The aging face: Medical versus surgical treatments

Freeman M.
Modern Medicine of Australia (Australia), 1997, 40/3 (36-39+41-42)

The aging process involves us all and is affected by endogenous and exogenous factors. Skin texture changes consistent with moderate to severe aging have been observed in 72% of men and 47% of women under 30 years of age in Queensland. Photo aging among men of all ages has been associated with outdoor occupations, outdoor leisure activities, a tendency to sunburn and previous skin cancer. There are also syndromes that have premature aging as their major feature. Indicators of aging such as grey hair, reduced skin elasticity and arcus senilis are strongly and independently related to chronological age. Prevention is important in minimising photoaging, and for aging skin in general there are medical and surgical treatments that may help.

Suppression of UV-induced erythema by topical treatment with melatonin (N-acetyl-5-methoxytryptamine). A dose response study

Bangha E.; Elsner P.; Kistler G.S.
Department of Dermatology, University of Zurich, Gloriastr 31, CH-8091 Zurich Switzerland
Archives of Dermatological Research (Germany), 1996, 288/9 (522-526)

Oxygen-centred free radicals play an important role in the pathogenesis of acute and chronic UV-induced skin damage as well as in skin aging. In this double-blind randomized study the efficacy of topicacetyl-5-methoxyt ryptamine), a potent free radical scavenger, in the suppression of UV-induced erythema was assessed. A group of 20 healthy volunteers were irradiated with 0.099 J/cm2 UVB on four 5-cm2 areas on the lower back and topically treated with various concentrations of melatonin (0.05, 0.1, 0.5%) in a nanocolloid gel as carrier or with carrier alone. The UV-induced erythema was examined 8 and 24 h after irradiation by visual scoring and chromametry. A distinct dose response relationship was observed between the topical dose of melatonin and the degree of UV-induced erythema. Significant differences (P < 0.05) were found in redness (chromameter a(*)-value and visual scoring) 8 h after irradiation between the areas treated with melatonin at 0.5% and those treated with melatonin at 0.05% or with the carrier. These results might open a new approach in the prevention and control of free radical-influenced skin diseases.

Photodermatitis and early aging of the skin. Significant regeneration by high dose vitamin A and E

Trieloff I.
Germany
TW Dermatologie (Germany), 1996, 26/2 (136-137)

(Abtract not available)

Sunscreens: The ounce of prevention

Wentzell J.M.
Billings Clinic, 2825 8th Ave. N., Billings, MT 59107-5100 USA
American Family Physician (USA), 1996, 53/5 (1713-1719)

Sun exposure is linked to visible signs of skin aging, skin cancer, photodermatoses, exacerbation of systemic disease and photoallergic, as well as phototoxic, drug eruptions. Sunscreens very considerably in their ability to protect patients from exposure to ultraviolet light and its effects. Inappropriate choice and use of sunscreen products can lead to worse problems than using no sunscreen at all. Controversies about sunscreen include adequate level of sun protection factor, appropriate age of users, and whether use of sunsfincreen products can prevent skin cancer. Instructing patients in how to select end use sunscreen can help prevent or mit end systemic diseases.

Alpha hydroxy acids in the cosmetic treatment of photo-induced skin aging

Morganti P.; Randazzo S.D.; Bruno C.
Department of Dermatology, Dermatologists Training School, II University of Naples, Naples Italy
Journal of Applied Cosmetology (Italy), 1996, 14/1 (1-8)

The continuous adverse effects of light of over the years add to normal aging processes. This increases the number and severity of wrinkles, reduces the efficiency of cell mechanisms responsible for the reparation of damaged genes due to UV rays in photo-exposed areas, causes actinic keratosis, slows down epidermic cell turnover and reduces surface lipids, the moisture level and, as a result, the suppleness of the skin. The noticeable adverse effects generally decrease with the use of retinoic acid-based drugs or cosmetic-based products including various active components, from collagen to sodium lactate and aminoacids, from gelatine-glycine to Pyrrolidone Carboxylic Acid (PCA) and the newly-used Alpha hydroxy acids (AHAs), such as, for example, glycolic acid. This double-blind study aims to control the activity of 8% AHAs and gelatin-glycine-based cosmetic emulsions over 90 days clinically evaluating the number of thin wrinkles. Furthermore, the surface lipid film, the pH value and the skin moisture level were tested with the computerized methodology 3C System (R). Finally, the cell turnover was tested with the 'Scrub technique'.

Skin photosensitizing agents and the role of reactive oxygen species in photoaging

Dalle Carbonare M.; Pathak M.A.
Department of Dermatology, Harvard Medical School, Massachusetts General Hospital, Boston, MA 02114 USA
J. Photochem. Photobiol. B Biol. (Switzerland), 1992, 14/1-2 (105-124)

In this paper, the role of reactive oxygen species in photoaging is presented. Many photosensitizing agents are known to generate reactive oxygen species (singlet oxygen (1O2), superoxide anion (O2.-) and .OH radicals). Although photoaging (dermatoheliosis) of human skin is caused by UVB and UVA radiation, the hypothesis tested here in the pathogenesis of photoaging of human skin is the free radical theory involving the generation of reactive oxygen species by UVA (320-400 nm) radiation and their damaging oxidative effects on cutaneous collagen and other model proteins. The UVA-generated reactive oxygen species cause cross-linking of proteins (e.g. collagen), oxidation of sulfydryl groups causing disulfide cross-links, oxidative inactivation of certain enzymes causing functional impairment of cells (fibroblasts, keratinocytes, melanocytes, Langerhans cells) and liberation of proteases, collagenase and elastase. The skin-damaging effects of UVA appear to result from type II, oxygen-mediated photodynamic reactions in which UVA or near-UV radiation in the presence of certain photosensitizing chromophores (e.g, riboflavin, porphyrins, nicotinamide adenine dinucleotide phosphate (NADPH), etc.) leads to the formation of reactive oxygen species (1O2, O2.-, .OH). Four specific observations are presented to illustrate the concept: (1) the production of 1O2 and O2.- by UVB, UVA and UVA plus photosensitizing agents (such as riboflavin, porphyrin and 3-carbethoxypsoralens) as a function of UV exposure dose, the sensitizer concentration and the pH of the irradiated solution; (2) the formation of protein cross-links in collagen, catalase and superoxide dismutase by 1O2 and O2.- (.OH) and the resulting denaturation of proteins and enzyme activities as a function of UVA exposure dose; (3) the protective role of selective quenchers of 1O2 and O2.- (e.g. alpha-tocopherol acetate, beta-carotene, sodium azide, ascorbic acid, etc.) against the photoinactivation of enzymes and the prevention of the protein cross-linking reaction; (4) the possible usefulness of certain antioxidants or quenchers that interact with the UVA-induced generation of reactive oxygen species in the amelioration of the process of photoaging.

An in vitro model to test relative antioxidant potential: Ultraviolet-induced lipid peroxidation in liposomes

Pelle E.; Maes D.; Padulo G.A.; Eun-Kyung K.; Smith W.P.
Estee Lauder Research and Development, Melville, NY 11747 USA
Arch. Biochem. Biophys. (USA), 1990, 283/2 (234-240)

Since antioxidants have been shown to play a major role in preventing some of the effects of aging and photoaging in skin, it is important to study this phenomenon in a controlled manner. This was accomplished by developing a simple and reliable in vitro technique to assay antioxidant efficacy. Inhibition of peroxidation by antioxidants was used as a measure of relative antioxidant potential. Liposomes, high in polyunsaturated fatty acids (PUFA), were dispersed in buffer and irradiated with ultraviolet (UV) light. Irradiated liposomes exhibited a significantly higher amount of hydroperoxides than liposomes containing antioxidants in a dose- and concentration-dependent manner. Lipid peroxidation was determined spectrophotometrically by an increase in thiobarbituric acid reacting substances. To further substantiate the production of lipid peroxides, gas chromatography was used to measure a decrease in PUFA substrate. In order of decreasing antioxidant effectiveness, the following results were found among lipophilic antioxidants: BHA > catechin > BHT > alpha-tocopherol > chlorogenic acid. Among hydrophilic antioxidants, ascorbic acid and dithiothreitol were effective while glutathione was ineffective. In addition, ascorbic acid was observed to act synergistically with alpha-tocopherol, which is in agreement with other published reports on the interaction of these two antioxidants. Although peroxyl radical scavengers seem to be at a selective advantage in this liposomal/UV system, these results demonstrate the validity of this technique as an assay for measuring an antioxidant's potential to inhibit UV-induced peroxidation.

Diminished stimulation of hyaluronic acid synthesis by PDGF, IGF-I or serum in the senescence phase of skin fibroblasts in vitro

Schachtschabel D.O.; Freudenstein G.
Institut fur Physiologische Chemie, Philipps-Universitat, Karl-von-Frisch-Strasse 1, 35033 Marburg Germany
Z. Gerontol. (Germany), 1994, 27/3 (177-181)

Human skin fibroblasts of phase II ('young' cells derived from populations with a low population doubling level) and of phase III ('old' cells from populations, which were approx. 2 population doublings before the last possible subculture) were kept under subconfluent conditions in a defined serum-free medium. Thereby the cells are in a non-proliferative 'quiescent' state. Glycosaminoglycan (GAG)- and especially hyaluronan (HA)-synthesis and release into the medium were investigated by the incorporation rate of 14C-glucosamine. About 95% of the synthesized (48 h) GAGs and HA were medium-released and 5% cell-bound. HA synthesis rate of Phase III-cultures was significantly reduced, as compared with phase II-cultures. Stimulation of HA-synthesis of phase III-cells - in comparison with phase II-cells - by serum, PDGF or IGF-I was strongly reduced. While HA-synthesis of phase II-cells was maximally stimulated by 5% FCS or 20 ng/ml PDGF, phase III-cells did not exhibit a saturation kinetics up to 20% FCS or 60 ng/ml PDGF. The strongly reduced HA-synthesis rate of phase III-cells - compared with phase II-cells - in the non-stimulated quiescent state as well as after stimulation by PDGF, IGF-I or serum might be considered as a biomarker of in vitro (and in vivo?) aging.

Ultrastructural study of hyaluronic acid before and after the use of a pulsed electromagnetic field, electrorydesis, in the treatment of wrinkles

Ghersetich I.; Teofoli P.; Benci M.; Lotti T.
Department of Dermatology, University of Florence, Via Alfani 37, 50121 Florence Italy
Int. J. Dermatol. (Canada), 1994, 33/9 (661-663)

Background. Treatment of wrinkles has become an increasing problem for dermatologists. Hyaluronic acid is a component of the family of glycosaminoglycans (GAGS, substances known for their property of retaining water), that significantly decreases with aging and in wrinkles. A new technique that uses a specific pulsed electromagnetic field, electrorydesis, has been introduced in the treatment of wrinkles associated with aging. The treatment is based on the reported in vitro effects of specific electromagnetic fields on fibroblast cultures (e.g., an increase in DNA synthesis and in the production of collagen and presumably also of GAGS).

Methods. The in vivo effects of the electromagnetic field on aged skin (3 subjects aged 50, 56 and 60 years), with particular focus on the ultrastructural modifications and GAGS amount before and after the treatment, were evaluated by electron microscope.

Results. The ultrastructural study (tissue stained with alcian blue) showed after treatment a significant increase (p < 0.005) of the electron-dense granules (corresponding to hyaluronic acid), located in collagen elastic fibers, and in the soluble matrix. This presumably leads to subsequent edema that was clinically evident after the treatment.

Conclusions. These data suggest that the increased levels of GAGS and the subsequent edema of the dermis could explain at least in part the clinical changes observed after electrorydesis treatment (e.g., swelling and 'disappearance' of the wrinkle).

Hyaluronic acid in cutaneous intrinsic aging

Ghersetich I.; Lotti T.; Campanile G.; Grappone C.; Dini G.
23, via Alighieri, 51016 Montecatini Terme (PT) Italy
Int. J. Dermatol. (Canada), 1994, 33/2 (119-122)

Background. In elderly individuals all components of the skin and subcutaneous tissue undergo histologic and ultrastructural changes. The turgidity of the dermis appears decreased, presumably due to altered patterns and levels of glycosaminoglycans (GAGS), especially hyaluronic acid and dermatan sulfate that are the most common. A linear, age-related decrease in the content of GAGS (mainly hyaluronic acid) has been hypothesized in human aged skin.

Methods. We used the cationic dye Alcian Blue to selectively stain hyaluronic acid within the dermis in old and young subjects to compare ultrastructurally its topography and variations with age.

Results. We demonstrated a progressive reduction in the number of electron-dense granules of hyaluronic acid and of their filaments until they were completely absent in subjects aged 60. Conclusions. We propose that the variations of the levels of hyaluronic acid in the dermis in aging could account for some of the most striking alterations of the aged skin, including decreased turgidity, less support for microvessles, wrinkling, and altered elasticity.

Stimulation of cell proliferation by hyaluronidase during in vitro aging of human skin fibroblasts

Moczar M.; Robert L.
LBTC CNRS URA 1460, Faculte de Medecine, Universite Paris XII, 94010 Creteil Cedex France
Exp. Gerontol. (USA), 1993, 28/1 (59-68)

The effect of the degradation of extracellular hyaluronan on the proliferation of human skin fibroblasts in serial cultures during in vitro aging was investigated. Human skin fibroblasts at different time intervals from 3rd to 36th passages were exposed after plating to bovine testicular hyaluronidase. The enzyme treatment resulted in an increase in cell proliferation (cell number vs. time) as compared to the untreated control fibroblasts. The effect was dose dependent, reversible, and was independent of the type of the glycosidic linkage cleaved in hyaluronan. The increased proliferation was observed at all passages when untreated cells underwent mitosis. The degradation of hyaluronan induced cell proliferation up to the presenescent phase. Depletion of hyaluronan did not induce proliferation of postmitotic fibroblasts. The incorporation of 3H-glucosamine into hyaluronan decreased with increasing cell passages (increase of the number of population doublings). Twenty-fourth passage fibroblasts accumulated about two time less hyaluronan in the medium than ninth passage cultures. Following hyaluronidase treatment, the amount of newly synthesized, labeled hyaluronan increased in the medium. Accordingly, the fibroblasts restored the degraded hyaluronan even in the declining phase of proliferation (phase III according to Hayflick).

Topical retinoic acid treatment of photoaged skin: Its effects on hyaluronan distribution in epidermis and on hyaluronan and retinoic acid in suction blister fluid

Lundin A.; Berne B.; Michaelsson G.
Department of Dermatology, University Hospital, S-751 85 Uppsala Sweden
Acta Derm.-Venereol. (Norway), 1992, 72/6 (423-427)

Topical treatment with retinoic acid (tretinoin, vitamin A acid) has been reported to partly reverse signs of photodamage. To determine whether the histochemical distribution of hyaluronan (hyaluronic acid, HYA) in the epidermis and dermis and the amounts of HYA and retinoic acid in suction blister fluid were influenced by such topical treatment, 14 subjects healthy apart from moderate photodamage were instructed to treat the lateral forearm with 0.01-0.05% retinoic acid cream for 6 months. In a study of the short-term effects, another six subjects applied 0.05% retinoic acid cream for 2 weeks. After 6 months the thickness of the vital epidermis had increased by 23%. The HYA staining was based on a specific immunohistochemical method in which hyaluronan-binding protein is used. Before treatment HYA was seen as a meshwork around the cells in the upper half of the stratum spinosum. After 6 months of treatment this meshwork had increased in thickness by 31% compared with pretreatment specimens. The HYA staining was already intense in the papillary dermis before treatment and no difference was observed after 6 months' treatment. The mean concentration of HYA in blister fluid had increased significantly (43%) after 2 weeks of treatment whereas after 6 months there was no significant difference in this respect between the treated and untreated arm. The increase in the thickness of the epidermal HYA meshwork after 6 months and the blister fluid HYA after 2 weeks may indicate that HYA is involved in the epidermal change induced by topical retinoic acid therapy. The mean concentration of retinoic acid in suction blister fluid after 2 weeks of treatment was 328plus or minus63 nM whereas before treatment retinoic acid was usually not detectable. After 6 months of treatment the mean retinoic acid concentration was 73plus or minus33 nM. The mechanisms for the lower retinoic acid values at 6 months compared with those at 2 weeks are unknown.

Werner's syndrome: Biochemical and cytogenetic studies

Gawkrodger D.J.; Priestley G.C.; Ross J.A.; et al.
Department of Dermatology, University of Edinburgh, Royal Infirmary, Edinburgh United Kingdom
Arch. Dermatol. (USA), 1985, 121/5 (636-641)

Werner's syndrome is a rare condition of autosomal-recessive inheritance, showing some features of accelerated aging. We describe the clinical findings and laboratory studies in a 29-year-old man with this disorder, who presented because of a leg ulcer. Skin fibroblasts from our patient were difficult to culture and proliferated more slowly than those of controls. They produced less glycosaminoglycans than those of controls but synthesized more collagen, which was normal in type. The patient's urinary glycosaminoglycan level was slightly elevated, with hyaluronic acid as a major component. His peripheral blood lymphocytes showed no chromosomal instability and responded normally to mutagens.

Urinary acidic glycosaminoglycans in Werner's syndrome

Murata K.
Dept. Med. Phys. Ther., Univ. Tokyo Sch. Med., Bunkyo-ku, Tokyo 113 Japan
Experientia (Switzerland), 1982, 38/3 (313-314)

The composition of urinary acidic glycosaminoglycans (AGAG) in 4 patients with Werner's syndrome was determined by an enzymatic assay system using chondroitinases and hyaluronidase. In Werner's syndrome, the amount of hyaluronic acid and heparan sulfates in the total AGAG increases. A compositional change in the chondroitin sulfate isomers occurs. The change of urinary AGAG in Werner's syndrome appears to reflect age-related changes.

Non-enzymatic degradation of acid-soluble calf skin collagen by superoxide ion: Protective effect of flavonoids

Monboisse J.C.; Braquet P.; Randoux A.; Borel J.P.
Lab. Biochim. Med., Fac. Med. Reims, 51095 Reims Cedex France
Biochem. Pharmacol. (England), 1983, 32/1 (53-58)

Calf skin acid-soluble collagen in microfibrillar form was incubated with free oxygen radicals produced by the system xanthine oxidase + hypoxanthine. This incubation liberated peptides of a size smaller than that of alpha-chains, as demonstrated by SDS-PAGE and by evaluation of the 4-hydroxyproline contained in small peptides. The amount of liberated peptides was found to increase with time. The process was inhibited by addition of superoxide dismutase to the medium but not by addition of catalase. Two flavonoids extracted from bilberries and a third one from grapes were demonstrated to protect collagen against this non-enzymatic proteolytic activity. This work confirms that collagen may be degraded during the process of inflammation and that some flavonoids are endowed with protective properties.

In vitro cytotoxic effects of enzymatically induced oxygen radicals in human fibroblasts: Experimental procedures and protection by radical scavengers

Noel-Hudson M.S.; De Belilovsky C.; Petit N.; Lindenbaum A.; Wepierre J.
Faculte de Pharmacie, Unite de Dermopharmacologie, CNRS UA 594, 92290 Chatenay Malabry France
Toxicol. Vitro (United Kingdom), 1989, 3/2 (103-109)

Introduction of hypoxanthine and xanthine oxidase into human fibroblast cultures induces a dose-dependent cytotoxicity as a result of free-radical formation. The influence of medium, cell density and the power of recovery after free-radical attack were investigated. It appears that toxicity is higher in physiological Dulbecco phosphate buffer or Hanks' balanced salt solution than in modified Eagle medium, is inversely proportional to cell density and that damage is most often irreversible. Using this model, we studied the protective effects of a hydrosoluble flavonoid, silybin, and of a well known antioxidant, BHT (butylated hydroxytoluene). These molecules were administered before and during free-radical attack. With BHT significant protection was observed when it was added before free-radical attack (24%) protection at a concentration of 10-4 M) and before and during exposure (20% protection at a concentration of 10-5 M). When silybin is applied during radical attack maximal activity is recorded at a concentration of 8 x 10-4 M (45%), but the most interesting results are observed when 1 x 10-4 and 8 x 10-4 M are used, respectively, before and during radical exposure (63% of activity).

Antiviral activity of plant components. 1st Communication: flavonoids

Wacker A.; Eilmes H.G.
Abt. Therapeut. Biochem., Zent. Biol. Chem., Univ. Frankfurt/M. Germany, West
Arzneim.-Forsch. (Germany, West), 1978, 28/3 (347-350)

Some drugs effective against influenza contain flavonoids. The authors therefore examined the antiviral effect of hesperidin, hesperidinmethylchalcon, trihydroxyethylrutin, catechol, quercitrin, rutin and aurantiin against vesicular stromatitis virus (VSV) action on mouse fibroblasts and that of hesperidin against influenza virus in HeLa cells system by means of dye uptake measurements (Finter) and by plaque reduction test, respectively. Preincubation of the cells with the flavonoids 6-8 h before virus addition was inevitable. Protection of cells against virus action persisted for about 24 h and it abruptly disappeared after an addition of hyaluronidase. Maximal inhibition of virus action was achieved with a concentration of 200 mug/ml flavonoid.

Therapy of radiation damage in mice with O (L hydroxyethyl) rutoside

Bruckner V.
Inst. Biophys. Strahlenbiol., Univ. Hamburg Germany, West
Strahlentherapie (Germany, West), 1973, 145/6 (731-734)

In a mammalian organism a massive irradiation causes vascular damages induced by thrombocytopenia. This again leads to internal haemorrhages and the invasion of bacteria into the blood stream. Because of the lymphocytopenia and granulocytopenia also induced by radiation the resistance of an organism against infection is greatly reduced. Here the critical phase of the acute radiation syndrome begins, which often ends fatally. The authors therefore wondered whether it would be possible to obtain a treatment for the radiation damage in mice with a vaso stabilizing agent. As a suitable substance they chose the semi synthetic flavonol glycoside O (beta hydroxyethyl) rutoside. When this flavonoid was applied orally after the exposure, the survival rate of the whole body X irradiated mice was increased significantly from 31% to 56%. Because of the fact that this substance has already been in use for many years in human medicine there is perhaps a possibility of treating radiation sickness in men (e.g. the victims of radiation accidents in nuclear installations) successfully with this drug, since blood transfusions and especially bone marrow transplantations are still problematical.

Anti-aging active principals by the oral route. Myth or reality?

Frances C.
Groupe Hospitalier Pitie-Salpetriere, Unite de Dermatologie, 47-83 Boulevard de l'Hopital, 75651 Paris Cedex 13 France
Nouv. Dermatol. (France), 1994, 13/6 (423-425)

Beta-carotene, precursor of vitamin A, has an anti-tumoral effect which is demonstrated in animals but not in man. Vitamin A has anti-free radical properties, but there is a toxicity when ingested at doses above 5000 IU/kg/day. Local applications of Vitamin-C reduce the cutaneous phototoxicity of UVA and UVB in animals. Vitamin E or tocopherol is potentially one of the most interesting vitamins against cutaneous aging. The preventive role of selenium, which is an essential oligo-element, is shown in certain photo-induced epidermal cell damages but not in cutaneous aging.

Topical 8% glycolic acid and 8% L-lactic acid creams for the treatment of photodamaged skin: A double-blind vehicle-controlled clinical trial

Stiller M.J.; Bartolone J.; Stern R.; Smith S.; Kollias N.; Gillies R.; Drake L.A.
Department of Dermatology, Massachusetts General Hospital, Boston, MA 02114 USA
Archives of Dermatology (USA), 1996, 132/6 (631-636)

Objective: To evaluate the efficacy and tolerability of 2 widely used topical alpha-hydroxy acids at low concentrations, 8% glycolic acid and 8% lactic (L-isoform) acid creams, in the treatment of photodamaged skin.

Design: A single-center, 22-week, double-blind, vehicle-controlled, randomized clinical trial assessed the overall severity of photodamage on the faces and forearms of volunteers, based on 7 individual clinical components of cutaneous photodamage.

Setting: The study was performed in an outpatient clinical research unit at the Massachusetts General Hospital, Boston.

Patient: Seventy-four women, aged 40 to 70 years, with moderately severe photodamaged facial skin were enrolled in the study. One subject withdrew from the study early because of skin irritation, and 6 subjects withdrew from the study for personal reasons. Interventions: Glycolic acid, L-lactic acid, or vehicle creams were applied twice daily to the face and outer aspect of the forearms.

Main Outcome Measures: Improvement in alpha-hydroxy acid-treated photodamaged skin as determined by patient self-assessments and physician evaluations of efficacy and irritancy.

Results: The percentage of patients using either 8% glycolic acid or 8% L-lactic acid creams on the face achieving at least i grade of improvement (using a scale from 0 through 9) in overall severity of photodamage was significantly greater than with the vehicle cream (76% glycolic acid, 71% lactic acid, and 40% vehicle; P<.05). On the forearms, after 22 weeks, treatment with glycolic acid cream was superior to the vehicle in improving the overall severity of photodamage and sallowness (P<.05). L-Lactic acid cream was significantly superior to the vehicle in reducing the overall severity of photodamage (P<.05), mottled hyperpigmentation (P<.05), sallowness (P<.05), and roughness on the forearms (P<.05) at week 22.

Conclusions: Topical 8% glycolic acid and 8% L-lactic acid creams are modestly useful in ameliorating some of the signs of chronic cutaneous photodamage. These agents are well tolerated and available without prescription.

Effects of alpha-hydroxy acids on photoaged skin: A pilot clinical, histologic, and ultrastructural study

Ditre C.M.; Griffin T.D.; Murphy G.F.; Sueki H.; Telegan B.; Johnson W.C.; Yu R.J.; Van Scott E.J.
NeoStrata Co., Inc., Princeton, NJ USA
Journal of the American Academy of Dermatology (USA), 1996, 34/2 I (187-195)

Background: alpha-Hydroxy acids (AHAs) have been reported to improve aging skin. The mechanisms of action of AHAs on epidermal and dermal compartments need clarification.

Objective: Our purpose was to determine the effects of AHAs on photoaged human skin by clinical and microanalytic means.

Methods: Patients applied a lotion containing 25% glycolic, lactic, or citric acid to one forearm and a placebo lotion to the opposite forearm for an average of 6 months. Thickness of forearm skin was measured throughout the study. Biopsy specimens from both forearms were processed for analysis at the end of the study.

Results: Treatment with AHAs caused an approximate 25% increase in skin thickness. The epidermis was thicker and papillary dermal changes included increased thickness, increased acid mucopolysaccharides, improved quality of elastic fibers, and increased density of collagen. No inflammation was evident.

Conclusion: Treatment with AHAs produced significant reversal of epidermal and dermal markers of photoaging.

Topical gelatin-glycine and alpha-hydroxy acids for photoaged skin

Morganti P.; Randazzo S.D.; Palombo P.; Bruno C.
I.S.C.D., Via Innocenzo XI, 41, 00165 Roma Italy
J. Appl. Cosmetol. (Italy), 1994, 12/1 (1-10)

Skin hydration and well-being are known to depend upon the amount of water in the horny layer. Hydration depends also on the level of NMF(S) (Natural Moisturizing Factors), thus on PCA (Pyrolydone Carboxylic Acid) and on the proper intensity of pespiratio insensibilis. This depends in turn on balanced surface lipidic film. So-called photoaging, connected with the amount of UV and light absorbed over a lifetime, causes a decrease in skin hydration and surface lipids and increase of fine wrinkling which results in early aging and skin xerosis. This work aims to demonstrate the rehydrating and lipid restoring action of different cosmetic emulsions. One hundred smoker women aging 52 to 63 have been investigated. They all frequented solar centers and were clearly affected by xerosis. They were treated with Gelatin-Glycine and Alpha Hydroxy Acids cosmetic emulsions for 120 days. Skin hydration and surface lipids were monitored through the new 3C System computerized equipment (Rome, Italy). Fine wrinkling was evaluated using a visual analog scale in subject randomly treated on one side by the active cream, the other side serving as control. Thanks to the increase from 36% and 82% in surface lipids and from 31% to 90% in horny layer hydration, and to the decrease of about 17% of fine wrinkling these cosmetic treatments seem adequate for premature skin aging caused by sun and environmental pollutants.

Antioxidants, fat and skin cancer

Sahl W.J.
717 Meade Street, Rapid City, SD 57701 USA
Skin Cancer (Portugal), 1995, 10/2 (97-101)

The incidence of actinic keratoses, basal cell carcinomas and squamous cell carcinomas increases proportionately with increasing cutaneous sun exposure. There is mounting evidence that dietary nutrients may play an important role in sun induced skin damage and skin cancer. In this brief discussion, the evidence is reviewed for a participatory interaction between ultraviolet radiation and dietary factors in cutaneous aging and carcinogenesis. In particular, this paper investigates the relationship between dietary antioxidants and cutaneous fat concentrations as the keys to understanding the possible relationship between diet and skin cancer.

Photoprotective effect of superoxide scavenging antioxidants against ultraviolet radiation-induced chronic skin damage in the hairless mouse

Bissett D.L.; Chatterjee R.; Hannon D.P.
Procter and Gamble Company, Miami Valley Laboratories, P.O. Box 398707, Cincinnati, OH 45239-8707 USA
Photodermatology Photoimmunology Photomedicine (Denmark), 1990, 7/2 (56-62)

Albino hairless mice (Skh: HR-1) exposed chronically to suberythemal doses of ultraviolet radiation develop visible skin changes, histological alterations, and tumors. Topical treatment of mice with solutions of superoxide-scavening antioxidants (such as alpha-tocopherol, ascorbic acid, propyl gallate and Trolox (R)) prior to each UVB radiation exposure reduced significantly the severity of these events. Tocopherol esters and ascorbyl palmitate were not as effective as the parent compounds in providing protection. The data suggest a role for superoxide in UVB radiation-induced skin photoaging and the protective potential of super oxide scavengers. In contrast, the severity of UVA radiation-induced mouse skin damage was not reduced by topical application of the antioxidants tested here.

Impairment of enzymic and nonenzymic antioxidants in skin by UVB irradiation

Fuchs J.; Huflejt M.E.; Rothfuss L.M.; Wilson D.S.; Carcamo G.; Packer L.
Membrane Bioenergetics Group, Lawrence Berkeley Laboratory, University of California, Berkeley, CA 94720 USA
J. Invest. Dermatol. (USA), 1989, 93/6 (769-773)

Antioxidants may play a significant role in ameliorating or preventing photobiologic damage in skin that could lead to cutaneous disorders such as cancer and premature aging. The objective of this study was to assess the acute cutaneous enzymic and nonenzymic antioxidant response to a single exposure of large fluence (300 mJ/cm2) ultraviolet radiation (>280 nm) in hairless mice. This treatment caused an immediate and statistically significant inhibition of glutathione reductase and catalase activity. Glutathione peroxidase and superoxide dismutase were not affected. Glutathione levels decreased and, conversely glutathione disulfide concentrations increased. A slight depletion of the total glutathione was observed, while the content of total ascorbic acid did not change. The lipophilic antioxidants alpha-tocopherol, ubiquinol 9 and ubiquinone 9 also decreased significantly, and the concentration of malondialdehyde remained constant. The free radical scavenging activity of epidermis, as assessed by reduction of the stable, cationic nitroxide radical (2,2,6,6-tetramethyl-1-piperidinoxy-4-(2',4',6'-trimethyl) methyl-pyridinium perchlorate) was considerably inhibited. The study indicates that immediately after exposure to a large fluence of ultraviolet radiation the enzymic and nonenzymic antioxidant capacity of skin decreases significantly.

Low levels of essential fatty acids are related to impaired delayed skin hypersensitivity in malnourished chronically ill elderly people

Cederholm T.E.; Berg A.B.; Johansson E.K.; Hellstrom K.H.; Palmblad J.E.W.
Karolinska Institute, Department of Medicine, Stockholm Slider Hospital, S-118 83 Stockholm Sweden
Eur. J. Clin. Invest. (United Kingdom), 1994, 24/9 (615-620)

Essential fatty acid (FA) deficiency, which may accompany protein-energy malnutrition CPEM), has been associated with impaired inflammatory reactions. We evaluated this relationship by analysing FA profiles and delayed cutaneous hypersensitivity in 20 malnourished elderly non-cancer patients and in 20 age matched control patients. As indicated by serum cholesterol and serum triglycerides, the lipid levels were decreased by about one-third in the subjects with PEM. In comparison with the controls, there was a reduction in the omega3 FA (e.g. eicosapentanoate) in total serum lipids (mg l-1) and serum phospholipids (%) of 40% and 47%, respectively. Reductions in serum omega6 FA (e.g. linoleate and arachidonate) levels corresponded to the drop in total FA concentrations (30%). The cutaneous hypersensitivity was impaired in 14 of the malnourished patients. The magnitude of the skin reaction was positively correlated (P < 0.05) to the concentrations of eicosapentanoate in serum lipids and serum phospholipids, as well as to the linoieate concentration in total serum lipids. Six of the malnourished patients took part in a nutritional intervention programme for 3 months. In parallel with an improvement in the nutritional status there was a 35% increase (P < 0.05) in the total omega3 FA serum concentration. Negative skin tests became positive and the median skin induration enlarged threefold (P < 0.05). Thus, deficiency of omega3 FA might be one factor contributing to cutaneous anergy in elderly malnourished patients.

Two concentrations of topical tretinoin (retinoic acid) cause similar improvement of photoaging but different degrees of irritation: A double- blind, vehicle-controlled comparison of 0.1% and 0.025% tretinoin creams

Griffiths C.E.M.; Kang S.; Ellis C.N.; Kim K.J.; Finkel L.J.; Ortiz-Ferrer L.C.; White G.M.; Hamilton T.A.; Voorhees J.J.
Department of Dermatology, Univ. of Michigan Medical Center, 1910 A. Alfred Taubman Health Center, 1500 E Medical Center Dr, Ann Arbor, MI 48109-0314 USA
Archives of Dermatology (USA), 1995, 131/9 (1037-1044)

Background and Design: The efficacy of topical tretinoin (all-trans-retinoic acid) in treating photoaging is well established. Questions that remain are

(1) whether irritation causes all or part of the improvement;

(2) the concentration of tretinoin that maximizes clinical response with minimal side effects; and

(3) the effects of long-term treatment on components of the cutaneous immune system.

To address these issues, 99 photoaged patients completed a 48-week study using 0.1% tretinoin cream (n=32), 0.025% tretinoin (n=35), or vehicle (n=32) once daily in a double-blind manner. Before and after treatment, we assessed histologic features, keratinocyte expression of HLA-DR and intercellular adhesion molecule-1, numbers of epidermal Langerhans' cells and epidermal and dermal T lymphocytes, and vascularity as measured by dermal endothelial cell area. Results: Both 0.1% and 0.025% tretinoin produced statistically significant overall improvement in photoaging of the face compared with vehicle; there were no clinically or statistically significant differences in efficacy be tween the two concentrations of tretinoin. After 48 weeks, 0.1% and 0.025% tretinoin produced similar statistically significant epidermal thickening (by 30% and 28%, respectively) compared with vehicle (11% decrease) and increased vascularity (by 100% and 89%, respectively) compared with vehicle (9% decrease). By various analyses, irritant side effects (erythema and scaling) were statistically significantly greater with 0.1% tretinoin than with 0.025% tretinoin. No significant changes occurred in any immunologic markers when tretinoin and vehicle treatments were compared. Conclusions: Tretinoin 0.1% and 0.025% produce similar clinical and histologic changes in patients with photoaging, despite significantly greater incidence of irritation with the higher concentration. The separation between clinical improvement and irritation suggests that mechanisms other than irritation dominate tretinoin- induced repair of photoaging in humans.

Topical tretinoin (retinoic acid) treatment for liver spots associated with photodamage

Rafal E.S.; Griffiths C.E.M.; Ditre C.M.; Finkel L.J.; Hamilton T.A.; Ellis C.N.; Voorhees J.J.
Department of Dermatology, 1910 Taubman Center, University of Michigan Medical Center, 1500 E. Medical Center Dr., Ann Arbor, MI 48109-0314 USA
New Engl. J. Med. (USA), 1992, 326/6 (368-374)

Background. The hyperpigmented lesions commonly called liver spots distress patients, in part because such lesions are associated with aging. We investigated their treatment with topical 0.1 percent tretinoin (retinoic acid).

Methods. Fifty-eight patients completed a 10-month randomized, double- blind study in which they applied either 0.1 percent tretinoin (n = 28) or vehicle (n = 30) cream daily to the face, upper extremities, or both. Fifteen patients who responded well were then randomly assigned to continue tretinoin therapy or use vehicle alone for six more months. Patients were evaluated by physical examination every month and by analysis of biopsy specimens of lesions obtained at base line and at the end of the 10-month trial.

Results. After one month of treatment the patients treated with tretinoin had significant lightening of hyperpigmented lesions as compared with the patients who received vehicle (P<0.002). After 10 months, 20 (83 percent) of the 24 patients with facial lesions who were treated with tretinoin had lightening of these lesions, as compared with 8 (29 percent) of the 28 patients with facial lesions who received vehicle. The results for lesions of the upper extremities were similar. As compared with vehicle, tretinoin caused a significant decrease in the degree of epidermal pigmentation and increases in the degree of compaction of stratum corneum, thickness of the granular cell layer, and epidermal thickness. Reductions in epidermal pigmentation evident on histologic analysis were significantly correlated with the degree of clinical lightening of lesions (r = -0.53, P<0.0001). During the 6-month follow-up study, specifically identified lesions that had disappeared during the first 10 months of tretinoin treatment did not return in any patient, and six of seven patients who continued to use tretinoin had further improvement.

Conclusions. Topical 0.1 percent tretinoin significantly improves both clinical and microscopical manifestations of liver spots; these lesions do not return for at least six months after therapy is discontinued.

The effects of an abrasive agent on normal skin and on photoaged skin in comparison with topical tretinoin

Marks R.; Hill S.; Barton S.P.
Department of Medicine, University of Wales College of Medicine, Heath Park, Cardiff CF4 4XN United Kingdom
Br. J. Dermatol. (United Kingdom), 1990, 123/4 (457-466)

Two studies were designed to assess the effect of abrasive preparations on the skin and to test the specificity of the effect of topical tretinoin in the management of chronic photodamage to the skin. In the first study two abrasive preparations (Brasivol (R) fine and Brasivol (R) medium) were compared with white soft paraffin and no treatment in eight volunteer subjects for their effects on the epidermis. The study was conducted over 3 days and measurements were taken of the effects on dansyl chloride-induced fluorescence to assess desquamation, epidermal thickness, and the tritiated thymidine autoradiographic labelling index. The abrasives were found to increase the desquamation rate significantly and to increase epidermal thickness and the epidermal labelling index compared to white soft paraffin and no treatment. In the second study the effect of one of the abrasive preparations (Brasivol (R) medium) was compared with 0.05% tretinoin cream (Retin A (R)) on the photodamaged skin of the dorsal aspects of the forearms of 12 subjects over an 8-week period. Cutaneous blood flow measured by the laser-Dopper flowmeter was found to be significantly increased in the abrasive-treated sites, but there was only a non-significant trend to increased blood flow in the tretinoin-treated sites. Measurements of skin thickness using pulsed A-scan ultrasound demonstrated that both treatments produced significant increases in thickness over the 8-week period but the increase was greater for the abrasive treated site. Measurements of the skin extensibility at the treated sites were made using a uniaxial extensometer. Forces needed for 30% skin extension were increased in the abrasive-treated sites only. Measurements of epidermal thickness and of (3H)-thymidine autoradiographic labelling indices showed greater increases in the abrasive-treated sites than in tretinoin-treated sites compared to untreated sites, but these increases were not statistically significant. No significant inflammation and no changes in the degree of elastosis or the presence of a 'repair zone' were found in any of the post-treatment biopsies. The results indicate that some of the changes produced in the skin by topical tretinoin that are taken to indicate a specific antiphotoaging effect may not in fact be specific and can be achieved by an abrasive preparation.

Aging and the skin

Silverberg N.; Silverberg L.
University of California, Irvine, CA USA
Postgrad. Med. (USA), 1989, 86/1 (131-144)

Some of the damage caused by time cannot be stopped. The skin becomes thin and translucent, regenerates less quickly, and is prone to dryness and pruritus. However, pronounced changes in the skin, which we usually think of as the signs of aging, are caused by overexposure to the sun and can be avoided. Excessive exposure to UV light causes more than a damaged appearance. It is the most important predisposing factor in several types of skin cancer and some benign proliferative growths that can progress to skin cancer. The authors summarize what happens as skin ages and review how to prevent and reverse the sun's aging effects on the skin.

Topical tretinoind and photoaged skin

Goldfarb M.T.; Ellis C.N.; Weiss J.S.; Voorhees J.J.
Dermatopharmacology Unit, Department of Dermatology, University of Michigan Medical Center, Ann Arbor, MI 48109-0314 USA
Cutis (USA), 1989, 43/5 (476-482)

Topical tretinoin is a safe and effective agent when used for the reversal of photoaging. Although it causes only partial improvement in the skin appearance and causes an associated dermatitis early in the course of treatment, most patients are pleased with the results and can tolerate the treatment well. Further studies are underway to determine the effects of long-term treatment. Investigations into the reversal of the changes of intrinsic aging with topical tretinoin should also be undertaken in the future. Finally, new classes of topical retinoids are being synthesized that may have increased efficacy in the treatment of photoaging and less propensity for causing dermatitis.