Archives of Gerontology and Geriatrics 30 (2000) 139 150 www.elsevier.

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Effect of borage oil consumption on fatty acid metabolism, transepidermal water loss and skin parameters in elderly people
Thorolf Brosche *, Dieter Platt
Institute of Gerontology, Uni6ersity of Erlangen Nurnberg, Heimerichstr. 58, D-90419 Nurnberg, Germany Received 12 October 1999; received in revised form 28 January 2000; accepted 6 February 2000

Abstract Human skin is not able to biosynthesize gamma-linolenic acid (GLA, 18:3v6) from the precursor linoleic acid (LA), or arachidonic acid (AA) from dihomo-gamma-linolenic acid (DHGLA). Dietary supplementation with GLA-rich seed oil of borage skips the step of hepatic 6-desaturation of fatty acids (FA) and, therefore, compensates the lack of these essential FA in conditions with impaired activity of delta 6-desaturase. Twenty-nine healthy elderly people (mean age 68.6 years), received a daily dose of 360 or 720 mg GLA for 2 months, using Borage oil in gelatine capsules (Quintesal180, manufacturer Galderma Laboratorium GmbH, Freiburg, Germany). The effects of fatty acids derived from ingested borage oil capsules on skin barrier function were assessed by measurement of transepidermal water loss (TEWL). The consumption of borage oil induced a statistically signicant improvement of cutaneous barrier function in the elderly people, as reected in a mean decrease of 10.8% in the transepidermal water loss. Thirty-four percent of the people noted itch before borage oil consumption and 0% afterwards. Dry skin was claimed to be reduced from 42 to 14%, but no signicant alteration of skin hydration was measured. The FA-composition of erythrocyte membrane phospholipids demonstrated an increase of GLA ( +70%) and DHGLA ( +18%) and a reduction of saturated and monounsaturated FA. There was no signicant alteration in nervonic acid or in AA content, but an increase in the DHGLA/AA ratio (+23%). Thus, the consumption of borage oil by elderly people lead to alteration of FA metabolism and improved skin function. 2000 Elsevier Science Ireland Ltd. All rights reserved.

* Corresponding author. Tel.: +49-911-330959; fax: + 49-911-3788666. E-mail address: t.brosche@gerontologie.med.uni-erlangen.de (T. Brosche) 0167-4943/00/$ - see front matter 2000 Else6ier Science Ireland Ltd. All rights reser6ed. PII: S 0 1 6 7 - 4 9 4 3 ( 0 0 ) 0 0 0 4 6 - 7a

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Keywords: Aged; Borage oil; Gamma linolenic acid; Dietary supplementation; Skin; Transepidermal water loss; Skin dryness; Itch; Erythrocyte membranes; Fatty acids

1. Introduction Physiologic aging processes and the accumulation of exogenously induced damages cause age associated alterations of the skin. As a consequence, skin homeostasis in old age is disturbed. Even in healthy elderly people dry skin and itch are observed frequently. Aging is one of the factors proposed to attenuate the activity of the delta 6 fatty acid desaturase. This reduced activity to desaturate, e.g. linoleic acid (LA, 18:2v6) to gamma-linolenic acid (GLA, 18:3v6) was claimed to contribute to skin alterations observed in old age (Horrobin, 1989). Human skin is not able to biosynthesize GLA from the precursor LA, or arachidonic acid (AA, 20:4v6) from dihomo-gamma-linolenic acid (DHGLA, 20:3v6), because of lacking enzymes delta 6- and delta 5-desaturase (Chapkin and Ziboh, 1984; Chapkin et al., 1986). Therefore, metabolites of essential fatty acids (EFA) have to be synthesized in the liver and transported to the skin by the blood stream. Dietary supplementation with GLA-containing oils skips the metabolic step of 6-desaturation of LA to form GLA. Such a supplementation should compensate the lack of EFA in cases and in conditions with impaired activity of delta 6-desaturase, like in diabetes mellitus, atopic eczema or in normal aging (Brenner, 1982; Horrobin, 1983; Brenner, 1989). Since the seed oil of borago ofcinalis is rich in gamma-linolenic acid (GLA; up to 25% of total fatty acids), we used it to explore the inuence of dietary supplementation in 29 healthy elderly people on skin barrier function, skin water content and on fatty acid metabolism as reected in the erythrocyte membranes. The observed reduction of the transepidermal water loss (TEWL) indicates an improved cutaneous barrier function induced by 8 weeks of borage oil consumption. In addition, the volunteers reported improvement of itch. Skin dryness was not altered signicantly. As expected, portions of GLA and DHGLA in the erythrocyte membrane phospholipid fatty acid pattern were increased signicantly.

2. Materials and methods

2.1. Study design

In an open study 29 free living, apparently healthy elderly people, showing no signs of skin diseases, received a daily dose of 360 or 720 mg GLA for 2 months. The mean age of the 13 men and 16 women was 68.6 9 7.6 years (range: 54.484.5 years). Borage oil was applied using soft gelatine capsules (Quintesal180, manufacturer Galderma Laboratorium GmbH, Freiburg, Germany). One capsule contains 0.75 g 9 7.5% of borage oil with a GLA portion of 175 mg 9 7.5%. In addition 20 mg 9 7.5% of vitamin E (tocopherol-isomer-mixture) are present. The fatty acid

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composition of a batch of capsules employed in this study is given in Table 1. After a run-in phase of 4 weeks the test persons were randomly assigned to take two (n=14) or four (n =15) Quintesal 180 capsules daily, corresponding to 1.5 and 3 g of borage oil, respectively. For the evaluation of data the two groups with different dosing regimes were combined.

2.2. Skin parameter

The TEWL reects the integrity of the barrier function of the stratum corneum against passive water loss by means of diffusion (perspiratio insensibilis). The in vivo effects of fatty acids derived from the ingested borage oil capsules on skin barrier function were assessed by measurement of the TEWL on the right volar forearm, about 8 cm distal from the bent of the elbow. We used a Tewameter TM210 (Courage and Khazaka, Koln, Germany). Measurements were done with regard to the guidelines for standardisation of the European Society of Contact Dermatitis (Pinnagoda et al., 1990). Air convection, noise in the room and talking during the recordings were restricted. Since we observed intraindividual variations of TEWL values during daytime in preliminary experiments, all measurements were performed between 07:00 and 09:30 h after an overnight fasting of the test people. The single TEWL measurement data were considered as suited for evaluation at a
Table 1 The fatty acid composition of encapsulated borage oil used in this study, as compared to published values of borage oila Fatty acids 14:0 16:0 17:0 18:0 20:0 22:0 24:0 16:1v7 16:1v5 18:1v9 18:1v7 18:2v6 18:3v6 18:3v3 18:4v3 20:1v9 20:2v6 22:1v9 24:1v9
a

Phylactos et al. (1994) 0.1 9.3 2.8 0.6 0.4 0.1 0.4 14.2 38.0 25.0 0.3 4.2 2.7 1.5

Wretensjo et al. (1990) 9.77 3.44 0.22 0.14 0.21 14.80 0.52 37.51 24.58 0.20 0.18 4.18 0.22 2.51 1.11

Quintesal180 charge 165/553 0.10 9.91 0.07 3.50 0.25 0.17 0.08 0.14 0.18 14.62 0.65 38.47 22.42 1.03 0.16 3.87 0.24 2.69 1.47

Values are wt.% of total fatty acids from pooled oil of ten randomly selected capsules of a charge Quintesal180; manufacturer Galderma Laboratorien GmbH, Freiburg, Germany.

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point of time with minimal standard deviation of the signal in a stabilised recording data curve. TEWL values are given as loss of gram of water per hour and m2 of skin. The regulation of the skin barrier property is believed to lie in the composition of stratum corneum lipids, which occupy the intercellular space between cells of the stratum corneum. The water content of the stratum corneum plays an important role in providing the skin surface with suppleness and smoothness. We measured skin surface hydration in triplicate, employing a Corneometer CM 820 PC (Courage and Khazaka). The results are means, given in units without dimension. This measurement determines the electrical capacitance of the skin. In addition to the measurements, the test people estimated the state of their skin with regard to dryness and itch by marking three or four predened categories, respectively, according to the degree of skin alteration in the course of the study.

2.3. Red cell membrane lipids

On each visit venous blood samples were drawn to assess the erythrocyte membrane phospholipid fatty acid pattern by means of capillary gas chromatography (Brosche et al., 1985, 1986). Lyophilized, haemoglobin-free washed erythrocyte membrane ghosts were prepared (Platt and Schoch, 1974). Then the red cell ghost lipids were isolated and fractionated on silica columns. The isolated phospholipids were derivatized to fatty acid methyl esters (FAME) and fatty aldehyde dimethyl acetals (DMA) according to Morrison and Smith (1964). The obtained mixtures of FAME and DMA were quantied on a Hewlett Packard HP-5890A Series II instrument, equipped with a HP3365 Series II Chem Station A.03.34 and a ame ionization detector, kept at 300C, and a temperature-programmed injector (KAS, Gerstel GmbH, Muhlheim/Ruhr, Germany). Temperature-programmed analyses were performed on a WCOT BPX70 column (SGE Deutschland GmbH, Weiterstadt, Germany) in triplicate. The results are given as weight percent of total FAME and DMA.

2.4. Statistical analysis

The non-parametric Wilcoxon test was used to check for signicant differences between basal values and the values at the end of the study period. The Friedman test, a modied sign test, was employed for comparing means of groups (Theodorsson-Norheim, 1987), using the statistic program Stan Plus.

3. Results During the 2 months of dietary borage oil supplementation the barrier function of skin improved by 10.8% (mean), according to a reduction of TEWL values from 7.6592.96 to 7.20 9 2.58 and nally to 6.82 9 2.29 g/m2 h (mean, PB0.05; see Fig. 1). In addition, the water content of the stratum corneum increased slightly from 66.179 9.91 to 68.76911.58 and nally to 69.109 13.61 units (mean; statistically

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Fig. 1. Change of the TEWL in elderly people during 2 months of borage oil consumption (means 9 S.D., n = 29, P B0.05).

Fig. 2. Change in skin humidity under borage oil consumption. Values are means 9S.D. (n =29, ns).

Table 2 Frequencies of 29 elderly people indicating itch as not existent, weak, moderate or strong before and after 1 and 2 months of borage oil consumption Itch Months of Quintesal consumption 0 months Number Not existent Weak Moderate Strong 19 7 2 1 Percentage 66 24 7 3 1 month Number 20 8 0 1 Percentage 69 28 0 3 2 months Number 29 0 0 0 Percentage 100 0 0 0

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not signicant; see Fig. 2). Ten out of 29 people said to suffer from itch before supplementation, nine people after 1 month, and none after 2 months of borage oil consumption (Table 2). The percentage of study participants regarding their skin as more dry was reduced from 42 to 14% during the study (Table 3). As expected, the consumption of borage oil lead to highly signicant changes in the erythrocyte membrane phospholipid fatty acid composition (Table 4). According to the increased dietary supply of GLA, we observed increased portions of GLA and of the GLA metabolite DHGLA in the red cell membranes. Also, the relation of DHGLA/AA increased highly signicant. As is demonstrated in Fig. 3, taking 1.5 g of borage oil daily for 2 months resulted in an relative increase of membrane GLA of about 70%, similar to the effect of a supplement of 3 g for 1 month (+ 74%). Comparable results were obtained for DHGLA (+ 19 and + 17%, respectively; Fig. 4). When fatty acid concentrations are summarized according to families and classes (Fig. 5), the mean of the relative individual changes demonstrates the impact of borage oil consumption on the erythrocyte membrane composition: increases in double bond index, portions of polyunsaturated fatty acids and of the v6-fatty acid family, including LA-metabolites. Decreases were observed in portions of saturated-, monounsaturated- and v9-fatty acids, respectively (Fig. 5).

4. Discussion The outermost layer of the skin, stratum corneum, provides a barrier against the external environment and is responsible for skin impermeability for most agents. Reports on the physiological alterations of the barrier function of the stratum corneum in old age are sparse. A tendency to slightly increased TEWL measurements in older people indicates a decreased barrier function in old age (Raab and Kindl, 1991; Berardesca, 1993; Klein et al., 1993). The role of fatty acids in the skin has been under investigation since early reports on rats and mice with a deciency in EFA, demonstrating skin alterations including a dramatic increase in TEWL. On the other side, the topical application of LA and GLA can lower an increased TEWL (Hartop and Prottey, 1976; Prottey, 1977). Since the human skin is devoid of the enzymes delta 6- and delta 5-desaturase (Chapkin and Ziboh, 1984; Chapkin
Table 3 Frequencies of study participants indicating their skin as more dry, as more normal or as more wet Skin dryness Months of Quintesal consumption 0 months Number More dry More normal More wet 12 16 1 Percentage 42 55 3 1 month Number 5 21 3 Percentage 17 73 10 2 months Number 4 23 2 Percentage 14 79 7

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Table 4 Fatty acid and fatty aldehyde pattern of red cell membrane phospholipids of 29 elderly people before and after 4 and 8 weeks of borage oil consumption (wt.% of total fatty acids; mean 9S.D.) Fatty acida 14:0 16:0 17:0 18:0 20:0 22:0 24:0 trans 18:1 16:0 DMA 18:0 DMA 16:1v7 18:1v7 18:1v9 20:1v9 20:2v9 24:1v9 18:2v6 18:3v6 20:3v6 20:4v6 20:3v6/20:4v6 22:4v6 22:5v6 18:3v3 20:5v3 22:5v3 22:6v3 0 Weeks 0.389 0.08 22.619 1.25 0.329 0.03 12.259 1.18 0.389 0.06 1.629 0.19 4.419 0.54 0.419 0.11 1.779 0.18 3.109 0.28 0.299 0.10 0.989 0.13 11.689 0.70 0.229 0.03 0.109 0.03 4.429 0.78 9.799 1.24 0.049 0.01 1.3790.26 10.9291.48 0.139 0.03 2.169 0.44 0.389 0.09 0.109 0.03 0.779 0.52 1.939 0.35 4.2890.88 4 Weeks 0.37 90.07* 22.15 9 1.50** 0.31 90.04 12.68 9 1.44 0.37 9 0.06 1.59 90.18** 4.38 90.57 0.39 90.10 1.79 90.18 3.13 90.24 0.29 90.11 0.95 9 0.13*** 11.47 90.75 0.23 9 0.03 0.09 9 0.03 4.38 90.76 9.46 9 1.41 0.06 9 0.02*** 1.58 9 0.32*** 11.31 91.98 0.15 9 0.05*** 2.22 90.51 0.39 9 0.10 0.10 9 0.03 0.79 9 0.51 1.99 9 0.39** 4.44 90.93 8 Weeks 0.38 9 0.07 22.30 91.11** 0.31 90.03 12.22 9 1.26 0.37 9 0.06 1.58 90.20** 4.40 9 0.60 0.39 90.07 1.79 90.18 3.11 9 0.24 0.28 90.12 0.93 90.11***, c 11.54 90.71 0.22 9 0.03 0.10 90.04 4.42 90.70 9.63 9 1.39 0.07 90.02***, c c c 1.69 9 0.34***, c c c 11.11 91.60 0.16 90.05***, c c 2.19 90.42 0.38 9 0.09 0.10 90.03 0.75 9 0.50 1.96 9 0.39** 4.43 90.93

a The FAME and DMA are identied by the ratio of the total number of carbon atoms to the total number of double bonds in the fatty chain; v9, v6 and v3 mark the location of the alkyl-terminal double bond. * Statistically different from baseline value at the signicance level of 0.05, according to the Friedman test. ** Statistically different from baseline value at a signicance level of 0.01 or 0.001, respectively, according to the Friedman test. *** Statistically different from baseline value at a signicance level of 0.01 or 0.001, respectively, according to the Friedman test. c Statistically different from the 4-week value at a signicance level of 0.05, 0.01 or 0.001, respectively, according to the Friedman test. cc Statistically different from the 4-week value at a signicance level of 0.05, 0.01 or 0.001, respectively, according to the Friedman test. ccc Statistically different from the 4-week value at a signicance level of 0.05, 0.01 or 0.001, respectively, according to the Friedman test.

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Fig. 3. Percentual increase of the gamma linolenic acid (GLA, 18:3v6) content of red cell ghost membranes of 29 elderly donors after 1 and 2 months of borage oil consumption.

Fig. 4. Percentual increase of the dihomo-gamma-linolenic acid (DHGLA, 20:3v6) content of red cell ghost membranes after 1 and 2 months of borage oil consumption.

Fig. 5. Percentual change in double bond index, fatty acid families and classes and in fatty aldehyde DMA of red cell ghost membrane phospholipids from 29 elderly people consuming borage oil. SAT, MUFA and PUFA: saturated, monounsaturated and polyunsaturated fatty acids, respectively. v3, v6 and v9: fatty acid families. DBI, double bond index; v6-METAB, v6 fatty acid family without linoleic acid.

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et al., 1986), essential fatty acid metabolites have to be synthesized in the liver and transported by the blood to the skin. In old rats a signicant lower activity of hepatic microsomal 6 desaturase (E.C. 1.14.99.5) has been demonstrated, as compared to young adult animals. These enzyme activities were determined in vitro and corresponding alterations were measured in the fatty acid pattern of the hepatic microsomes of the rats (Hrelia et al., 1989, 1990). Thus, skin changes in old age might be, at least in part, a consequence of a relative lack of EFA in the skin, due to an age associated reduction in the activity of the hepatic 6 desaturase, as has been proposed by Horrobin (1989). Thus, the decreased transepidermal water loss observed after borage oil consumption by elderly people in this study (Fig. 1) may counteract the age associated decline of the skin barrier function. The mechanism of this effect on the epidermal permeability barrier homeostasis possibly is mediated by an inuence on crucial components of the barrier lipid complex. Simple incorporation of GLA into lipids of this complex is unlikely as the causing principle, since the content of this fatty acid in skin sample lipids of ve people was extraordinary low (unpublished data). Therefore, we suppose an inuence of borage oil consumption on other potential regulatory mechanisms of cutaneous barrier function (Elias et al., 1993) including key enzymes of cholesterol, fatty acid and ceramide synthesis, of extracellular ions like calcium and potassium, of cytokines or of eicosanoides. An inuence of fatty acid metabolism by 12-lipoxygenase on skin permeability barrier function in mice has been demonstrated recently (Johnson et al., 1999). Contrasting results have been reported on the hydration of stratum corneum in older persons: slightly increased values have been described (Thune, 1989; Klein et al., 1993), as well as a reduced water content with dry skin (Potts et al., 1984; Takenouchi et al., 1986). The elderly people in this study subjectively noted some improvement of skin dryness (Table 3). However, our measurement of skin hydration revealed no change in skin humidity (Fig. 2). The comprehensive measurement of differently bound compartments of skin water might be a suitably technique to register age associated alterations of skin hydration or effects of borage oil consumption (Takenouchi et al., 1986). Itch is frequently observed even in normal elderly people without skin diseases. The effect of borage oil consumption to reduce itch took place in all of the elderly participants indicating this condition (Table 2). A similar effect has been noted in a pilot study with patients under chronic haemodialysis treatment (Knopf et al., 1996). In every second patient undergoing chronic haemodialysis a nephrogenic pruritus is observed. Borage oil consumption proofed as a successful treatment of itch in these patients (Knopf et al., 1996). The biochemical factors inducing the reduction of itch remain to be investigated. The consumption of borage oil rich in GLA induced a mean increase of about 70% of GLA portions in phospholipids of erythrocyte membranes (Fig. 3). Normally GLA is synthesized by the hepatic delta 6-desaturase from LA. No signicant change of LA portions of erythrocyte membrane phospholipids was observed (Table 4), although it is a main constituent of borage oil (Table 1). This indicates

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a good supply of the essential fatty acid LA by the normal diet of our study participants. GLA is metabolized to DHGLA by enzymatic chain elongation. DHGLA content was increased by borage oil consumption by about 18% (Fig. 4 and Table 4). DHGLA is the precursor of the monoenic prostaglandins. Its increased portion in cell membranes is an essential factor in reducing the proinammatory effect of AA, the precursor of dienoic prostaglandins. Therefore, it is important to note the relative increase of DHGLA over AA, as reected in the ratio DHGLA/AA. There was no alteration of AA concentration in the erythrocyte membrane phospholipids (Table 4), demonstrating the well known low activity of the further metabolization of DHGLA to AA by the human hepatic delta 5-desaturase (Stone et al., 1979). The effect of the consumption of borage oil on the fatty acid composition of individual phospholipids in human platelets also lead to increased DHGLA levels and DHGLA/AA ratios without an accompanying rise in AA (Barre and Holub, 1992). These results are conrmed by our measurements in erythrocyte membrane phospholipids. In contrast, we observed no change of nervonic acid (NA, 24:1v9; Table 4), statistically not signicant increases in the v3 fatty acid family (Fig. 5), and even a signicant increase of the v3 docosapentaenoic acid (DPA, 22:5v3; Table 4) content in erythrocyte membranes. In platelet membrane phospholipids an increase of NA was observed (Barre and Holub, 1992). The NA content of the borage oil employed in our study of 1.5% (Table 1) was comparable to that used by Barre and Holub (1992) of 1.8%. Circulating red cells have no enzymes to desaturate or elongate phospholipid fatty acids but incorporate mainly from plasma intact phospholipid molecules with fatty acids of dietary and hepatic origin. Thus, the different modication of erythrocyte and platelet phospholipid fatty acid composition by borage oil consumption may be due to the different study design employed by Barre and Holub (1992), or to a specic regulation of platelet membrane functioning. Since our study participants reportedly did not change their normal diet or take sh oil, the slight but statistically signicant increase in DPA concentration after borage oil consumption (+ 2%, Table 4) seems paradox. Possibly the low amount of the unusual stearidonic acid in borage oil (18:4v3, Table 1) exerted this effect. Consumption of this fatty acid also skips the metabolic step of delta 6-desaturation. On the other side, Eskimos are unlikely to eat borage oil. Nevertheless, they have been questioned to be obligate carnivores, since there is an apparent increase in DHGLA in their plasma triglycerides (Gibson and Sinclair, 1981; Sinclair, 1981), in addition to the well known replacement of AA by v3-eicosapentaenoic acid (EPA, 20:5v3). Finally, we have no compelling explanation for the reduced levels of 18:1v7 after borage oil consumption (Table 4). In conclusion, consumption of borage oil rich in GLA was found to induce a statistically signicant improvement of cutaneous barrier function in elderly people, as reected in transepidermal water loss. The study participants noted a reduction of itch, which was indicated in 34% of the cases before and in 0% after borage oil consumption. Whereas the portion of people claiming dry skin was reduced from 42 to 14% in the course of the study, we could not measure any statistically signicant alteration of skin hydration. The fatty acid composition of erythrocyte membrane phospholipids demonstrated an increased incorporation of GLA and DHGLA and

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a reduced content of saturated and monounsaturated fatty acids. There was no signicant alteration in NA or in AA content of the membranes, but a signicant increase in the DHGLA/AA ratio and of DPA content.

Acknowledgements This work was supported by Galderma Laboratorien GmbH, Freiburg, Germany. The authors are indebted to Dr Hartmut Eicher, Institute of Gerontology, University of Erlangen Nurnberg, for providing the computer program STAN PLUS.

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