb photons
from UV light and generate singlet oxygen. Singlet oxygen, a highly
reactive oxygen species, can, in turn, generate other ROS, and in
combination, attack cellular components such as cell membranes, cel-
lular proteins, lipids, and nuclear and mitochondrial DNA.4
Skin is also equipped with protective antioxidant systems, includ-
ing chemical and enzymatic antioxidants. Chemical antioxidants can
be water-soluble (vitamin C, glutathione, lipoic acid, uric acid etc.), or
lipid-soluble (vitamin E and other tocopherol forms, ubiquinone, car-
otenoids etc.). Enzymatic antioxidants include superoxide dismutase,
catalase, glutathione peroxidase, and glutathione transferase. These
antioxidants protect the skin from ROS and free radicals; however,
with age and environmental stress, such as UV and ozone exposure,
the levels of these antioxidants are depleted, making the skin more
vulnerable to damage.5,6 A variety of antioxidants can be included in
topical products to “boost” the endogenous antioxidant systems
within the skin. These include common vitamins already found in
skin, activators of antioxidant enzyme systems present within the
skin, or plant-derived compounds that have strong antioxidant prop-
4
erties.
Recent research has demonstrated that skin is a target for addi-
tional spectra of solar radiation outside the UV bandwidth. For
example, visible light can cause changes in skin similar to that of
UVA including the induction of skin pigmentation and skin
FIGURE 1 Solar spectrum
| 125
inflammation. Near-infrared radiation (IR-A) acts via similar mecha-
nisms as UV, inducing skin damage related to UV.7 In addition to
solar radiation, air pollution has also been extensively studied for its
effect on human skin. Recent studies have shed light on the complex
interaction of intrinsic aging that is accelerated by these extrinsic
atmospheric factors. This review summarizes our current knowledge
on solar radiation (UV, visible, IR), as well as air pollution (with an
emphasis on ozone) and their effect on skin. We also discuss current
and new therapeutic approaches to preventing and treating atmo-
spheric skin aging, including the use of novel topical antioxidants
and other agents.
2 | PART 1: UV AND SKIN AGING—ROLE
OF UVB AND UVA
The solar spectrum reaching the surface of the earth is divided into
3 main segments based on wavelength: UVC (100-290 nm), UVB
(290-320 nm), and UVA (320-400 nm) (Figure 1). UVA can further
be divided into short length UVA2 (320-340) or long length UVA1
rays (340-400 nm). The most energetic and highly toxic of the UV
spectrum, UVC, is filtered by atmospheric ozone and moisture, and
consequently does not reach the earth’s surface. Generally, UVA
represents up to 95% of total UV reaching the earth, with UVB
accounting for 4-5%. On a mid-summer day, twenty times more
UVA reaches the earth’s surface than UVB8 (Figure 2). UVA is less
energetic than UVB, but exhibits higher penetration properties,
reaching the lower dermis and leading to deeper cutaneous damage.
The contribution of UVA to human photocarcinogenesis,9 skin pho-
toaging,10 and immunesuppression11 has been well established. Both
UVA and UVB have acute and chronic effects on human skin12
(Table 1 summarizes the types of solar radiation and their effects on
skin).
It has been established that approximately 50% of UV-induced
photodamage is caused by the generation of free radicals, while
126 | MCDANIEL
FIGURE 2 Different solar radiations and their penetration into
skin
direct cellular injury accounts for the remainder of the damage.13
UV-induced cellular responses occur due to oxidative processes initi-
ated by cellular photosensitization. After UV absorption by cellular
chromophores (DNA, nucleic acids, urocanic acid, aromatic amino
acids tryptophan and tyrosine, and other UV-absorbing endogenous
molecules such as NADH, quinones, flavins, and porphyrins), singlet
14,15
oxygen, hydrogen peroxide, or hydroxyl radicals are generated.
Most of these endogenous chromophores absorb in the UVB range.
Although UVA exposure results in more oxidation than UVB, cuta-
neous UVA chromophores are largely unknown, except for trans-
14
urocanic acid.
The reactive oxygen species generated by UV can cause damage
to cellular proteins, lipids, nucleic acids, cell membranes, and cell
organelles such as mitochondria. UV and infrared (IR-A) exposure
cause disturbance in the electron transport chain resulting in lower
energy production and decreased mitochondrial function in human
fibroblasts.16
UVB is directly absorbed by DNA in epidermal cells causing
the production of characteristic DNA mutations including cyclobu-
tane pyrimidine dimers and pyrimidine cross-linked dimers.17 The
damaged DNA products, particularly pyrimidine dimers, also acti-
vate skin melanogenesis, thereby providing protection to skin from
further UV damage.17 The damaged DNA causes a block in the
production of RNA and activation of p53 proteins inducing apop-
tosis of keratinocytes in the epidermis, leading to the formation
of “sunburn” cells in the epidermis. Prolonged irradiation can sup-
press the p53-mediated apoptosis process resulting in the accumu-
lation of damaged cells and the initiation of mutagenesis and
photocarcinogenesis.3 UVA renders DNA damage primarily through
oxidation of guanine to 8-hydroxyguanine resulting in 8-oxogua-
nine (8oG).
Although the skin possesses an elaborate antioxidant system (de-
scribed in more detail in Section 6) to deal with the UV-induced
oxidative stress, chronic exposure can overcome the endogenous
antioxidant capacity of the skin leading to further damage.18
ET AL.
Figure 3 shows the complex interaction between UV radiation
and skin epidermal and dermal cells. Following sun exposure, activa-
tion of inflammatory reactions within the skin and other cell types
such as monocytes, macrophages, lymphocytes, and vascular
endothelial cells occurs due to upregulation of nuclear factor NF-kB
pathway.19 This signaling pathway causes epidermal keratinocytes to
release primary pro-inflammatory cytokines: tumor necrosis factor
alpha (TNF-a) and interleukin 1 (IL-1).20 Other secondary inflamma-
tory cytokines IL-3, IL-6, IL-8, IL-7, and IL-10 are also released fol-
lowing the initial inflammatory response. UV exposure also activates
the cyclooxygenase and lipoxygenase enzyme systems (COX-2 and
LOX) increasing the production of further pro-inflammatory prosta-
glandins and leukotrienes. Additional factors such as GM-CSF
released by the skin keratinocytes can cause immunosuppression.21
A complex cascade of reactions initiated by the primary inflamma-
tory mediators ultimately stimulates factors involved in macrophage
activation.
Photoaging results largely from the effects of UVA on the dermal
matrix. ROS upregulate transcription factor activator protein 1 (AP-
1), increasing the production of matrix metalloproteinases (MMPs),
the enzymes that breakdown collagen.19 MMPs such as interstitial
collagenase (MMP-1), stromelysin (MMP-3), and gelatinase (MMP-9)
are produced, and keratinocytes, macrophages, and leukocytes lead
to the destruction of dermal matrix proteins. Damage to collagen,
elastin, and glycosaminoglycans contributes to the photoaged pheno-
type, and causes solar elastosis and wrinkling. Furthermore, AP-1
inhibits collagen production in the dermis by inhibiting transforming
growth factor beta (TGF-ẞ) and reducing gene expression of type I
and III procollagen. Thus, chronic UV exposure results in a net loss
in dermal collagen due to both degradation and attenuation of pro-
duction.22
Acute exposure to UVB causes sunburn that peaks 6-24 hours
after exposure. The redness and swelling associated with sunburn
are due to the release of pro-inflammatory mediators and vasodila-
tion of dermal blood vessels. UVA and UVB differ in their pigment
darkening response and mechanism of action. The short-term con-
sequence of UVA exposure is immediate pigment darkening (IPD),
an immediate gray-brown discoloration/pigmentation resulting from
photooxidation of melanin and its redistribution within the ker-
atinocytes.17 In contrast, delayed tanning response (DT), caused by
UVB, is due to melanogenesis activation. IPD fades rapidly, but
after sufficient UVA doses (>10 J/cm²), it is followed by a residual
pigmentation known as persistent pigment darkening (PPD).23 This
is a significant problem for pigmented skin populations, because of
their high susceptibility to hyperpigmented lesions.24,25 Most stud-
ies on the damaging effects of UV have been studied in Caucasian
skin types; the molecular impact of UV exposure in darker skin
phototypes is only beginning to gain attention in recent years.26
Using RT-PCR methods, it has been demonstrated that the UVA1-
induced genetic changes in oxidative stress response, inflammation,
extracellular remodeling, and cancer development are modulated in
the same manner in Caucasian, Indian, and African American skin
types.26
MCDANIEL ET AL. | 127

T A B L E 1 Summary of solar radiation and its effects on skin

Effects UVC UVB UVA Visible IR
Wave lengths (nm) 200-290 290-320 UVA-2 320-340 400-700 IR-A = 700-1400
UVA-1 = 340-400 IR-B = 1400-3000
IR-C = 3000-10 000
Energy Very High High Medium Medium-low Low
Amount reaching None. Atmospheric 4-5% of total solar 90% of total UV 40% of total solar Almost half of solar
surface of earth Ozone and moisture UV radiation. radiation reaching radiation reaching energy reaching earth
absorbs it Highest in summer earth is UVA surface of earth surface is IR
and depends on
time of day
Skin Penetration Does not penetrate Epidermal layers Dermis and Down to dermis and Deeper layers of skin
skin subdermis below
Time line for effects None (from solar Immediate within Chronic effects Chronic effects Immediate burning
on skin (Acute vs. exposure) hours sensation with IR-B
chronic) and IR-C
Damage to skin No damage in vivo; Causes skin burning Chronic exposure Damaging effects Oxidative stress on
Highly toxic to cells and erythema and causes dermal similar to UVA skin, rises skin
and kills organisms chronic exposure matrix damage, and temperature,
when exposed can cause eventually “ solar collagenase induction,
in vitro carcinogenesis elastosis” and skin and matrix degradation
cancers
Skin pigmentation None Activates skin Immediate pigment Increased skin IR-A can cause skin
melanogenesis and darkening (IPD) and darkening in darkening in darker
causes skin persistent pigment pigmented skins. skin types
darkening in all skin darkening (PPD), IPD response for IR-
types within days of especially in darker A. No significant
exposure (delayed skin types effects on lighter
tanning response) skin types (I, II)
Mechanism of Epidermal DNA Oxidative stress Oxidative stress, Oxidative stress,
action on skin damage, depletion induction; depletion actinic dermatitis, activation of matrix
of AOX in of AOX in dermis, phototoxic, and degradation in lighter
epidermis, activation MMP activation, photoallergic skin types
of skin inflammatory collagen reactions in skin
reactions, degradation,
photocarcinogenesis inflammatory cell
influx from blood
vessels.
Beneficial effects on Vitamin D synthesis Certain UVA has Therapeutic benefits Used therapeutically for
skin been used to treat for blue light and certain skin disorders
skin wrinkles (blue pulsating yellow
light laser) light for collagen
stimulation
Traditional Sunscreens. Most Certain new broad- Clothing, umbrella Clothing, umbrella and
protective commonly used spectrum and moving out of moving out of direct
measures sunscreens protect sunscreens provide direct sunlight sunlight
skin from UVB partial protection
New Therapeutic Novel sunscreens Novel topical and Topical and systemic Topical and systemic
and protective with antioxidant systemic antioxidants to antioxidants to
measures properties antioxidants to prevent ROS prevent ROS
prevent ROS generation within generation within skin
generation within skin
skin

As oxidative stress and the release of ROS molecules are a common ROS within the skin. Topical application of antioxidants in combination
initial step in the damage caused by UVA, and to a lesser extent UVB, with sunscreens has been used to effectively protect skin from UV
strategies have been developed to protect skin from generation of the damage. This strategy is discussed in detail in part VI of this review.
 128 | MCDANIEL
3 | PART II VISIBLE LIGHT AND SKIN
AGING
Visible light (VL) (400-700 nm) lies outside of the spectral range
of what photobiologists historically define as deleterious radiation.
Visible light comprises approximately 40% of the solar radiation
that reaches the surface of the earth. Only a few studies have
evaluated the effects of the visible light range of wavelengths
on skin. Considering that during outdoor activities, skin is exposed
to the full solar spectrum, including visible light; this research is
quite relevant. Visible light can cause various dermatologic condi-
tions such as solar urticaria, chronic actinic dermatitis, phototoxic
and photoallergic skin reactions, porphyrias, erythema, and pigmen-
tation induction. Detailed studies carried out by Kollias et al
‫برنزه‬ showed that VL can induce skin pigmentation, which was sus-
27
tained for up to 10 weeks. It has also been demonstrated, using
a xenon-mercury lamp, that VL (up to 470 nm) can induce imme-
28
diate pigment darkening (IPD) similar to that of UVA1. The peak
for the IPD response was shown to be between wavelengths 300
and 500 nm,29 closer to the UVA1 range as might be expected.
Visible light has been shown to induce erythema and a tanning
response in dark skin, but not in fair-skinned individuals.23 Skin
type IV-VI responded to VL by increased skin pigmentation while
skin type II showed no visible response to VL.25 In addition to
pigmentation, VL also induced skin erythema. This response was
greater for darker skin types than lighter skin types. This is likely
due to the higher amount of chromophores (eg, melanin) in darker
skin than lighter skin. The melanin absorbs light-generating heat
25
causing vasodilation, followed by skin erythemal response.
ET AL.
FIGURE 3 Skin inflammatory response
to UVR
Studies have also shown that a single exposure to visible light in-
duced very little pigmentation, whereas multiple exposures
with visible light resulted in darker and sustained pigmentation.30
The mechanism by which VL induces skin damage appears to be,
at least in part, attributable to inducing oxidative damage to skin
cells. Using in vitro methods, it was determined that VL exposure
leads to micronuclei formation without cyclobutane pyrimidine
dimers (a hallmark of UVB damage), which is associated with the
induction of oxidative DNA damage in skin cells.31 The peak wave-
length range for this DNA base modification has been determined to
be between 400 and 450 nm.32 In vitro and ex vivo studies have also
established the pro-inflammatory, ROS-generating effects of visible
light. Irradiation of human skin equivalents with visible light induced
production of ROS, pro-inflammatory cytokines, and matrix metallo-
proteinase (MMP)-1 expression. Using clinical models to assess the
generation of free radicals from oxidative stress, higher levels of free
radical activity were found after visible light exposure.33 Exposure to
VL also generated hydrogen peroxide in a dose-dependent fashion.
Pretreatment of cells with antioxidants prevented this free radical
generation in skin cells by VL, suggesting a potential modality of pre-
vention of VL damage to skin. In addition to the MMP-1 induction,
VL has also been shown to increase pro-inflammatory cytokines (IL-
1 alpha, IL-1 receptor antagonist, IL-6, GM-CSF, and IL8), induction
of MMP-1 and -9, and activation of EGFR/ERK pathway.33
In terms of current knowledge on protection against VL, com-
mercially available sunscreens were found to have minimal effects
on reducing visible light-induced ROS, suggesting that traditional
UVA/UVB sunscreens do not protect the skin from visible light-
induced responses. There is a need to identify strategies that can be
MCDANIEL ET AL.
successfully employed in the future to achieve more comprehensive
34
photoprotection of human skin beyond ultraviolet radiation.
This need has been further heightened by recent research exam-
ining high-energy visible light (HEVL), or blue light, which ranges in
wavelength from 400 to 500 nm. Previously, blue light had been pri-
marily known as a therapeutic treatment option for several cuta-
neous disorders.35 More recently, data showing blue light causing
ROS-mediated photoaging, inflammation, and genetic expression
changes in markers, such as MMP1 and IL8, have been published.
Additional data demonstrate the ability of antioxidants such as toco-
pherol to block or prevent this ROS-mediated blue light skin dam-
age.33,36 Most recently, blue light has been studied as it relates to
pigmentation and the inducible generation of the tyrosinase-dopa-
chrome tautomerase complex in type III-VI melanocytes, which
causes sustained tyrosinase activity. The key sensor for melanocyte
detection of blue light is thought to be Opsin-3 (OPN3), a calcium-
dependent protein that can activate tyrosinase activity, and other
37
pathways/mechanisms such as CAMKII, CREB, p38, and MITF.
HEVL has been overlooked as a photoaging causative agent as evi-
denced by the fact that of the 40 000 skincare products launched in
35
2016, only 9 claimed to have HEVL/blue light protection.
4 | PART III: HEAT, INFRARED LIGHT, AND
SKIN AGING
Infrared (IR) radiation consists of wavelengths from 800 nm to
1 mm, and it is subdivided into 3 regions of increasing wavelength,
IR-A (700-1400 nm), IR-B (1400-3000 nm), and IR-C (3000 nm-
1 mm). Given that almost half of the solar energy reaching the
earth’s surface is in the IR range, solar IR is expected to have signifi-
38
cant biological effects on human skin. In direct sunlight, the tem-
perature of human skin rises to about 40◦C following the
conversion of absorbed IR into heat. Skin temperature rise is also
higher in skin of color as compared to fair skin.23 So far, our knowl-
edge of the effects of IR radiation or heat on skin aging is limited.
IR-B and IR-C do not penetrate deeply into the skin, although
they cause increases in skin temperature. More than 65% of the
more highly energetic IR-A reaches the dermis and subcutaneous
layers without increasing skin temperature.38 Human skin is increas-
ingly exposed to IR-A radiation; most relevant sources are (i) natural
solar radiation consisting of over 30% IR-A, (ii) artificial IR-A sources
used for therapeutic or wellness purposes, and (iii) artificial UV
sources contaminated with IR-A. As part of natural sunlight, IR-A sig-
nificantly contributes to extrinsic skin aging.39 Recent studies have
demonstrated that the solar radiation which induces skin damage
can occur not only from ultraviolet (UV) radiation alone, but also
from longer wavelengths, in particular near-infrared radiation (IR-A
radiation, 700-1400 nm).40
Different skin types react differently to IR-A. Lightly pigmented
skin is most vulnerable with reduction in collagen synthesis and
increase in MMP-1 and MMP-3 expression, while highly pigmented
skin has minimal effect on collagen and MMPs, but demonstrates
| 129
stimulation of melanin production.41 Recent work demonstrates that
IR and heat exposure each induce cutaneous angiogenesis and
inflammatory cellular infiltration, disrupt the dermal extracellular
matrix by inducing matrix metalloproteinases, and alter dermal struc-
tural proteins, thereby contributing to premature skin aging.38 IR-A
radiation, in addition to UV, has been demonstrated to alter the col-
lagen equilibrium of the dermal extracellular matrix in at least 2
ways: (a) by leading to an increased expression of the collagen-
degrading enzyme matrix metalloproteinase 1 and (b) by decreasing
the de novo synthesis of the collagen itself. IR-A-induced expression
of matrix metalloproteinase-1 (MMP-1) was found to be mediated
by the formation of intracellular reactive oxygen species (ROS). It
was demonstrated in vivo that exposure of normal skin to IR-A radi-
ation caused upregulation of MMP-1 mRNA expression by a factor
of 3 to 4 times.34 In response to IR irradiation, mitogen-activated
protein kinase signaling pathways were activated mediating the
upregulation of matrix metalloproteinase-1 expression.7
Paradoxically, low-level IR-A has been shown to have stimulatory
effects on cellular mechanisms and even collagen production,
through a nonthermal process known as photobiomodulation. This
effect has been demonstrated in cultured human fibroblasts by vary-
ing ratios of wavelengths in a dual wavelength LED system com-
prised of 595/870 nm wavelengths and a total energy fluence of
0.1 J/cm2.42 Additionally, low-level exposure to IR-A has been
shown to have increased healing benefits as well as application in
preconditioning the skin to be better prepared for upcoming insult
or trauma. Known as photoprevention, this process has been shown
in laboratory experiments, but mimics the natural world as the red
and IR-A wavelengths present in early morning sunlight may have
evolved to ready the skin for later, more deleterious UVR as the day
progresses.43 Uncontrolled, frequent, or long-term exposure to near-
infrared can also cause thermal burns and aging effects such as
“Bakers Arms” or “Glassblowers Face.”38
While there are some similarities in the cutaneous biological
effects of IR-A and UV radiation exposure, there are also significant
differences. The cellular response to IR-A irradiation involves the
mitochondrial electron transport chain.40,44 IR-A-irradiated cells
revealed an increase in mitochondrial superoxide anion production.
The treatment of fibroblasts with the mitochondrial targeted antioxi-
dant MitoQ completely abrogated the IR-A, but not the UVB or
UVA1 response.45 ROS relevant for IR-A-induced signaling originated
from the mitochondrial electron transport chain, because (i) chemical
inhibition of the electron transport chain prevented IR-A, but not
UVB or UVA1, radiation-induced MMP-1 expression, and (ii) peroxi-
some proliferator-activated receptor gamma coactivator-1 (PGC-1),
overexpressing fibroblasts with increased electron transport chain
content were hypersensitive to IR-A radiation-induced gene expres-
sion. When healthy human subjects were exposed to physiologically
relevant doses of IR-A, eighty percent of the tested individuals
responded to IR-A radiation by upregulation of MMP-1 expression.
Specifically, IR-A irradiation caused increased expression of MMP-1
in the dermis, but not in the epidermis. Raman spectroscopy
revealed that IR-A radiation also caused a significant decrease in the
130 | MCDANIEL
antioxidant content of human skin. In vitro studies had previously
shown that IR-A-induced MMP-1 expression was mediated through
an oxidative stress response, which originates from the mitochon-
drial electron transport chain. In addition, IR-A also causes the stimu-
lation of extracellular signal-regulated kinase 1/2 activation in human
7
dermal fibroblasts. IR-A induced a variety of genes at the transcrip-
tome level in primary human skin fibroblasts. Microarray analysis
revealed 599 IR-A-regulated transcripts. The IR-A-induced transcrip-
tome differed from changes known to be induced by UV. IR-A-
responsive genes included the following categories: extracellular
matrix, calcium homeostasis, stress signaling, and apoptosis.46 Using
RT-PCR technology and chemical inhibitors for the various signaling
pathways, ERK1/2, p38, JNK, PI3K/AKT, STAT3, and IL-6, as well as
the calcium-mediated signaling pathways, were identified as specifi-
cally targeted by IR-A. This IR-A gene response is triggered by mito-
chondrial and, to a lesser extent, nonmitochondrial production of
reactive oxygen species.46 In addition to MMP-1, IR and heat also
stimulate the expression of tropoelastin and fibrillin-1, 2 main com-
ponents of elastic fibers, and matrix metalloproteinase (MMP)-12,
the most active MMP against elastin, in human skin in vivo. This
suggests that the abnormal production of tropoelastin and fibrillin by
heat in human skin, and their degradation by various MMPs, such as
MMP-12, may contribute to the accumulation of elastotic material in
photoaged skin.40
Protection from heat and IR-A has been demonstrated by pre-
treatment of skin with antioxidants, N-acetyl cysteine or genistein,
for 24 h prior to heat or IR-A.47 It has also been demonstrated
in vitro that the effects of IR-A can be abolished by incubation of
cultured human dermal fibroblasts or treatment of human skin with
specific antioxidants.48 Thus, heat and IR-A irradiation most likely
promote premature skin aging and skin elastosis, and topical applica-
tion of appropriate antioxidants may represent an effective photo-
protective strategy.
5 | PART IV: OZONE AND SKIN AGING
Ozone (O3) is considered one of the most toxic environmental stres-
sors to which humans are continuously exposed. The human skin, par-
ticularly the upper layer of the epidermis, acts as an effective barrier
between the body and the environment, but can also be a major tar-
get of air pollutants, making the skin one of the most susceptible tis-
sues to the oxidative damaging effect of O3. The average
tropospheric amount of O3 is generally less than 0.08 ppm, much
lower than in the stratosphere (10 ppm). Yet, in large metropolises
such as Mexico City, as well as European cities such as Rome, Milan,
and Paris, O3 can reach very high toxic concentrations, especially dur-
49
ing the summer. Anthropogenic emissions, mainly of nitrogen oxi-
des, as well as methane, carbon monoxide, and sulfuric compounds,
have caused a progressive increase in O3 concentration up to
0.8 ppm or more in the last 30 years.50
While O3 is not able to penetrate the skin, the damage induced
by O3 is mainly a consequence of its ability to induce oxidative
ET AL.
stress via the formation of lipid peroxidation products. Chronic expo-
sure to high levels of atmospheric ozone has been shown to induce
antioxidant depletion, as well as oxidation of lipids and proteins,
within the outermost skin layer (stratum corneum) and the lung res-
piratory tract lining fluids (RTLFs).51 O3 can react readily with protein
nucleophiles via Michael addition and Schiff base formation. The tar-
gets of O3 are cysteine, histidine, and lysine residues of protein, and
affect lipids of skin by 4-hydroxynonenal-protein adducts (HNE
adduct) formation and skin lipid peroxidation1 (Figure 4). In addition
to damaging cellular lipids and proteins, O3 can also deplete skin of
its essential antioxidants. Studies in hairless mice SKH-1 demon-
strated that when exposed to 0.8 ppm of O3, the depletion of alpha-
tocopherol in lung and plasma, and the induction of heme oxygenase
1, cyclooxygenase 2, and proliferation of cell nuclear antigen in both
skin and lung were observed. O3-exposed animals showed a similar
extent of upregulation of COX-2 and PCNA in lung and skin,
whereas HO-1 was more responsive in skin than in lung (sevenfold
induction vs. twofold induction). This study demonstrated
that skin exposure to high levels of O3 not only affects antioxidant
levels and oxidation markers in the SC, but also induces stress
responses in the active layers of the skin, most likely by indirect
mechanisms, as it is unlikely that O3 itself penetrates the protective
SC layers.52 Murine skin also responded to O3 by an increase in 4-
hydroxynonenal-protein adducts and a rapid upregulation of HSP27
(20-fold), and more delayed induction of HSP70 (2.8-fold) and heme
oxygenase-1 (fivefold). O3 exposure also led to the induction of
nitric oxide synthase (iNOS) 6-12 h following the exposure. This
study suggested that skin exposure to high levels of O3 not only
affects antioxidant levels and oxidation markers in the SC, but also
induces stress responses in the active layers of the skin.53
In vitro studies using cultured keratinocytes have demonstrated
the damaging effects of O3 on skin cells and the protective effects of
antioxidants against the O3-induced skin damage.54 O3 exposure
induced cytotoxicity, inhibited cellular proliferation, and increased the
formation of 4-hydroxynonenal (HNE) protein adducts. Furthermore,
O3 decreased activation of the redox-sensitive transcription factor NF-
kB, which is involved in transcribing pro-inflammatory cytokines, and
therefore constitutes one of the main players associated with O3-
induced skin inflammation. Cells exposed to O3 demonstrated a dose-
dependent increase in p65 subunit nuclear expression as a marker of
NF-kB activation. NF-kB is a master regulator of a variety of cellular
responses responsible for apoptosis signaling pathways, cell prolifera-
tion, angiogenesis, metastasis, tumor promotion, and inflammation.
Therefore, O3 can indirectly activate pathways in skin that can be dam-
aging to the skin as well as the whole organism. Indeed, direct activa-
tion of O3 on the skin cell NF-kB has been demonstrated.49 O3 also
activates the pro-inflammatory cytokine IL-8 expression in skin.54
Additional downstream effects of O3 in skin include activation of ker-
atin 10, PCNA gene, stress proteins such as heat shock proteins, HO1,
and AhR (aryl hydrocarbon receptor), and pro-inflammatory markers
(COX 2 and iNOS).55 Pretreatment of keratinocytes with a topical vita-
min C compound mixtures prevented the aforementioned O3-induced
cytotoxicity in skin keratinocytes and in 3D skin models.54
MCDANIEL ET AL.
FIGURE 4 Ozone effects on human skin
In an epidemiological study conducted in Shanghai, China, a
time series analysis was conducted to evaluate the association
between emergency room (ER) visits for skin conditions and O3
exposure. A variety of skin conditions including urticaria, eczema,
contact dermatitis, rash⁄other nonspecific eruption, infected skin
disease, and other skin diseases were correlated with daily air pol-
lution data obtained from the Shanghai Monitoring Centre, includ-
ing O3, particulate matter with aerodynamic diameter of 10 lm or
less (PM10), sulfur dioxide (SO2), and nitrogen dioxide (NO2).
There were direct correlations only between environmental O3
content and the skin conditions.56 These findings are biologically
plausible due to the propensity of O3 to be highly reactive, with
a high oxidizing power, which can react with biomolecules in the
skin to form ozonides and free radicals. This study provides evi-
dence that the current atmospheric level of O3 has an adverse
effect on the skin health of the general population and strength-
ens the rationale to further investigate the harmful effect of O3
on human skin, as well as to evaluate possible measures to coun-
teract its effect.
A recent in vivo clinical study further validated the O3-induced
skin damage that was observed in vitro and in 3D skin models. O3
exposure increased epidermal levels of 4-hydroxynonenal (4HNE)
and 8-iso Prostaglandin F2 alpha (8-iso PGF2a), confirming the O3
interaction with skin lipids. In addition, after O3 exposure, there was
a clear and significant increase in NF-kB p65 subunit activation that
paralleled the increased levels of cyclooxygenase-2 (COX-2) and
metalloproteinase-9 (MMP-9). Of note, after O3 exposure, there was
a dramatic decrease in both types I and III collagen (Col I and III).
Pretreatment with topical vitamin C compound mixtures was able to
prevent the O3-induced skin damage. (details in Section 6).
| 131
6 | PART V: SMOG AND OTHER
PARTICULATE MATTER AND SKIN AGING
Epidemiological studies suggest a correlation between increased air-
borne particulate matter (PM) and adverse health effects. A study
on the combined effects of 3 ambient air pollutants, ozone (O₃),
nitrogen dioxide (NO₂), and fine particulate matter (PM) with a
median aerodynamic diameter of less than 2.5 lm (PM (2.5)), corre-
lated the short-term changes in AQHI (Air Quality Health Index)
with emergency department (ED) visits for urticaria in Windsor-area
hospitals in Canada. Urticaria is among the skin pathologies com-
monly associated with pollution. Positive and significant correlations
were observed between AQHI levels and OR or ED visits for urti-
caria in Windsor. This study clearly demonstrated associations
between ambient air pollution and urticarial, confirming that air pol-
lution affects skin conditions.57 A recent epidemiological study
showed a link between traffic-related air pollution and the forma-
tion of lentigines in Caucasian and Asians populations.58 Soot,
which frequently results from diesel exhaust, is a mixture of carbon
particles covered by organic compounds including polycyclic aro-
matic hydrocarbons. Polycyclic aromatic hydrocarbon-induced acti-
vation of aryl hydrocarbon receptor signaling in epidermal cells
might provide a mechanistic explanation for these epidemiological
observations.59 Indeed, stimulation of primary human epidermal ker-
atinocytes with ambient soot was recently shown to cause an acti-
vation of the aryl hydrocarbon receptor and subsequent gene
transcription.60
The mechanisms of PM health effects are believed to involve
oxidative stress and inflammation. To gain further insight, the as to
the effects of PM on skin, investigations were conducted using
reconstituted human epidermis (RHE). RHE was exposed to concen-
trated ambient particles (CAPs) (25 or 100 lg/ml) for 24 or 48 hours.
A local reactive oxygen species (ROS) production increase, presum-
ably generated from metals present on the particle, contributed to
observed lipid oxidation. Furthermore, as a consequence of altered
redox status, NF-kB nucleus translocation was increased upon CAPs
exposure, as well as an increase in cyclooxygenase 2 and cyto-
chrome P450 levels, which may be involved in the inflammatory
response initiated by PM. CAPs also triggered an apoptotic process
in skin.61 Transition electron microscopy revealed that CAPs were
able to penetrate skin tissues. These findings contribute to the
understanding of the cutaneous pathophysiological mechanisms initi-
ated by CAPs exposure, where oxidative stress and inflammation
may play predominant roles.
7 | PART VI: THERAPEUTIC INTERVENTION
OF ATMOSPHERIC SKIN AGING
Photoprotection of human skin by means of sunscreens or daily
skincare products is traditionally centered on the prevention of acute
(eg, sunburn) and chronic (eg, skin cancer and photoaging) skin dam-
age that may result from exposure to ultraviolet rays (UVB and
132 | MCDANIEL ET AL.

UVA). Within the last decade, however, it has been appreciated that
wavelengths beyond the ultraviolet spectrum, in particular visible
light and infrared radiation, contribute to skin damage. As a result,
an effort has been made to develop skincare products that not only
protect against UVA or UVB radiation, but provide photoprotection
against visible light and infrared radiation as well. The role of exoge-
nously supplied antioxidants or natural compounds possessing high
antioxidant capacity has been evaluated.
7.1 | Skin endogenous antioxidant systems:
Human skin is equipped with an array of antioxidants and enzyme
systems to protect the cells from damaging effects of free radicals
(Table 2). Antioxidant molecules such as vitamin A, vitamin C, and
vitamin E slow the process of aging either by preventing free radicals
from oxidizing sensitive biological molecules or by reducing the for-
mation of free radicals and quenching the already formed ROS.18 In
addition, enzymes such as superoxide dismutase, (SOD), catalase,
and glutathione biosynthesizing enzymes protect the tissues from
free radicals. The levels of these antioxidants, as well as antioxidant
enzymes, are reduced by intrinsic and extrinsic factors such as age
and atmospheric aggressors. Replenishing these antioxidants either
by topical application or by dietary supplementation can protect skin
from ROS.5,6
Primary or free radical scavenging antioxidants inhibit oxidation
via chain terminating reactions. Inhibition occurs by transfer of a
proton to the free radical species. Examples of primary antioxidant
molecules include glutathione (GSH), alpha-tocopherol, (vitamin E
and derivatives), and ascorbic acid (vitamin C). GSH and ascorbic acid
are water-soluble, whereas vitamin E and biquinols are fat-soluble
and membrane-bound. Because the ability of different antioxidants
to interact with each other creating the already described “antioxi-
dant network,” the combined use of more than one molecule has
been suggested.51 Secondary antioxidants are often used in combi-
nation with primary antioxidants to yield synergistic stabilization
effects. They protect primary antioxidants from degradation. In
human skin, lipoic acid (an organic sulfur containing molecule) serves
T A B L E 2 Endogenous antioxidants present in human skin
Antioxidant compounds Antioxidant enzyme systems
Glutathione (water-soluble) Glutathione peroxidases
Vitamin C (water-soluble) Glutathione transferases
as a secondary antioxidant. Lipoic acid is both water- and lipid-solu-
ble and acts as an essential cofactor for several enzyme systems. It
is able to regenerate (reduce) primary antioxidants such as vitamin C,
glutathione, and vitamin E. N-acetyl cysteine, a thiol amino acid
derivative, which can also regenerate GSH, is another example of a
secondary antioxidant.3
Antioxidant enzyme systems are those enzymes that can regen-
erate antioxidants. These include the following: GSH peroxidases,
GSH reductase, glutathione S-transferases (GSTs), and other
enzymes that directly neutralize ROS, such as superoxide dismutases
(SODs) catalases and quinone reductases. Many of these enzymes
are reduced in aging and photoaged skin. Some of these enzymes
require metal cofactors such as Cu, Mn, and Zn for SOD and Se for
catalase. Providing bioavailable metals to skin can thus boost their
activities and provide improved antioxidant protection to skin.
Although some metal ions are cofactors of antioxidant enzymes,
metal ions can also act as pro-oxidants. For example, under certain
conditions, Fe and Cu can cause oxidation reactions in skin and dam-
age proteins and cell organelles (eg, Fenton reaction catalyzed by
Fe2+ ion). Therefore, metal chelating agents that can neutralize tran-
sition metals and prevent their production of free radicals in skin can
also be considered secondary antioxidants. In addition, several small
metabolites generated within the skin (uric acid, urocanic acids, urea,
several natural amino acid derivatives etc.) can also act as potent
antioxidants. The endogenous (biological) antioxidants present in the
skin (vitamin C, E, GSH, lipoic acid) show a gradient in human epider-
mis (high levels in basal layers to low levels in upper layers). The
levels of these antioxidants decrease with age and photooxidation,
thus providing a rationale for the supplementation of these antioxi-
dants topically in cosmetic formulations. Glutathione, however, is a
tripeptide, and its ionic charges would make it an unlikely candidate
for substantial percutaneous absorption.62 Therefore, further
research is required to substantiate the effectiveness of GSH.
Solar ultraviolet (UV) radiation is one of the most significant
environmental DNA-damaging agents to which humans are exposed
constantly. Sunlight, specifically UVB and UVA, triggers various types
of DNA damage. DNA damage may have several deleterious conse-
quences, such as cell death, mutagenesis, photoaging, and cancer.
UVA and UVB photons can not only be directly absorbed by DNA
creating direct damage, but also by other chromophores leading to
the formation of reactive oxygen species, which may indirectly
cause DNA damage.63 The current preventative measures, such as
sunscreens and topical antioxidants, have not shown to be com-

Tocopherols (Vitamin E) (lipid-soluble)
Ubiquinone (lipid-soluble)
Lipoic acid (water- and lipid-soluble)
Glutathione reductase
Superoxide dismutases
(Cu/Zn and Mn)
Catalase
pletely effective in blocking the effects of UV radiation.
Topical application of DNA repair enzymes serves to supplement
intrinsic DNA repair mechanisms. Several DNA repair enzymes criti-
cal to the prevention of cutaneous nonmelanoma cancers have been

Carotenoids (lycopene, lutein,
zeaxanthin, beta-carotene)—all
from dietary sources
Uric acid, urocanic acid, and other
minor components of amino acid
metabolites (N-acetyl cysteine) in skin
Heme oxygenase
Quinone reductase
isolated and added to topical preparations designed for skin cancer
prevention. These DNA repair enzymes can enhance DNA re-
pair and provide a more efficient response to carcinogenesis and sun
damage.64 UV-induced DNA damage in the epidermis (and to some
extent in the dermis) occurs mainly as UV-induced cross-linked DNA
base pairs and the formation of cyclobutane pyrimidine dimers
MCDANIEL ET AL. | 133

(CPD’s), 6-4 photoproducts (6-4PPs), and 8-oxo-20 deoxyguanosine.
The DNA repair enzymes consist of photoylases (enzymes that
remove CPDs), endonucleases (breakdown the intra-DNA base pairs
or base excision enzymes), and 8-oxoguanine DNA glycosylase-
OGG1 (repair of 80 HdG).65 Topical preparations containing these
DNA repair enzymes have been successfully used for patients with
nonmelanoma skin cancer and Xeroderma pigmentosum66 and actinic
67
keratosis. Topical creams containing these enzymes encapsulated
in liposomes have been used as a successful strategy for treatment
and reversal of these skin conditions. These treatment options
resulted in decreased solar elastosis, reduction in actinic keratosis
and improvement in lentigines, smoothness, moisture and overall
appearance.68
7.2 | Exogenously supplied topical antioxidants for
skin protection
Plant-derived compounds such as carotenoids and polyphenols are
an important group of compounds showing excellent antioxidant
T A B L E 3 Polyphenols and their natural sources commonly used
in Skincare products to protect skin from photodamage
properties. Polyphenols comprise several families of compounds
including tannins (gallic acid esters of glucose or other sugars), lig-
nins, and flavonoids. Flavonoids include several thousand com-
pounds, among them the flavonols, flavones, catechins, flavanones,
anthocyanidins, and isoflavonoids.69,70 A list of commonly used
polyphenols derived from natural sources is shown in Table 3. In
addition to pure polyphenolic compounds, a variety of phytoextracts,
rich in polyphenols, have also been used in cosmetic products for
protection from sun damage. A major challenge in topical antioxidant
supplementation lies in providing the optimal formulation.71 An
effective formula must be optimized for compatibility (between
antioxidants and with other formulation components), stability, pene-
tration, and dosage. In general, antioxidants such as vitamin C are
unstable in neutral and alkaline pH, and are stable at or below the
pKa of the acid form (pH 3.5 or lower). Vitamin C can also be stabi-
lized by other antioxidants such as ferulic acid; this strategy is used
to keep high vitamin C formulas stable. Using appropriate surfac-
tants, emollients, and solvents to enhance the penetration of antioxi-
dants in the skin is a common strategy to enhance the skin
availability of antioxidants. The optimum concentration of an antioxi-
dant is another critical variant. The “higher the better” approach
does not always apply with topical formulations. Stability, bioavail-

Polyphenol compounds Natural sources ability, and the inclusion of supplemental ingredients all impact the
optimal concentration of an antioxidant that can be incorporated in
Resveratrol Red grape skin, peanuts, mulberry,
blueberry, and bilberry. Red wine a formulation. There is evidence that the skin absorption of vitamin
contains significant amounts C is only dose-dependent up to a certain point, and increasing the
Epigallocatechin-3-gallate Green tea, black tea concentration beyond that has been shown to affect the formula-
(EGCG) and other epicatechins tion’s stability. The inclusion of antioxidants in formulations, specifi-
Caffeine, caffeic acid, quinic acid, Grains, fruits coffee fruit cally sunscreens, has been a topic of interest in recent years. It is
chlorogenic acid, and ferulic
well known that pH-dependent antioxidants, such as vitamin C, can-
acid
not be effectively combined with sunscreen formulations. Recent
Quercetin Fruits, leafy vegetables, berries,
studies indicate that select combinations of antioxidants in sunscreen
tomato broccoli etc.
formulas have evidence of clinical efficacy. Further developments in
Phloretin and its glucoside Apple skin
phloridzin this area are still required to understand the parameters for antioxi-
dant usage.
Genistein, daidzein, and their Soya extract
derivatives
Rosmarinic, ursolic and carnosic Sage, rosemary, lavender, oregano 7.3 | Clinical studies using topical antioxidant
acids and other pentacyclic thyme, peppermint, and other
triterpenes herbs
protection against atmospheric skin damage
Silymarin Milk thistle UV-induced erythema can be prevented in human skin by the topical
Curcuminoids From the root of Curcuma longa application of vitamin C compound mixtures. The pretreatment of an
(turmeric) antioxidant mixture consisting of 10% L-ascorbic acid + 2%
Isothiocyanates (sulforaphane) Broccoli sprouts and other similar Phloretin + 0.5% Ferulic Acid has been shown to inhibit erythema
vegetables
induced by 1-5 MED of solar UV radiation.70 UV exposure resulted
Ellagic acid Pomegranate in erythema, sunburn cell formation, thymine dimer formation,
Chlorogenic acid Green coffee beans and fruit MMP-9 expression, and p53 protein expression induction. These sun
Glycyrrhizic acid Licorice damaging effects were suppressed by the topical pretreatment of a
Polyphenols comprise of thousands of natural, plant-derived compounds. vitamin C compound mixture 5 days prior to UV exposure.
They are generally classified as hydrolysable tannins (gallic acid esters of A similar approach using vitamin C compound mixtures (MIX1
sugars) and phenylpropanoids such as lignins, flavonoids, and condensed (15% L-ascorbic acid + 1% Alpha-tocopherol + 0.5% Ferulic Acid)
tannins. Flavonoids include thousands of compounds including flavonols,
and MIX2 (10% L-ascorbic acid + 2% Phloretin + 0.5% Ferulic Acid)
flavones, catechins, flavanones, anthocyanidins, and isoflavonoids. The
following table is a partial list of these antioxidant compounds that are was successful in reducing the ozone-induced damage in human skin
used in cosmetic compositions Oresajo et al.6 in vivo.72 The forearms of subjects were exposed to O3 (0.8 ppm)
134 | MCDANIEL
for 5 days (3 hr per day for 5 consecutive days), which caused the
induction of pro-inflammatory cytokines, NF-kB expression, p65 sub-
unit activation, and increased levels of COX2 and MMP-9 with a
concomitant decrease in type I and III collagen in skin. On the sites
of the forearm pretreated with the vitamin C compound mixtures,
the damage caused by O3 was inhibited. These results suggest that
topical treatment with vitamin C compound mixtures can help pre-
vent the noxious effects of ozone in skin.
Vitamin C compound mixtures (MIX1 (15% L-ascorbic acid + 1%
Alpha-tocopherol + 0.5% Ferulic Acid) and MIX2 (10% L-ascorbic
acid + 2% Phloretin + 0.5% Ferulic Acid) were also proven effective
in preventing IR-A-induced skin damage. Pretreatment of human skin
in vivo with the vitamin C compound mixtures significantly
decreased IR-A-induced MMP-1 expression.34 Photoaging may be
prevented and treated with a variety of modalities, including combi-
73
nation therapies comprised of topical antioxidants and sunscreens.
A combination of SPF 30 sunscreen with and without an antioxidant
cocktail containing grape seed extract, vitamin E, ubiquinone, and
vitamin C was evaluated for protection of human skin against IR-A
radiation-induced MMP-1 upregulation.74 As expected, exposure to
IR-A radiation significantly upregulated MMP-1 expression, as com-
pared to unirradiated skin, and this response was significantly
reduced with the application of the SPF30 sunscreen plus the
antioxidant cocktail prior to IR-A radiation. In contrast, treatment of
human skin with the SPF30 sunscreen alone did not provide signifi-
cant protection.
The common denominator that links skin damage to the different
solar wavelengths is the enhanced production of reactive molecule
species (RMS) within the skin cells followed by increased oxidative
stress. A clinical study which evaluated a combination of broad-spec-
trum sunscreen and select antioxidants, that provide protection from
total radiation while promoting skin repair, was conducted.75 In vitro
studies have indicated this combination could play a role in prevent-
ing the formation of UV-induced sunburn cells and cyclobutane
pyrimidine dimers while preserving or improving the expression of
ECM genes. In addition, ex vivo studies suggest the combination
may prevent IR-A-triggered fragmentation of elastin fibers and
expression of MMP-1. Initial clinical studies indicate that this broad-
spectrum sunscreen in combination with select antioxidants reduces
the increase in surface temperature seen with IR radiation. A signifi-
cant improvement in the appearance of lines and wrinkles was
reported as early as week 2 in patients using this blend. This study
suggests that select antioxidants along with SPF protection can help
counterbalance the deleterious effects of free radicals on skin cells
by promoting endogenous repair.75
8 | PART VII: FUTURE TRENDS
New approaches for therapeutic intervention of atmospheric skin
damage are emerging. While our current understanding of the full
impact atmospheric aggressors have on premature skin aging is still
incomplete, recent discoveries are providing compelling new
ET AL.
scientific information which are guiding future therapies. The gaps in
current protective measures are clear, and innovative new
approaches are required to address these issues. The concept of
inside/outside protection from environmental exposure requires fur-
ther exploration, as well as how to produce sustained protection
throughout daily exposure. As direct protective measures are not
available or are impractical for some of the emerging light and pollu-
tion damage, the role of antioxidants is a vital part of defending
against this damage. In addition to topical antioxidant treatment, oral
antioxidant therapies have also been shown to be effective in pre-
venting sun damage to skin. The benefits of a multicomponent nutri-
tional supplement on photodamaged skin were recently
demonstrated.76 Twenty-four-week dietary supplementation with a
multicomponent nutritional supplement improved the skin quality
index in healthy 35- to 65-year-old women with Fitzpatrick skin
types I-IV. A number of studies have also demonstrated the effec-
tiveness of antioxidants on photoprotective benefits when given
orally.77–80
New in vivo testing methods to evaluate the content as well as
the efficacy of antioxidants on human skin are being developed.81
Direct detection of reactive oxygen species (ROS) has recently been
developed for evaluating antioxidant efficacy in vivo, under physio-
logical conditions over time.82 Successful evaluation of ROS species
and scavenging of these molecules via fluorescence measurements
of tape strips to measure skin’s natural antioxidant defense capabil-
ity,83 and the efficacy of topically applied antioxidants, have been
developed.84 New fluorescent probes are being developed to reveal
the presence of the ROS on tape strips of stratum corneum.
In the area of ingredient development, novel phytoextracts with
improved antioxidant activity are continuously explored. New syn-
thetic antioxidants with sunscreen booster capabilities are being
developed to provide UV protection from outside, as well as antioxi-
dant protection from the inside of the skin.41 Plant stem cells pre-
sent a novel approach and show promise for future formulations.
Antioxidant conjugates with anti-aging peptides are patented for skin
applications.85,86 New formulations (eg, liposomes) and novel deliv-
ery options (eg, iontophoresis or carrier molecules) for targeted and
specific delivery are being evaluated.
In addition, combinations of multiple antioxidants and chemical
components have been designed with the intent of providing protec-
tion for all types of ROS to provide complete protection. This com-
plex was tested both in vitro and in vivo in a series of tests. First,
the measurement of ROS in skin explants following application of
the new complex, another current AOX serum, and saline controls. A
standard peroxide assay was completed in 2 separate trials on the
samples, and it was determined that there was a reduction of 53%
and 41% peroxide in the new complex relative to the current AOX
serum (P = .01, test 1; P = .005, test 2, respectively). The complex
was also tested for minimal erythemal dose (MED) in 5 human sub-
jects. Two 5 cm 9 5 cm sites were marked on the lower back, one
was randomized to be treated by the AOX complex for 4 days and
the other served as untreated control. The treated and untreated
sites were irradiated with 19, 29, and 39 each subject’s MED
MCDANIEL ET AL.
(determined for each individually previously). Digital images, redness
measurements, and 3 mm punch biopsies were collected from each
subject for analysis of biomarkers. The AOX complex-treated sites
demonstrated 94%, 76%, and 50% less UV-induced erythema at 19,
29, and 39 MED (P = .025, P < .001, and P = .004, respec-
tively).Additionally, there was skin illustrated by reductions in thy-
mine dimers (P < .02), MMP-9 (P < .005), p53, and sunburn cells.
Education of both the public and the medical community about
these dangers will be required. Overall, the future focus of skincare,
with regard to combatting the effects of atmospheric skin aging, will be
the development of novel evaluation technologies and the use of
potent and stable topical antioxidants both to prevent and repair dam-
age.
ACKNOWLEDGMENT
The authors would like to thank Sewon Kang MD, MPH, FAAD for
his contributions to the visible light segment of this manuscript, and
Kumar Pillai PhD for his critical review and editorial assistance with
this manuscript.
ORCID
David McDaniel http://orcid.org/0000-0002-7595-5456
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How to cite this article: McDaniel D, Farris P, Valacchi G.
Atmospheric skin aging—Contributors and inhibitors. J
Cosmet Dermatol. 2018;17:124–137.
https://doi.org/10.1111/jocd.12518
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