Experimental Gerontology 43 (2008) 629–632

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Experimental Gerontology

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Mini Review

The role of near infrared radiation in photoaging of the skin

Peter Schroeder *, Judith Haendeler, Jean KrutmannInstitut fuer Umweltmedizinische Forschung (IUF), Heinrich-Heine-University Düsseldorf gGmbH, Auf’m Hennekamp 50, D-40225 Duesseldorf, Germany

a r t i c l e i n f o a b s t r a c t

Article history:Received 8 January 2008Received in revised form 3 April 2008Accepted 14 April 2008Available online 27 April 2008

Keywords:InfraredMatrix metalloproteinase-1SkinReactive oxygen speciesAntioxidantsAging

0531-5565/$ - see front matter � 2008 Elsevier Inc. Adoi:10.1016/j.exger.2008.04.010

* Corresponding author. Fax: +49 211312976.E-mail address: peet@gmx.de (P. Schroeder).

Infrared (IR) radiation is non-ionizing, electromagnetic radiation with wavelengths between 760 nm and1 mm, which is further divided into IRA, IRB and IRC. IR accounts for more than half of the solar energythat reaches the human skin. While IRB and IRC do not penetrate deeply into the skin, more than 65% ofIRA reaches the dermis. Human skin is increasingly exposed to IRA-radiation; most relevant sources are(i) natural solar radiation consisting of over 30% IRA, (ii) artificial IRA sources used for therapeutic or well-ness purposes and (iii) artificial UV sources contaminated with IRA. As part of natural sunlight, IRA sig-nificantly contributes to extrinsic skin aging.This article reviews the cutaneous effects of IRA-radiation, the underlying molecular mechanisms and theavailable protective strategies.

� 2008 Elsevier Inc. All rights reserved.

1. Physical properties of infrared A, natural and artificialsources

Solar radiation reaching the earth surface includes the wave-lengths from 290 to 4000 nm and is divided into three majorbands: ultraviolet (UV) radiation (k = 290–400 nm), visible light(k = 400–760 nm) and infrared (IR) radiation (k = 760 nm–1 mm).Infrared radiation is further divided into IRA (near IR, k = 760–1440 nm), IRB (mid IR, k = 1440–3000 nm) and IRC (far IR,k = 3000 nm–1 mm). The main source of IR radiation is the sun,but artificial IR sources are constantly gaining importance. Theyare used for therapeutic (e.g. in rheumatoid arthritis and in photo-dynamic therapy) as well as for lifestyle purposes (e.g. for fatreduction), and beside the many beneficial effects, the questionsof detrimental effects, especially due to unsupervised non-medicaluse poses a problem.

While the photon energy of IR is lower than that of UV, the totalamount of energy transferred by the sun consists of �54% IR whileUV only accounts for 7%. The largest part of solar IR radiation is IRA(�30% of total solar energy), which deeply penetrates into humanskin while IRB and IRC only affect the upper skin layers (Kochevaret al., 2008).

The actual solar IRA dose reaching the skin is influenced by thesame factors as the UV dose, i.e. ozone layer, position of the sun,latitude, altitude, cloud cover and surface reflections.

ll rights reserved.

2. Photoaging

The term photoaging refers to changes in the skin that superim-pose the alterations of chronological aging. Clinically, photoaging isassociated with the formation of coarse wrinkles, uneven skin pig-mentation, loss of skin elasticity and a disturbance of skin barrierfunctions (Yaar, 2006). These changes are present due to chronicsolar radiation exposure. Among the wavelength bands that reachthe earth’s surface the best investigated in terms of photoaging areUVA (k = 320–400 nm) and UVB (k = 280–320 nm), but recent re-sults emphasis the role of infrared A (IRA, 760–1440 nm) in photo-aging of the skin (Kim et al., 2005, 2006b; Schieke et al., 2002;Schroeder et al., 2008), which has first been described more than25 years ago (Kligman, 1982). UVA, UVB and IRA all penetrate intothe skin, with UVB being mainly absorbed in the epidermis, whileUVA reaches epidermis and dermis (Yaar, 2006). IRA penetratesdeeply into the skin and reaches even the subcutis, approximatelyhalf of the IRA is absorbed in the dermis (Schroeder et al., 2006).

Although IRA has been shown to have effects on cells of thefast regenerating epidermis as well, this review focuses on thedermal compartment of the skin, as changes in the dermis arelonger lasting (Krutmann and Gilchrest, 2006). Changes in thecells and the extracellular matrix of the dermis contribute signif-icantly to photoaging; collagen degradation and accumulation ofabnormal elastic fibres are hallmarks of photoaged skin. Thesealterations are due to changes in expression of several genes, inparticular matrix metalloproteinases (MMPs), which are inducedby IRA (Schieke et al., 2002), UVA (Tyrrell, 1996) and UVB (Brenn-eisen et al., 2002). Under physiological conditions, MMPs are partof a coordinated network and are precisely regulated by their

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endogenous inhibitors, the tissue inhibitors of MMPs (TIMPs).Unbalanced activity of MMPs due to extrinsic noxae is a majorpathophysiological factor in skin aging and several diseases suchas rheumatic diseases, hepatic cirrhosis, tumor invasion andmetastasis (Westermarck and Kahari, 1999).

The expression of MMPs is governed by the cellular signal trans-duction machinery of kinases and phosphatases (Schieke et al.,2003). Increased levels of reactive oxygen species (ROS) due toUVA (Wlaschek et al., 1995), UVB (Brenneisen et al., 2002) or IRA(Schroeder et al., 2007) have been shown to initiate the signalingevents involved. However, the primary radiation-induced reactionstriggered by UVA, UVB and IRA differ substantially.

3. Biological effects of infrared A radiation on the skin

More than 25 years ago, Kligman observed that IR irradiationenhances UV induced actinic skin damage, and that IR alone causedactinic skin damage similar to that found in UV exposed skin (Klig-man, 1982) in albino guinea pigs. Similarly, in 2005 IRA alone wasshown to lead to wrinkle formation in hairless mice and to inten-sify the detrimental effect of UV radiation (Kim et al., 2005).

Concerning the molecular mechanisms involved, it was shownthat IRA treatment of human skin fibroblasts leads to an increasedexpression of matrixmetalloproteinase-1 (MMP-1) without an con-comitant increase in expression of the respective inhibitor TIMP-1(Schieke et al., 2002). In hairless mice Kim et al. showed increasedlevels of MMP-3 and MMP-13 (Kim et al., 2005). Mitochondrial ROSwere shown to be the initiating event and to induce increased tran-

IRA

mitochondrialROS

cytosolicROS

? ?

? ?

MAPKinaseactivity

gene expression

? ?

? ?mitochondrial respiratory chainNADPH oxidase?Xanthine oxidase?

mitochondrial membranepotential?

mitochondrial ion fluxes?retrograde signaling events

receptor kinases?phosphatases?

transcriptionfactors

Fig. 1. IRA induces the formation of mitochondrial reactive oxygen species leads tochanges in gene expression. It has been demonstrated, that IRA irradiation leads toan increased level of mitochondrial ROS which in turn leads to increased cytosolicROS levels. Besides the mitochondrial respiratory chain, NADPH oxidase and Xan-thine oxidase are discussed to play a role in the increased ROS production. Via thusfar unknown mechanisms, which might involve disturbance of mitochondrial fu-nctions, mitochondrially induced ion fluxes, other retrograde signaling events (e.g.via mTOR, Ca2+-dependent kinases), altered activity of upstream kinases and/oraltered phosphatase activity, the activity of MAPKinases is increased. At least theMAPKinases p38 and ERK1/2 are involved in this signaling cascade. These kinasesalter the expression of genes like MMP-1 and MMP-9 via modification of tran-scription factors. Involvement of AP-1 and other known targets of the MAPKinasesactivated by IRA are likely, but remain to be investigated.

scription and translation of the MMP-1 gene via activation of theMAPKinases ERK1/2 (see Fig. 1) (Schieke et al., 2002; Schroederet al., 2007).

An influence of IRA on the mitochondria was suggested by thefinding, that IRA is absorbed by components of the mitochondrialrespiratory chain (Karu, 1999). This might cause a disruption ofthe mitochondrial electron flow, which is known to result in turnin an increased production of mitochondrial ROS. Such a disruptionof the mitochondrial function could trigger retrograde signalingprocesses which regulate nuclear gene expression (Butow andAvadhani, 2004). Triggering of such a mitochondria to nucleus re-sponse would clearly distinguish the IRA response from other nox-ae including UVA and UVB. Indeed, the mitochondrial ROSgeneration induced by IRA is highly specific compared to theUVs: UVA and UVB induced increased expression of MMP-1 arenot affected by the use of antioxidants which specifically targetthe mitochondria (MitoQ) or by manipulation of function or massof mitochondrial respiratory chain components, while the IRA re-sponse is substantially altered by these strategies (Schroederet al., 2007). Recent advances in understanding the UVA responsesupport this, because plasma membrane electron transport sys-tems instead of the mitochondrial respiratory chain have beenidentified to be crucially involved in UVA induced ROS formation(Schauen et al., 2007). Although Schieke et al. demonstrated a dif-ference in induction of MMP-1 between IRA irradiation and a mildheat shock (42 �C) treatment in human dermal fibroblasts (Schiekeet al., 2002), Shin et al. recently reported that exposure of HaCatcells to 44 �C leads to increased MMP-1 and MMP-9 expression(Shin et al., 2008). They further reported that beside an involve-ment of the mitochondrial respiratory chain NADPH oxidase andXanthine oxidase mediate this heat shock induced effect.

The involvement of the MAPKinases ERK1/2 is a common fea-ture of MMP-1 induction by UVA, UVB and IRA. In general, threedistinct MAPK pathways have been characterized: the extracellularsignal regulated kinase 1/2 (ERK1/2) pathway (Raf-MEK1/2-ERK1/2), and the c-Jun N-terminal kinase (MEKK1/3-MKK4/7-JNK1/2/3)and p38 (MEKK-MKK3/6-p38 a–d) pathways; the latter two alsotermed stress-activated protein kinases (SAPKs). The ERK1/2 path-way is inducible by mitogen such as growth factors, whereas theSAPK pathways are predominantly induced by inflammatory cyto-kines as well as environmental stress such as UV, heat and osmoticshock. All three pathways have been described to react to changesin the redox-status of the cells, such as increased ROS production.Activated MAPKs translocate to the nucleus, where they phosphor-ylate and activate transcription factors such as c-Jun, c-Fos, ATF-2and ternary complex factors (TCF) leading to the formation andactivation of homo- or heterodimeric forms of the transcriptionfactor AP-1 (Chang and Karin, 2001; Hazzalin and Mahadevan,2002; Kyriakis and Avruch, 2001). The promoter region of MMP-1 carries multiple AP-1-binding sites (Angel et al., 1987; Gutmanand Wasylyk, 1990). For IRA, it was demonstrated that ERK1/2and p38 are activated in dermal fibroblasts, and that inhibition ofERK1/2 activation subdues the IRA-induced increase of MMP-1while inhibition of p38 had no influence on IRA-induced MMP-1expression (Schieke et al., 2002).

In addition to its effect on MMP-1, several other cellular andphysiological responses to IRA-radiation are known. Kim et al. re-ported, that infrared exposure is involved in neoangiogenesis inhuman skin, because IRA induces an angiogenic switch by alteringthe balance between the angiogenic inducer VEGF and the angio-genic inhibitor TSP-2 (Kim et al., 2006a). Interestingly, increasedneoangiogenesis is a prominent feature of photoaged human skin(Yaar, 2006). Others found that IRA irradiation led to a decreasein epidermal proliferation, Langerhans cell density and contacthypersensitivity reaction in mice (Danno and Sugie, 1996) and asubsequent study by the same group indicates, that IRA influences

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cutaneous wound repair by altering the levels of transforminggrowth factor (TGF)-b1 and MMP-2 (Danno et al., 2001). Yet an-other study showed an influence of IRA on protein expression offerritin: an increased ferritin expression was detected after IRAirradiation of keratinocytes and fibroblasts (Applegate et al.,2000). Induction of this putative defence system in human skinmost likely reflects a cellular response to oxidative processes trig-gered by IRA. Frank et al. showed that IRA interferes with apoptoticpathways, namely with the mitochondrial apoptosis pathway(Frank et al., 2004) and reported, that IRA signals via p53 (Franket al., 2006).

The involvement of at least two of the three MAPKinase path-ways, supported by reports of an influence of IRA on transcriptionand translation of several genes, implies that the regulation of geneexpression by IRA-radiation represents a more global response.

Recent human in vivo investigations confirmed the IRA-inducedupregulation of MMP-1 with a concomitant lack of TIMP-1 upreg-ulation in human skin (Schroeder et al., 2007). The increase inMMP-1 was confined in the dermal compartment of the skin,which underlines the contribution of IRA-radiation to skin aging,as changes to the dermal extracellular matrix are mainly responsi-ble for the clinical aging phenotype.

While human dermal fibroblasts withstand IRA doses up to atleast 1200 J/cm2 (Schieke et al., 2002) the gene regulatory effectscan already be observed at much lower doses, e.g. (54 J/cm2 (Dan-no et al., 2001), 240 J/cm2 (Buechner et al., in this issue), or 360 J/cm2 (Schroeder et al., 2007). Increased levels of cytosolic and mito-chondrial ROS were detected even after a treatment with 30 J/cm2

(Schroeder et al., 2007).Taken together, these findings imply that IRA-radiation is capa-

ble of altering gene expression which brings forward a pro-agingphenotype of the skin. Apart from minimising exposure to naturalIRA and responsible use of artificial IRA sources, the questionsarises how a protection against the detrimental effects of IRA canbe achieved.

4. Protective strategies

One obvious approach to protect against IRA would be the useof IRA reflecting mineral pigments (e.g. titanium dioxide). Thedownside of using such a strategy is the lack of consumer accep-tance due to cosmetic issues; such substances would not be invis-ible after topical application and therefore not be used.

Thus, another promising approach is the use of antioxidants. Invitro N-acetylcysteine, MitoQ, ascorbic acid and flavonoids haveproven to provide effective protection against IRA-induced upreg-ulation of MMP-1 (Schroeder et al., 2007; 2008). In vivo, topical useof an antioxidant mixture resulted in more than 60% reduction ofIRA-induced MMP-1 upregulation.

Also, use of thioredoxin-1 shows protective potential againstIRA-induced upregulation of MMP-1 and downregulation of pro-collagen 1A1 (Col1A1), one of the major collagens of the extracel-lular matrix of human skin, in vitro in primary human dermalfibroblasts (Buechner et al., in this issue). The use of thioredoxin-1 and MitoQ was specific in terms of not protecting against UVA,UVB and IRA equally effective. This emphasises that the importantchallenge is to provide a combination of several protective ap-proaches to develop strategies which are suitable and effectiveagainst the full solar spectrum.

An approach on the basis of hormesis (Rattan and Ali, 2007)might also be possible to achieve protection against detrimental ef-fects. Antioxidative responses of cells to IRA treatment have beenshown in several studies (Applegate et al., 2000; Schroeder et al.,2007), therefore a small dose of IRA or small repetitive IRA treat-ments might result in a protection against larger IRA doses.

5. Concluding remarks

IRA-radiation is an omnipresent environmental factor that is apotent regulator of gene expression in skin cells. In order to under-stand and exploit its beneficial effects responsibly and to minimizeand protect against its detrimental effects, it is crucial to furtherunderstand its modes of action. It is without doubt that modernphotoprotection of human skin has to include protection againstIRA-radiation as well.

References

Angel, P., Baumann, I., Stein, B., Delius, H., Rahmsdorf, H.J., Herrlich, P., 1987. 12-O-Tetradecanoyl-phorbol-13-acetate induction of the human collagenase gene ismediated by an inducible enhancer element located in the 50-flanking region.Mol. Cell. Biol. 7, 2256–2266.

Applegate, L.A., Scaletta, C., Panizzon, R., Frenk, E., Hohlfeld, P., Schwarzkopf, S.,2000. Induction of the putative protective protein ferritin by infrared radiation:implications in skin repair. Int. J. Mol. Med. 5, 247–251.

Brenneisen, P., Sies, H., Scharffetter-Kochanek, K., 2002. Ultraviolet-B irradiationand matrix metalloproteinases: from induction via signaling to initial events.Ann. NY Acad. Sci. 973, 31–43.

Buechner, N., Schroeder, P., Kunze, K., Maresch, T., Calles, C., Krutmann, J.,Haendeler, J., 2008. Changes of MMP-1 and collagen 1A1 by UVA, UVB,and IRA are differentially regulated by Trx-1. Exp. Gerontol. 43, 633–637.

Butow, R.A., Avadhani, N.G., 2004. Mitochondrial signaling: the retrograde response.Mol. Cell 14, 1–15.

Chang, L., Karin, M., 2001. Mammalian MAP kinase signalling cascades. Nature 410,37–40.

Danno, K., Mori, N., Toda, K., Kobayashi, T., Utani, A., 2001. Near-infrared irradiationstimulates cutaneous wound repair: laboratory experiments on possiblemechanisms. Photodermatol. Photoimmunol. Photomed. 17, 261–265.

Danno, K., Sugie, N., 1996. Effects of near-infrared radiation on the epidermalproliferation and cutaneous immune function in mice. Photodermatol.Photoimmunol. Photomed. 12, 233–236.

Frank, S., Menezes, S., Lebreton-De Coster, C., Oster, M., Dubertret, L., Coulomb, B.,2006. Infrared radiation induces the p53 signaling pathway: role in infraredprevention of ultraviolet B toxicity. Exp. Dermatol. 15, 130–137.

Frank, S., Oliver, L., Lebreton-De Coster, C., Moreau, C., Lecabellec, M.T., Michel, L.,Vallette, F.M., Dubertret, L., Coulomb, B., 2004. Infrared radiation affects themitochondrial pathway of apoptosis in human fibroblasts. J. Invest. Dermatol.123, 823–831.

Gutman, A., Wasylyk, B., 1990. The collagenase gene promoter contains a TPA andoncogene-responsive unit encompassing the PEA3 and AP-1 binding sites.EMBO J. 9, 2241–2246.

Hazzalin, C.A., Mahadevan, L.C., 2002. MAPK-regulated transcription: acontinuously variable gene switch? Nat. Rev. Mol. Cell Biol. 3, 30–40.

Karu, T., 1999. Primary and secondary mechanisms of action of visible to near-IRradiation on cells. J. Photochem. Photobiol. B 49, 1–17.

Kim, H.H., Lee, M.J., Lee, S.R., Kim, K.H., Cho, K.H., Eun, H.C., Chung, J.H., 2005.Augmentation of UV-induced skin wrinkling by infrared irradiation in hairlessmice. Mech. Ageing Dev. 126, 1170–1177.

Kim, M.S., Kim, Y.K., Cho, K.H., Chung, J.H., 2006a. Infrared exposure induces anangiogenic switch in human skin that is partially mediated by heat. Br. J.Dermatol. 155, 1131–1138.

Kim, M.S., Kim, Y.K., Cho, K.H., Chung, J.H., 2006b. Regulation of type I procollagenand MMP-1 expression after single or repeated exposure to infrared radiation inhuman skin. Mech. Ageing Dev. 127, 875–882.

Kligman, L.H., 1982. Intensification of ultraviolet-induced dermal damage byinfrared radiation. Arch. Dermatol. Res. 272, 229–238.

Kochevar, I.E., Taylor, C.R., Krutmann, J., 2008. Fundamentals of cutaneousphotobiology and photoimmunology. In: Wolff, K., Goldsmith, L.A., Katz, S.,Gilchrest, B., Paller, A.S., Lefell, D.J. (Eds.), Fitapatrick’s Dermatology in GeneralMedicine, seventh ed. McGraw-Hill, New York.

Krutmann, J., Gilchrest, B.A., 2006. Photoaging of skin. In: Gilchrest, B., Krutmann, J.(Eds.), Skin Aging. Springer-Verlag, Berlin/Heidelberg, pp. 33–44.

Kyriakis, J.M., Avruch, J., 2001. Mammalian mitogen-activated protein kinase signaltransduction pathways activated by stress and inflammation. Physiol. Rev. 81,807–869.

Rattan, S.I., Ali, R.E., 2007. Hormetic prevention of molecular damage duringcellular aging of human skin fibroblasts and keratinocytes. Ann. NY Acad. Sci.1100, 424–430.

Schauen, M., Hornig-Do, H.T., Schomberg, S., Herrmann, G., Wiesner, R.J., 2007.Mitochondrial electron transport chain activity is not involved in ultraviolet A(UVA)-induced cell death. Free Radic. Biol. Med. 42, 499–509.

Schieke, S., Stege, H., Kurten, V., Grether-Beck, S., Sies, H., Krutmann, J., 2002.Infrared-A radiation-induced matrix metalloproteinase 1 expression ismediated through extracellular signal-regulated kinase 1/2 activation inhuman dermal fibroblasts. J. Invest. Dermatol. 119, 1323–1329.

Schieke, S.M., Schroeder, P., Krutmann, J., 2003. Cutaneous effects of infraredradiation: from clinical observations to molecular response mechanisms.Photodermatol. Photoimmunol. Photomed. 19, 228–234.

632 P. Schroeder et al. / Experimental Gerontology 43 (2008) 629–632

Schroeder, P., Lademann, J., Darvin, M., Stege, H., Marks, C., Bruhnke, S., Krutmann, J.,2008. Infrared radiation induced matrix metalloproteinase in human skin:implications for protection. J. Invest. Dermatol. (Epub ahead of print)PMID:18449210.

Schroeder, P., Pohl, C., Calles, C., Marks, C., Wild, S., Krutmann, J., 2007. Cellularresponse to infrared radiation involves retrograde mitochondrial signaling. FreeRadic. Biol. Med. 43, 128–135.

Schroeder, P., Schieke, S., Morita, A., 2006. Premature skin aging by infraredradiation, tobacco smoke and ozone. In: Gilchrest, B., Krutmann, J. (Eds.), SkinAging. Springer-Verlag, Berlin/Heidelberg, pp. 45–54.

Shin, M.H., Moon, Y.J., Seo, J.E., Lee, Y., Kim, K.H., Chung, J.H., 2008. Reactive oxygenspecies produced by NADPH oxidase, xanthine oxidase, and mitochondrial

electron transport system mediate heat shock-induced MMP-1 and MMP-9expression. Free Radic. Biol. Med. 44, 635–645.

Tyrrell, R.M., 1996. Activation of mammalian gene expression by the UV componentof sunlight – from models to reality. Bioessays 18, 139–148.

Westermarck, J., Kahari, V.M., 1999. Regulation of matrix metalloproteinaseexpression in tumor invasion. FASEB J. 13, 781–792.

Wlaschek, M., Briviba, K., Stricklin, G.P., Sies, H., Scharffetter-Kochanek, K., 1995.Singlet oxygen may mediate the ultraviolet A-induced synthesis of interstitialcollagenase. J. Invest. Dermatol. 104, 194–198.

Yaar, M., 2006. Clinical and histological features of intrinsic versus extrinsic skinaging. In: Gilchrest, B., Krutmann, J. (Eds.), Skin Aging. Springer-Verlag, Berlin/Heidelberg, pp. 9–21.