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33
Antiaging Actives in Sunscreens
Karl Lintner
Sederma, Paris, France
Introduction
Strategies of Antiaging Actives in Sunscreens
Prevention of Damage (“Slowing Down the Aging Process”)
Vitamins
Botanicals
Enzymes
Miscellaneous
Treatment of UV-Induced Age Symptoms
Barrier Repair
Tissue Repair
Conclusions
References
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INTRODUCTION
The first and second editions of Sunscreens did not contain a chapter equivalent
to the present one. Including “antiaging actives” in the present book reflects some
of the changes occurring in cosmetic formulations and marketing strategies. As in
so many other domains, we see a blurring of frontiers, a mixing of categories, and
a (deliberate?) gradual disappearance of clear distinctions and definitions.
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Although the title of Sunscreens has not changed and certainly suggests
to most readers the general category of “cosmetic products used on the skin
during extensive sun exposure in order to protect the skin against the deleterious effects of direct sunlight,” the apparent simplicity of this description is deceptive. Even more ambiguity is contained in the title of this chapter, with the two
powerful, but vague, concepts of “antiaging” and “actives” (or “cosmeceuticals,”
as these ingredients are sometimes, erroneously, called). It appears therefore necessary to start with a few definitions of our own, that we will use within the scope of this
chapter, without prejudice to different meanings in other parts of the book.
Let us call “sunscreens” the finished cosmetic consumer product that bears
a clear message of “protection against solar radiation” such as the prevention of
erythema, sunburns, sometimes even cancer. This would include in most cases
“suntan lotions,” “sun care products,” “sunblocks,” and the like. Generally, it
would not include “after-sun lotions” and “self-tanning products.” Although
the word “sunscreen” is sometimes also used to designate the chemical entity
that blocks the sunlight from reaching the skin, these chemicals contained in
“sunscreens” should be called ultraviolet (UV) filters or UV reflectors.
Difficulties in nomenclature also arise because of different legislations in
different parts of the world (cf. the section on regulatory aspects) and because
of technical and marketing considerations: a “sunscreen” of today contains,
more and more often, specific skin and/or body care active ingredients, accompanied by a corresponding claim (this is the reason for this chapter); on the other
hand, an increasing number of classic “skin care” (i.e., face care, lip care,
makeup, body care, and even hair care) products boast sun protection factors
(SPFs) in the 5– 15 range. These products have primary skin care claims
(moisturizing, antiwrinkle, firming, . . .) and offer the sun protection as an
additional benefit. So where is the borderline between the two? A “sunscreen”
of SPF 15 with an additional antiwrinkle claim is a “sunscreen” (e.g., Biotherm’s
recent launch with exactly that name: “Antiwrinkle Suncare”) because the
marketeer positions the product as such (advertising, point of sale, timing of
promotional activity), whereas Yves-Saint Laurent’s spring launch of Age
Expert (“age-defying cream”) has an SPF15 but is clearly not positioned as a
“sunscreen”. It claims to contain DHEA-like actives and lycopene as a free
radical scavenger and is a “classical” face care product.
In any case, the New Zealand Society of Dermatology proposes on its website
that “sunscreens should be applied daily, more often when outdoors.” While this
makes sense, it is certainly not the daily routine of the general population.
How about “actives”? My opinion and arguments for it can be found in the
proceedings of the PCIE conference (1). Briefly, any cosmetic ingredient that has
(i) demonstrated cosmetic activity on human skin (or its appendages), (ii) a substantiated claim, and (iii) a plausible “story” to go with it can be considered an
active: this encompasses then the wide field of ingredients (such as found in
the CTFA/INCI dictionary) from botanicals (various types of plant extracts) to
pure chemical entities that possess a function that is clearly different from the
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galenic purpose (emulsifiers, texturizers, thickeners, preservatives, fragrances
etc.). Again, it may occur that an ingredient functions as an “active” in one
product (positioned as such by the marketeer) and as a basic ingredient in
another product (glycerin, lecithin, and lanolin come to mind). In the main body
of this chapter, we shall concentrate on “actives” that are particularly suited or are
already in use in the general category of “sunscreens,” “actives” that make sense
in the context of sun care and skin protection/treatment.
We can therefore now drop the quotation marks from the word active.
Finally, “antiaging” (again with quotation marks): the term is catchy,
seductive, but very vague. Some countries have regulations forbidding the use
of this “claim” in cosmetic advertising or on the packaging.
As usual, there are two aspects to the concept: prevention and treatment.
Antiage prevention implies that a consumer product helps “reduce the speed of
the appearance of the clinical signs of (cutaneous) aging,” based on the protective
active contained in the product. Antiage treatment promises to reverse (some of )
the visible signs of skin aging (such as wrinkle reduction, firmness improvement,
moisturization of dry skin, etc.), based on actives that “restore, regenerate,
repair, . . .” skin items such as “barrier, extracellular matrix, collagen fibers,
hydrolipid balance” and the like.
If one really wants to get a more global perspective of the antiaging field in
general, books like Pharmacological Intervention in Aging and Age-Associated
Disorder (2) are a good place to start. Yu and Yang introduce the discussion
there with a “critical evaluation of the Free Radical Theory of Aging” (see in
following text, the impact of free radicals and antioxidant strategies). Many
articles and references therein are useful for finding ideas in “antiaging”.
In the following sections we consider both types of “antiaging” actives and
their respective merits in sunscreens.
I apologize for the lengthy introduction and the many quotation marks and
hope the reader has thus a clear picture of where this chapter is headed and what
the various terms are meant to convey.
In view of the many detailed chapter headings before and after this one in
the present book, it would be redundant to repeat much that is described about the
dangers of the sun to our skin, about the photobiology, the physics of filters, the
differences between chronological aging and photoaging. If modern UV filters
are so well suited to protect us against the sun’s dangerous rays, for what
reason (other than a marketing and/or label claim) should the formulator of a
modern sunscreen add antiaging actives to his product?
For one, and most importantly, UV filters are not absolute: even an SPF 60
(not allowed as a claim everywhere) will wear off with time, or may not be
applied in sufficient amount from the beginning, or the exposure of the person
wearing it continues beyond the period of protection. Any well-chosen additional
active in the product will help decrease the damages that are not prevented by the
UV filter. For instance, this seems to be particularly true for the combination
of UV-A filters with antioxidant protective molecules. The presently available
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UV-A filters are rarely (not?) able to block out all of the UVA radiation such as to
prevent all free radical generation in the deeper layers of the skin.
Second, the trend in all cosmetic formulas and products goes that way:
makeup mascaras, foundations, lip sticks, powders, also cleansers, body care,
and scalp care SKUs all contain actives for additional benefits. True skin care
needs a global, and continuous, approach. We need the sunlight for the synthesis
of vitamin D and for our psychic well-being (“healthy tan”), and we desire silky,
youthful skin: for this we need the optimum combination of sunscreen and skin
care actives.
Before reviewing the traditional actives used and useful in sunscreens and
presenting a few new ideas in the final section, Table 33.1 summarizes the rationale for the different types of actives that might make sense in sunscreens,
Table 33.1
Rationale for Adding Different Types of Actives to Sunscreens
Type of danger/
damage
Dryness
Dryness
Skin sagging
Wrinkles
Skin thinning
Roughness
Inflammation
(redness)
Melasma, age
spots
Yellowing,
elastosis
Telangiectasis
Blackheads,
whiteheads
Free radical
damage
Lipoperoxidation
Enzyme damage
DNA damage
Apoptosis
Type of active
proposed
“Cause”
Moisturizer/humectant
Barrier repair: ceramides
Firming, elasticity
enhancing
Tissue repair: ECM,
collagen stimulation,
cell metabolism,
skin tighteners
Tissue repair: ECM,
collagen stimulation,
cell metabolism, skin
tighteners
Smoothing, emollients
Anti-inflammatories,
soothing actives
Skin “whitening”
IR, UV-A, UV-B
UV-B
UV-A, UV-B
Elastase inhibitors
UV-A, UV-B
Anticouperose, veinotonic
Antiacne
UV-B
UV-B
Radical scavengers
UV-A
Antioxidants
Enzymes, pseudoenzymes
DNA repair
Cell repair
UV-A
UV-A, UV-B
UV-B
UV-B
Increased
sophistication
UV-A, UV-B
UV-A, UV-B
UV-B
UV-A, UV-B
UV-A
P
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although some appear far-fetched. Very roughly, one can partition these actives
along the following lines.
UV-B rays generate actinic damages that need antiage treatment (long-term),
UV-A radiation needs to be addressed with actives more immediately: to prevent
oxidation, to scavenge the radicals, to reduce local inflammation and thus avoid
long-term damages of molecular nature to accumulate (antiage Prevention).
STRATEGIES OF ANTIAGING ACTIVES IN SUNSCREENS
Prevention of Damage (“Slowing Down the Aging Process”)
Vitamins
One of the first and most widely used categories of actives formulated in sunscreens is the one comprising the vitamins C and E, sometimes A (retinoids)
or a few of the B group.
The literature on the effects of vitamins C and E as photoprotective agents
in cell cultures (in vitro) and on animals is impressively large. Although general
consensus is expressed that the protective effect afforded by these molecules
“might be beneficial” to human skin, there is astonishingly little documentation
of the benefits of vitamin uses in cosmetic finished products, especially sunscreens, on human skin (in vivo). Pehr and Forsey concluded in 1993, that
“after 44 years of research there is still scant proof of vitamin E’s effectiveness
[. . .]; it is of no use in [. . .] skin damage induced by ultraviolet light” (3). It is not
the purpose of this chapter to present an exhaustive review of this topic, as
antioxidants will also be discussed in a separate chapter. Such a review can be
found, for instance, in Pinnell (4) in the form of a lecture, followed by a quiz.
A rapid overview of the literature however shows that research into the
effects of topical vitamin application continues, many papers focusing on combinations of vitamins, such as E and C, E and A.
Vitamin E (a-tocopherol) is a ubiquitous, liposoluble molecule, the major
activity of which is as an antioxidant. Although more powerful antioxidants can
be found in nature, vitamin E is most accessible, by synthesis or extraction, is
colorless and well documented as being toxicologically safe. Ritter et al. (5)
show the beneficial effects of tocopherol application before UV irradiation on
mice. They note an increase in epidermal thickness, which might contribute to
the decrease in the number of sunburn cells. The concentration of tocopherol in
the vehicle (50% in ethanol) is however quite unrealistic in cosmetic and sunscreen
applications. Saral et al. (6) studied vitamin E acetate (the more stable ester form of
vitamin E that is preferentially employed in sunscreens) by applying it topically for
3 weeks on guinea pigs before a single UV-B dose. Measuring lipid peroxide levels
and enzyme scavenging activity (cf. also following text) these authors find
that tocopherol acetate did prevent the UV-B-induced effects. Trevithick et al.
(7) studied the application of tocopherol acetate immediately after UV-B irradiation on mice and found decreases in sunburn cell number, inflammatory infiltration,
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and edematous swelling. Even delayed application (8 h after irradiation) afforded
some protection, again however at high concentrations (5%).
Another interesting study was carried out on the antioxidant activity of
a-tocotrienol in topical application (8). Although it did not address UV
irradiation, the oxidant damages were induced by benzylperoxide (10%).
Application of a 5% w/v preparation of a-tocotrienol for 7 days reduced the
BPO-induced lipid peroxidation significantly. For cosmetic purposes, 5%
vitamin E again appears unrealistically high.
Vitamin C has several properties, which make it attractive to the formulator
of sunscreens. Not only does the molecule possess antioxidant (reducing)
activity, but it also stimulates the synthesis of collagen (in vitro) and contributes
to the hydroxylation and the correct lay-down of collagen fibers in skin tissue. Its
cosmetic use is found particularly in “antiwrinkle” creams (based on the collagen
stimulation claim) and in “skin whitening” products (based on the inhibition of
melanogenesis).
Darr et al. (9) investigated the topical use of vitamin C on pigskin and
found protection against UV-B damages as measured by erythema and sunburn
cell formation. As innate vitamin C concentrations decrease as a result of UV
irradiation, topical supplementation is a potential strategy to counter this deleterious effect of sunlight. Follow-up studies later confirmed the protective effect of
vitamin C, when formulated together with a UV filter (oxybenzone) (10).
An even more broad-spectrum protection is achieved with the combination of
vitamin C, vitamin E and the sun-filter, as vitamin C affords particular protection
against the UV-A-mediated phototoxicity in this animal model.
Some more recent studies suggest benefits to using vitamin C together with
vitamin E in topical products such as sunscreens. Moison et al. (11) describe a
synergistic effect between the two molecules in protecting the lipids, also on
pigskin; moreover, the inherent vitamin C and E content of the skin is maintained
at its levels, against depletion by UV-B radiation. Steenvorden and Beijersbergen
(12) investigated vitamins C and E independently and conjointly: topical application on mice before UV-B irradiation led to reduced immunosuppression. In
their model, no synergy was found, however. Both studies cited showed that
vitamin C concentration needed to be about 500 – 1000 times higher than
vitamin E to obtain comparable efficacy.
Human in vivo studies were carried out by Dreher et al. (13) using
three antioxidant molecules, alone or in combination: vitamin C, vitamin E,
and melatonin. Slight synergistic results are obtained by combining the ingredients two by two or in a threesome and applying them in a vehicle 30 min
before UV exposure. Skin color and skin blood flow were used as markers for
UV-induced damage.
The same authors then studied the effects of these combinations when
applied 30 min, 1 h, and 2 h after UVR exposure, using the same end-points
(14). As no protective effect whatsoever was noted, the authors concluded that
UVR-induced skin damage is rapid; antioxidants can alleviate or prevent
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damages only when present before or during sun exposure. Melatonin is of course
used in oral supplementation against jet lag, but Reiter et al. (15) describe in
much detail its antioxidant, radical scavenging activity, and life span prolongation! Lin et al. (16) tried a further combination of 15% vitamin C and 1%
vitamin E on pig skin and found that repeated application of this cocktail
reduced erythema, sunburn cells, as well as thymidin dimers (DNA damage)
generated by repeated UV irradiation with a solar simulator. While the protection
against this latter aspect is of importance in the prevention of mutations and their
consequences, the sunscreen formulator may again have difficulties in incorporating these levels of ingredients in the finished product.
And what about vitamin A and its derivatives? Kligman (17) in 1987 recommended the use of retinoic acid to replenish the inherent pool of this molecule
in the skin after its depletion by UV light. Together with Schwartz (18) he also
demonstrated that post-UV irradiation treatment with 0.05% retinoic acid stimulated collagen synthesis in vivo in albino hairless mice. Ho et al. (19) showed in
1992 that retinoic acid augments UV-induced melanogenesis, an interesting side
effect to all other activities known for retinoids. The study was carried out on a
specific mouse strain and confirmed on two human volunteers. As retinoic acid is
considered a prescription drug in most countries, the cosmetic industry became
interested in retinol, retinol esters, and retinaldehyde. Thus, more recently,
Boisnic et al. (20) published a study with a retinaldehyde cream, applied to an
ex vivo human skin model. Eighteen days of regular UV-A exposure simulated
photoaging; this was followed by application of the retinaldehyde cream for
2 weeks. The UV-A-induced alterations of collagen and elastic fibers were
reversed by the retinaldehyde, and collagen synthesis rates were restored to the
levels of unexposed skin. Sorg and colleagues (21,22) have interested themselves
in the combination effects of retinoids and vitamin E; they find certain specific
benefits, depending on the type of irradiation (UV-A, UV-B), the time of application (before or after exposure), and other parameters.
More data on human volunteers in studies on retinoids in conjunction with
UV radiation can be found in Kang et al. (23). One opposing opinion is, however,
expressed in Ref. (24) under the aggressive title: “Tretinoin and cutaneous
photoaging: new preparation. Guaranteed adverse effects!”
Knowing that the skin contains various antioxidants all together, a more
holistic approach was taken by Greul et al. (25) where a combination of
b-carotene, lycopene, vitamin C, vitamin E, selenium, and proanthocyanidins
was tested in a double-blind placebo-controlled human study involving UV
irradiation and skin analysis. Findings concerned significant differences in
MMP 1 and MMP 9 expression and a slowdown in the development and grade
of UV-induced erythema. This reference is given tongue in cheek (excuse
the pun), as the study did not use the antioxidant mixture topically, but orally.
Somewhat similar results were obtained in the SUVIMAX study (26).
In summary, “vitamins are good for you.” Their use in sunscreens is widespread; based on the numerous studies, even if most of them are animal or in vitro
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studies, their claim to “antiaging” activity is not far-fetched. Vitamins C and E
would be considered more of the “preventive” type (antioxidant, to be used
before or during sun exposure), vitamin A and derivatives are more the
“repair” type, undoing some of the UV-caused damages. Their main drawback
is the difficulty in formulating stable vehicles, such that the right amount of efficacious vitamins can be guaranteed for sufficient shelf life.
Botanicals
Like the antioxidants, botanicals, also called plant extracts, are also discussed in
another chapter in the present book. Nevertheless, they merit a short mention
here, as an increasing number of ingredients of plant origin are offered and
used that are tested and positioned as “antiaging” actives, and thus used or
useful in sunscreens.
Plant extracts cover the spectrum from hydroglycolic solutions of analytically ill-defined nature to pure, isolated, chemically identified molecules, and all
products that present intermediate stages of purification. The reputation of the
plant kingdom is one of almost unlimited source of potential healing activities,
thousands of substances yet undiscovered.
A closer look reveals, however, that with some notable exceptions, a few
broad categories suffice to describe the benefits obtained from plant extracts
for cosmetic claims: we find antioxidant activity (polyphenols, vitamins, flavonoids), anti-inflammatory properties (nonsteroidal enzyme inhibitors), tissue
repair molecules (di- and triterpenes). All of these activities can be employed
for “antiage” claims, all of them make sense in the context of sunscreen formulation. A few references gleaned from the peer-reviewed literature shall illustrate
this concept. It is of course impossible to list here all the commercially available
plant-derived cosmetic ingredients (cf. CTFA dictionary) that are claimed to be
antiaging based on some or another in vitro, ex vivo, or even in vivo test with or
without UV irradiation included in the test protocol.
Green tea is a favorite among the botanicals with well-known reputation.
In vitro scavenging of hydrogen peroxide and prevention of UV-induced
oxidative damages on skin cells in culture by various fractions of green and
black teas, including purified epigallocatechin gallate (EGCG) were described
by Wei et al. (27). The pure molecule enhanced the observed activity and is considered the major active substance in these preparations. An in vivo study by
Vayalil et al. (28) on hairless mice confirmed the prevention of UV-induced
lipid peroxidation by green tea polyphenols, such as EGCG. Interestingly, the
authors also quantified the amount of inherent antioxidant enzymes (catalase,
glutathione peroxidase): whereas UV irradiation depleted these enzymes in
the skin, EGCG application before single UV-B doses prevented this loss by
50 –90% (see also following text).
Less well known botanical extracts such as those obtained from methanolic
maceration of Capparis spinosa L. buds (29), crude ethanol extracts from Culcitium reflexum H.B.K. (30), or Chromolaena odorata (31), to cite just a few exotic
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ones, all contain flavonoids, phenolic acids, coumarins and the like. They all
show in vitro antioxidant activity that can be used for antiage claims in sunscreens. Prunus persica Batsch extracts rich in kampferol glycoside derivatives
(32) also showed inhibition of UV-induced edema on mouse ear and tumor
prevention (33) in UV-B- and UV-C-irradiated mice.
A further aspect, not yet widely recognized or mentioned in this context of
sunscreen protection by antiaging products is discussed by Okano et al. (34). It is
known that with advancing age, proteins and sugar molecules react, unspecifically, in a process called glycation to give what has been aptly termed, advanced
glycation endproducts (AGEs). Okano et al. describe that AGEs are not
only inherently a sign of aging skin (less elasticity of the glycated proteins)
but also contribute actively to aging by reducing fibroblast proliferation,
matrix synthesis, and by generating reactive oxygen species (ROS) during
UV exposure! He then describes that unspecified extracts of Paenia suffruticosa
and Sanguisorba officinalis inhibit AGE formation and scavenges hydrogen
peroxide at the same time.
A review of photochemoprevention by botanical antioxidants in view of
their use in sunscreens is given in Ref. (35).
A typical example of anti-inflammatory activity of a botanical extract
useful in a suncare product is described by Hughes-Formella et al. (36). UV-B
irradiation, provoking erythema on the back of 30 volunteers was followed by
application of a Hamamelis virginiana lotion 7, 24, and 48 h after irradiation.
Significant differences in erythema values (chromameter, visual scoring) were
observed with respect to the vehicle lotion. This type of use is, however, better
suited for after-sun products than for the sunscreen itself and we shall not
dwell on these applications.
Enzymes
We have cited earlier two studies (6,28) that mentioned antioxidant enzymes of
the skin. This aspect has received less attention in the sunscreen and protection
field; two reasons may account for this. Technical difficulties in analyzing enzyme
activities on human skin, and the inherent instability of enzymes which
make them hard to formulate and stabilize in finished cosmetic sunscreens.
Nevertheless, basic research into the innate enzyme defense system of the skin
has progressed, and a number of in vitro, animal and human in vivo studies
point to the delicate balance that is required between the various enzymes in
the skin.
We shall first review the salient facts about cutaneous defense enzymes and
then discuss the possibility of using antiaging actives within this scope.
Once again, the problem turns around the free radicals, lipoperoxidation,
and other oxidative damages. ROS such as superoxide anion, hydroxyl radical,
singlet oxygen, and hydrogen peroxide cause numerous deleterious effects on
structural and functional (enzyme) proteins, lipid membranes, tissue polysaccharides, and genetic material (DNA). The molecules present in the skin that are
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supposed to protect us against these damages are the vitamins (see preceding
text), a few other antioxidants (melanin, urocanic acid, glutathione, and ubiquinone) and specific enzymes: essentially superoxide dismutase (SOD), glutathione
peroxidase (GPO), and catalase.
It now has become evident that these inherent antioxidant defense systems
of the skin are rapidly overwhelmed by the amount of sun exposure we stress
them with in today’s lifestyle. Not only are vitamins C and E depleted in the
skin by UV irradiation, but the same also occurs with the enzymes. Miyachi
et al. (37) describe the decrease of SOD activity in mice after a single dose of
UV light, Pence and Naylor (38) confirm this observation in hairless mice and
add that catalase activity also was significantly depressed. Punnonen et al. (39)
extended this observation to human epidermis. A quantitative analysis of the
localization of these enzymes (and nonenzymatic antioxidants) in murine skin
and their decrease after UV exposure is presented by Shindo et al. (40). These
acute effects are in opposition to long-term irradiation, as Okada et al. (41)
show: after 36 weeks of regular UV exposure, SOD activity increased with
UV-B, but not with UV-A; catalase activity however was strongly depressed
by UV-A. Although catalase, which detoxifies hydrogen peroxide into water
and molecular oxygen is the enzyme most frequently cited as being necessary
in conjunction with SOD, which transforms the superoxide anion into hydrogen
peroxide (itself a cytotoxic molecule), the two enzymes do not react in similar
ways to long-term UV exposure. A few, more pointed investigations into the
details can be found in Shindo and Hashimoto (42), Filipe et al. (43), Aricioglu
(44), and Naderi-Hachtroudi et al. (45) and references therein.
A thorough investigation on humans, carried out over winter and summer
season, confirms this fact: catalase is easily destroyed by UV-A light in summer,
more active in winter (oh, the logic of nature!), whereas SOD is much more resilient (46). This then leads to a potential buildup of hydrogen peroxide in the skin,
not necessarily the best thing to occur. The need for a balanced antioxidant
enzyme system thus becomes apparent.
Two approaches are possible: (a) to stimulate and/or protect the innate
enzyme system, so that even under UV exposure, it retains its efficacy, and (b) to
supply the lacking enzymes by topical application, for instance, within a sunscreen, as well as presun or postsun products.
Hoppe and colleagues (47), as well as Maes and coworkers (48) presented
examples of the first strategy: they show that molecules such as salicin in skin
fibroblasts (Hoppe) and vitamin D derivatives or betulinic acid in keratinocytes
(Maes) are able to stimulate the synthesis of heat shock proteins which are
able to protect the catalase against UV-induced degradation. These molecules
could therefore be used advantageously in sunscreens as antiaging actives in as
much as they induce protection of our own antiaging defense systems. Other
molecules that induce heat shock could be worthwhile looking for. A more controversial proposal is put forward by Inal et al. (49) who show that treatment of
rats with quercetin (a plant-derived molecule) reduces the UV induced damages
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to SOD, catalase, GPO significantly. Quercetin is often described as mutagenic
(based on Ames tests) and its behavior under UV light (photostability) would
need investigation.
Once more it may be instructive to refer to orally administered substances
such as deprenyl, a monoamine oxidase B inhibitor which upregulates SOD
activity and has shown to prolong the “remaining life span of old rats” (50).
Antiaging concepts may be found in many strange places.
Strategy (b) has a few limitations. Usually available enzymes such as SOD
and catalase (extracted from yeast or other biotech sources) are not easy to stabilize in cosmetic formulas, to say the least. Complicated packaging stratagems or
encapsulation techniques may overcome the problem; it is, however, well known
that enzymes—relatively large proteins—are inherently unstable in aqueous
environments, and also heat and UV sensitive. Furthermore, SOD alone on the
skin would lead, at least theoretically, to a buildup of hydrogen peroxide,
already described by Maes and colleagues (46) as being the “natural” problem
of seasonal variations of these enzyme activities. Adding the fragile catalase is
not only difficult, it is also not possible for any formula sold in Europe
because of an archaic prohibition of catalase use in cosmetic products (51).
A neat solution to this problem is afforded by antioxidant enzymes originating from organisms that live and thrive under extreme conditions of heat: the
“extremophiles.” Discovered a little more than a decade ago, these bacteria
live close to the hydrothermal vents at the bottom of the ocean, at temperatures
that can reach 80 –1008C. It is possible today to cultivate these organisms at sea
level, in industrial fermenters, and to extract heat-stable antioxidant enzymes that
mimic the skin’s SOD, catalase and GPO activity. Further, the enzymes are the
more active, the hotter it gets, up to 1008C (which is unrealistic from a cosmetic
point of view anyway). They are thus ideal for incorporation into sunscreens
where the exposure to UV and to the sun’s heat will not only not destroy the
defensive activity afforded by them, but also even increase it with increasing
outside temperature of irradiation. An active ingredient based on this concept
is described by Lintner et al. (52,53). Thermus thermophilus bacteria, harvested
6000 ft below the California coast, are fermented at 758C, then extracted and concentrated to yield a high potency solution containing superoxide anion dismutating (SOD), hydrogen peroxide converting, and GPO mimicking activity. In vitro
tests carried out on this cosmetic ingredient include protection of human
fibroblasts in culture, lipoperoxidation inhibition, protection of DNA against
the formation of 8-oxo-guanidine, collagen contraction. Studies on human
volunteers show the persistence of cutaneous catalase against UV-A irradiation
and a decrease in in vivo lipoperoxidation of the stratum corneum.
Miscellaneous
A few more (nonexhaustive!) ingredients of diverse nature that might be of interest in photoprotection can be found in the literature. Pinnell and coworkers have
reviewed the evidence supporting the antioxidant role of zinc in UV protection
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(54), Mitani et al. (55), on the other hand, reminds us that iron is bad for the skin
and that Kojic acid treatment prior to sun exposure may help reduce UV-induced
wrinkling (in hairless mice).
A complex but very promising concept is presented by Maes and coworkers
(56): they found that creatine, the precursor molecule to phosphocreatine (PCr),
protects cells from UV damage either by pretreatment or after UV irradiation.
The story involves cellular energy, as creatine is neither a filter, nor an antioxidant, but a key molecule in the chemical energy management (ATP, PCr) of
the cells. The additional energy reserves afforded by supplementation in the
culture medium with creatine allow the repair mechanisms (thymidine dimer
excision, for instance) to function more efficiently, thus protecting the cells
against apoptosis and further damage. These authors confirm the beneficial
effects of creatine in a clinical study where they show that the number of UVinduced sunburnt cells is diminished by topical application of creatine.
An intriguing study from back in 1978 shows that caffeine and theophylline
protect mice ears from UV-induced tumors (57). Knowing that these molecules
stimulate the pool of cyclic AMP (an essential ingredient in the cellular processes
of both melanogenesis and lipolysis), their use in sunscreens has been promoted
in Sun Active Body Refiner (SPF 8) by Lancaster/Coty in a recent launch.
Treatment of UV-Induced Age Symptoms
As mentioned in the introduction, “reversing” some of the signs of aging is of
course also considered “antiage” activity. Is it realistic? Can anything but retinoic
acid reduce some of the wrinkles, the sagging skin, the dryness, and loss of tonus
that comes with (photo)aging?
And even if so, does it make sense to include these antiaging actives in
sunscreens? Apart from price considerations in the highly competitive market,
the relatively seasonal aspect of sunscreen use and the relatively short contact
times (when compared with “standard” skin care products) would cast doubt
on the proposition.
Whatever the theoretical considerations say, the market has already acted
and begun to introduce sunscreens that contain various actives with some type
of antiage and repair claims. It is not for us to judge the scientific validity, but
to describe possible concepts and ideas that may be useful to the marketeer, if
sufficiently documented by experimental evidence.
Once more, it is not possible to review here the enormous mass of antiage
and wrinkle repair ingredients of synthetic, marine, botanical, or biotechnological
origin proposed on the market, which all might be considered, based on their
merit, for inclusion in sunscreens.
We shall examine two major aspects—barrier repair of the skin surface and
tissue repair in the deeper layers—and discuss some actives that appear to have
clearly perceivable, demonstrated benefits. Contrary to the “prevention type”
products discussed above, the interaction between the repair active and the
Antiaging Actives in Sunscreens
685
sunscreen and/or the UV irradiation is not compulsory. We shall simply review
the “repair” aspect as a possibility to boost sunscreen marketing appeal, an added,
but logical, benefit to the use of these products.
Barrier Repair
Scanning the literature on the relationship between skin barrier and UV
irradiation, one realizes quickly that the subject is more complex than expected.
First: definitions. For our purpose here, we limit the terms barrier, barrier
function, and barrier repair to the epidermis, essentially to the stratum corneum
(SC) where ceramides, cholesterol, and corneocytes constitute the cutaneous
barrier. Although this is purely arbitrary—and not necessarily consistent with
my general view of barrier repair—it is convenient and simple for the purpose
at hand.
On one hand, UV-B irradiation stimulates barrier synthesis: the epidermis
thickens, ceramide synthesis is increased, involucrine (a distinct marker protein
of cell differentiation and cornification) increases (58 –60). On the other hand,
this seems to be a transient effect, an immediate reaction of the skin to the
danger of UV rays. Long-term effects of UV exposure clearly lead, especially
in old age, to a diminished barrier function (61,62); all systems of the skin
suffer through photoaging, and so does the capacity to repair the important structure that is called stratum corneum: enzymes necessary for the process are
fewer in number and less active, lipids are peroxidized, the skin is thinner, and
the normal desquamation process is altered.
When should barrier enhancement actives be used in a sunscreen? Only for
“mature” skin? Starting when? Or as a preventive (again?) measure, right from
the start, even on young skin? Too few in vivo studies are available to form a
clear prescription. A few ideas may help in making one’s own decision on the
type of “barrier function antiage” active to use in sunscreens.
Hydroxy acids: Lactic acid, one of the most widely used actives in skin
care, is known to stimulate many processes in skin, in particular the proliferation
of keratinocytes and barrier repair. A 4-week in vivo study by Rawlings et al. (63)
showed that L -lactic acid increases ceramide synthesis by 38% over baseline.
This is confirmed by a similar study using TEWL as a measure of barrier
repair. Rendl et al. (64) investigated more immediate effects in a model of
human skin (reconstituted epidermis) and found that lactic acid in a cream
increased growth factors (VEGF), and decreased angiogenin secretion. They
conclude that the regulation of keratinocyte growth factors and cytokines by
AHA may explain some of the therapeutic effects observed in treating photoaged
skin with lactic acid. Scott (65) reviewed a large number of AHA and BHA
containing preparations and found only a few of them active on photoaged
skin. Glycolic acid, found in fruit and milk sugars is described as a cosmetic
ingredient with photoprotective activity. Hong et al. (66) describe its inhibition
of UV-induced skin tumorigenesis in hairless mice and investigate some of the
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complex mechanisms involved. However, a more recent study of 2003 by
Kaidbey et al. (67) suggests that AHAs can increase the sensitivity of the
skin to UV light. After pretreatment for 4 weeks (24 applications of a 10%
glycolic acid product or placebo on the back of 29 Caucasian subjects) the
skin was irradiated with 1.5 MED. They observed increased sunburn-cell induction and lowered MEDs and conclude that 10% glycolic acid sensitizes the skin to
the damaging effects of UV light. Thus, clearly more systematic studies are
needed to determine the benefits of hydroxy acids in sunscreens for antiaging
purposes.
Ceramides: The large family of complex lipids called ceramides needs
no review here. They are the essential element in the cement of cell cohesion
of the stratum corneum; long-chain lipids, highly insoluble, ceramides are not
so much “biologically active” as structurally important. There is thus less possible controversy about their use in sunscreens. In view of the outdoor activities
that go with the use of sunscreens, the abrasion, frequent bathing and the sun
exposure, it seems reasonable to use ceramides or ceramide promoting actives
in the formula. Any barrier repair contribution will be beneficial to the skin.
The improvement of barrier function by ceramides in general has been described
in numerous papers (68 and references therein), rarely though in conjunction
with UV irradiation. Various studies report the effects of substances that stimulate keratinocyte differentiation and ceramide synthesis: niacinamide (vitamin
B3) (69,70), avocadofuran (71), vitamin C (72), calcium (73), mevalonic acid
(74), ursolic acid liposomes (75), and others.
The T. thermophilus ferment described in the previous section (52,53) has
one additional antiaging benefit. Not only does it contain the heat-stable
anti-oxidant SOD and catalase-like enzymes to protect the skin against the
heat and the free radicals, it also turns out to stimulate keratinocyte differentiation, involucrin synthesis, and barrier repair by increased ceramide and cholesterol production. In vivo, this translates to greater resistance of the skin barrier
against aggression and to better moisture retention, both important antiage
concepts (76).
Tissue Repair
The most important antiage activity, from a cosmetic point of view, is to reduce
wrinkles. Wrinkles are of course, as we have said at the outset, a major, visible,
consequence of the actinic damages sunlight, rather excessive sunlight, generates
in the skin. Does it therefore make biological, physiological, scientific sense, to
include antiwrinkle actives in sunscreens? Similar arguments as those used for
barrier repair actives in sunscreens hold here, too. Sunscreens, if properly used,
are in contact with the exposed skin for quite some time. During the outdoor
activities that incite the consumer to use a sunscreen, she or he will hardly use
other skin care products. But the benefits of truly active tissue repair, antiage
molecules lie in extended use, regular exposure to their action, and constancy.
Antiaging Actives in Sunscreens
687
In the way a good modern skin care (face care) product should offer at least some
SPF—even if not positioned as a sunscreen (cf. Introduction), in the same way a
sunscreen may offer tissue repair ingredients to bridge the periods between
morning face preparation and the night cream.
Two major categories of antiage ingredients are presently of great interest,
that follow the wave of hydroxy acids and retinoids discussed earlier: the isoflavones (phytohormones), which are proposed as plant-derived “(pseudo)substitutes” of estrogen, for mature (i.e., postmenopausal) skin, and the matrikines,
natural protein fragments with specific, tissue repairing activity which are
wound healing research inspired new cosmetic ingredients. We shall limit our
discussion mainly to those two fields.
Isoflavones: Although there appears to be an impressive amount of literature on the benefits of isoflavones (genistein, daidzein, puerarin, biochanin A,
and others), more of it is again concentrated on demonstrating the antioxidant
(and thus protective) effects of these molecules (extracted most often from soy,
sometimes from red clover or more exotic plants) than on their wound-healing
and tissue repair activities. At least, this is true with respect to peer-reviewed published studies. But hundreds of references to the stimulating and repair activating
properties of these molecules—in pure form or presented as enriched extracts—
are nevertheless found on websites and in promotional documents. Two recent
publications by Widyarini et al. (77) and Kang et al. (78) describe the protective
effect of isoflavones against UV-induced inflammation and photoaging. More in
the spirit of the present section and of significant interest is the study by Myazaki
et al. (79), which shows that topical genistein and daidzein stimulate hyaluronic
acid production in human keratinocyte culture and in hairless mice. This is tissue
repair of a type that antiaging claims require. Schmid and Zülli (80) have gone
further and measured the skin thickness increase by topical application of soy
isoflavones in a human, placebo-controlled trial. The most recent document on
soy isoflavone activity in human skin is by Kawai (81), demonstrating the
ability of these extracts to stimulate collagen synthesis in the skin.
Cosmetic research has most certainly produced many more examples and
data about the skin repair benefits of isoflavone (“phytoestrogens”); for reasons
of intellectual property and fierce competition, only a small portion of this
research sees publications in peer-reviewed journals. It can thus only be surmised
that the use of these ingredients in sunscreens helps keep the skin in better
(i.e., more youthful) condition.
Matrikines: A whole new concept in tissue repair, and thus in antiaging
strategy, is offered by the discovery of matrikines. The term was coined by
Macquart (82) to designate protein fragments (peptides) of small size, which
are generated by the gradual hydrolysis of natural, structural proteins in the
connective tissue. But not just any breakdown product of proteins will be a
matrikine. During wound healing and/or inflammation, proteolytic enzymes
break down collagen, elastin, fibronectin, and other structure proteins into smaller
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pieces. Certain peptide sequences, thus released, possess mediator (“kinin”) or
messenger (ormon1 ¼ “hormone”) function: they act on nearby cells (fibroblasts) to stimulate them into neosynthesis of tissue macromolecules, or to
attract them to the damaged tissue site (chemotaxis). Like all mediators or
signal molecules, these peptides of specific amino acid sequence, act at very
low (nano- to micromolar) concentration, but achieve dramatic effects in the
rapid regeneration of tissue.
These peptides, derived from the natural sequence of the damaged proteins,
are usually in the tri- to hexamer range.
Some of these matrikines have found cosmetic use, for which it was necessary to attach a lipophilic, fatty acid chain in order to assure skin diffusion and
bioavailability (83). It has thus been shown that a few parts per million of the tripeptide palmitoyl-Gly-His-Lys (a serum protein fragment) is able to stimulate
collagen and GAG synthesis in vitro, which translates into skin thickening and
antwrinkle effects in vivo. Equally low concentrations of palmitoyl-Val-GlyVal-Ala-Pro-Gly (a fragment of elastin) or palmitoyl-Gly-Gln-Arg-Pro (a fragment
of Immunoglobulin IgG) have potent skin repair activities (84,85) that may be
used in antiaging compositions.
As a concrete example of cosmetic use of this concept, the matrikine
peptide palmitoyl-Lys-Thr-Thr-Lys-Ser shall be presented in more detail in the
following.
Discovered by Katayama et al. (86) during wound healing related research
on lung cells, it was investigated for skin applications (87) first in in vitro studies
on normal human fibroblasts which demonstrate the extracellular matrix (ECM)
stimulation by the palmitoylated peptide: collagen I and GAG are increased
over baseline by amounts varying between 50% and 250%. This is confirmed
on full thickness skin tissue where 2 ppm of Pal-KTTKS achieve the same
result as 1000 ppm of vitamin C and in clinical, vehicle, or benchmark
(retinol, moisturizer) controlled studies using the Pal-KTTKS peptide in topical
antiwrinkle creams (87 – 89). The use of 3 – 5 ppm of Pal-KTTKS in a topical
formula leads to significant, measurable, and consumer perceivable benefits
in reducing wrinkle volume, depth, density, and to overall improvement of the
facial skin when used for up to 6 months. Skin biopsies that were taken during
one of the panel studies (88) on both the Pal-KTTKS treated group and the
placebo group, at time points T ¼ 0, T ¼ 2 months, and T ¼ 4 months show
that the treated skin has improved collagen IV and elastin fiber assemblies
whereas the control group showed no notable changes in the skin samples.
Matrikines such as Pal-KTTKS are thus ideal candidates for cosmetic tissue
repair.
Nothing in the nature, activity, or mechanism of action of these molecules
with true antiaging properties prevents them from being used in sunscreens. They
are compatible with any kind of formulation, they are stable, their mode of action
is unperturbed by UV and outdoors. They are clearly an additional benefit to
sunscreens, as they demonstrably can repair some of the actinic photodamage.
Antiaging Actives in Sunscreens
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CONCLUSIONS
Some aspects of this chapter may appear somewhat polemic and/or tongue in
cheek. Whereas UV absorbing molecules are clearly designated as sun filters
and constitute a well-defined category of chemicals, the notion of “antiage”
actives (cosmeceuticals?) is much less well characterized, whence the occasional
asides.
We have tried to demonstrate that the notion of antiaging actives in
sunscreens opens many possibilities to the formulator to improve the basic
sunscreen products, to add real benefits and to allow for variety in claims and
marketing positioning.
Prevention of sun damages on the skin can be reinforced by some of the
antioxidant and photoprotective agents; treatment of sun damage during or
immediately after sun exposure with repair actives is also justified. Teaching
the consumer on how to “manage” the sunlight (prevention goes beyond using
sunscreens and includes wearing adequate clothes, avoiding the hottest hours
of the day, etc.) has become part of the marketeer’s obligation.
Depending on the country, however, from the USA to Europe to East Asia,
the legislations on sunscreens, claims, and formulations, are quite different and
complex. Adding antiage actives to these sunscreens makes the legal situation
even more complex with respect to advertised claims. Other chapters in this
book address the regulatory aspects of sunscreens per se: the notion of which
actives can legally be called “actives” varies even more. From my understanding,
in the USA, a “cosmetic antiaging active” is an oxymoron [if it is physiologically
active, it is a drug and not a cosmetic (90)], in Europe, neither sunscreens nor
cosmetic actives are specifically regulated other than by the general European
directive and its seven amendments (the notion of active is used in the industry,
but not in legal texts), in Korea, certain actives (for wrinkle reduction, thus
antiage) have become “functional ingredients,” that is, quasidrugs, similar to
the eponymous Japanese category.
Harmonization seems a far way off in the future. Careful wording of any
antiaging claims in sunscreen is thus recommended, no matter how many
studies one cites in support of this added benefit.
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