Expanding Our Understanding of Human Skin Aging
2016; Elsevier BV; Volume: 136; Issue: 5 Linguagem: Inglês
10.1016/j.jid.2016.02.020
ISSN1523-1747
Autores Tópico(s)Air Quality and Health Impacts
ResumoTwo very different studies expand our understanding of human skin aging. In the first study, Hüls et al. show an association between nitrogen dioxide levels in outdoor air and number of lentigines on the cheek. In the second study, Bowman and Birch-Machin show that mitochondrial complex II activity in human skin fibroblasts decreases with age. Two very different studies expand our understanding of human skin aging. In the first study, Hüls et al. show an association between nitrogen dioxide levels in outdoor air and number of lentigines on the cheek. In the second study, Bowman and Birch-Machin show that mitochondrial complex II activity in human skin fibroblasts decreases with age. Two very different studies expand our understanding of human skin aging. In the first study, a "Letter to the Editor," Hüls et al., 2016Hüls A. Vierkötter A. Gao W. Krämer U. Yang Y. Ding A. et al.Traffic-related air pollution contributes to development of facial lentigines: further epidemiological evidence from Caucasians and Asians.J Invest Dermatol. 2016; 136: 1053-1056Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar show an association between nitrogen dioxide (NO2) levels measured in the environment and the geometric mean number of cheek lentigines in two separate populations. Environmental pollution in the form of poor air quality is a major worldwide health problem, and recognition of the significant effects of air pollution on the skin is growing. Cigarette smoking and ambient soot levels are known to promote clinically visible skin changes (Vierkotter et al., 2010Vierkotter A. Schikowski T. Ranft U. Sugiri D. Matsui M. Kramer et al.Airborne particle exposure and extrinsic skin aging.J Invest Dermatol. 2010; 130: 2719-2726Abstract Full Text Full Text PDF PubMed Scopus (294) Google Scholar). Hüls et al., 2016Hüls A. Vierkötter A. Gao W. Krämer U. Yang Y. Ding A. et al.Traffic-related air pollution contributes to development of facial lentigines: further epidemiological evidence from Caucasians and Asians.J Invest Dermatol. 2016; 136: 1053-1056Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar report a new association between an environmental pollutant, NO2, which is generated from combustion such as from vehicles, and visible cheek lentigines. A dose effect of NO2 on the geometric mean number of cheek lentigines was observed: an increase of 10 μg/m3 in NO2 level was associated with 24–25% more cheek lentigines. The strength of the Hüls et al., 2016Hüls A. Vierkötter A. Gao W. Krämer U. Yang Y. Ding A. et al.Traffic-related air pollution contributes to development of facial lentigines: further epidemiological evidence from Caucasians and Asians.J Invest Dermatol. 2016; 136: 1053-1056Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar article is in the association between NO2 levels and cheek lentigines in two separate populations, one in Germany and the other in China, both in individuals over 50 years old. There is evidence suggesting that environmental insults to the skin are more likely to manifest with clinically visible phenotypes in individuals with genetic susceptibility. Recently, wrinkle severity has been reported in elderly women to be associated with decreased lung function (specifically the ratio of forced expiratory volume to forced volume capacity), but only in individuals who carry specific matrix metalloproteinase promoter variants (Vierkotter et al., 2010Vierkotter A. Schikowski T. Ranft U. Sugiri D. Matsui M. Kramer et al.Airborne particle exposure and extrinsic skin aging.J Invest Dermatol. 2010; 130: 2719-2726Abstract Full Text Full Text PDF PubMed Scopus (294) Google Scholar). The Hüls et al., 2016Hüls A. Vierkötter A. Gao W. Krämer U. Yang Y. Ding A. et al.Traffic-related air pollution contributes to development of facial lentigines: further epidemiological evidence from Caucasians and Asians.J Invest Dermatol. 2016; 136: 1053-1056Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar article did not genotype the participants in the two cohorts, but determining whether the increased lentigo phenotype is visible only in individuals carrying a specific genotype could be informative, especially if the genetic associations are the same across two populations. Furthermore, if this association between NO2 and increased numbers of cheek lentigines could eventually be shown to serve as a marker for damage to other organ systems such as the lungs (as wrinkle formation has been reported to associate with decreased lung function), individuals could be screened for susceptibility to pollution so that they could minimize exposures.Mitochondria and pollution: two studies expanding our understanding of human skin aging. Mitochondria and pollution: two studies expanding our understanding of human skin aging. Another important question the Hüls et al., 2016Hüls A. Vierkötter A. Gao W. Krämer U. Yang Y. Ding A. et al.Traffic-related air pollution contributes to development of facial lentigines: further epidemiological evidence from Caucasians and Asians.J Invest Dermatol. 2016; 136: 1053-1056Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar study brings up is whether the increase in number of cheek lentigines is attributable to a systemic effect from chronic inflammation via the lungs or attributable to more regional effects on the skin. Hüls et al., 2016Hüls A. Vierkötter A. Gao W. Krämer U. Yang Y. Ding A. et al.Traffic-related air pollution contributes to development of facial lentigines: further epidemiological evidence from Caucasians and Asians.J Invest Dermatol. 2016; 136: 1053-1056Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar did not detect a significant association between NO2 levels and the number of lentigines on other sun-exposed areas such as the forehead, dorsal hand, or forearm. This suggests that a regional effect is likely needed—for instance, through NO2 exposure to cheek skin. One possibility is that NO2 (or its breakdown products, such as photolysis-mediated hydroxyl radicals [Trebs et al., 2009Trebs I. Bohn B. Ammann C. Rummel U. Blumthaler M. Konigstedt R. et al.Relationship between NO2 photolysis frequency and the solar irradiance.Atmos Meas Tech. 2009; 2: 725-739Crossref Scopus (53) Google Scholar]), may penetrate cheek skin more effectively than other sun-exposed anatomic sites. Although Hüls et al., 2016Hüls A. Vierkötter A. Gao W. Krämer U. Yang Y. Ding A. et al.Traffic-related air pollution contributes to development of facial lentigines: further epidemiological evidence from Caucasians and Asians.J Invest Dermatol. 2016; 136: 1053-1056Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar did not show a mechanistic connection between NO2 levels and cheek lentigines, it is known that NO2 can undergo photolysis, with generation of reactive breakdown products that can potentially affect both the skin and lungs (Ayyagari et al., 2007Ayyagari V.N. Januszkiewicz A. Nath J. Effects of nitrogen dioxide on the expression of intercellular adhesion molecule-1, neutrophil adhesion, and cytotoxicity: studies in human bronchial epithelial cells.Inhal Toxicol. 2007; 19: 181-194Crossref PubMed Scopus (36) Google Scholar). Mechanisms hypothesized to promote the so-called "environmentally-induced lentigo" include macromolecular damage and activation of aryl hydrocarbon receptors on skin cells (Nakamura et al., 2015Nakamura M. Morita A. Seite S. Haarmann-Stemmann T. Grether-Beck S. Krutmann J. Environment-induced lentigines: formation of solar lentigines beyond ultraviolet radiation.Exp Dermatol. 2015; 24: 407-411Crossref PubMed Scopus (35) Google Scholar), although the specific role of NO2 remains to be determined. Ultraviolet radiation has been shown to induce pigmentation via the aryl hydrocarbon receptor in mice (Jux et al., 2011Jux B. Kadow S. Luecke S. Rannug A. Krutmann J. Esser C. The aryl hydrocarbon receptor mediates UVB radiation-induced skin tanning.J Invest Dermatol. 2011; 131: 203-210Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar), and it can also induce mitochondrial DNA damage (Berneburg et al., 2004Berneburg M. Plettenburg H. Medve-Konig K. Pfahlberg A. Gers-Berlag H. Gefeller O. et al.Induction of the photoaging-associated mitochondrial common deletion in vivo in normal human skin.J Invest Dermatol. 2004; 122: 1277-1283Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar). Clearly, ultraviolet radiation is the primary environmental insult driving lentigo formation, and Hüls et al., 2016Hüls A. Vierkötter A. Gao W. Krämer U. Yang Y. Ding A. et al.Traffic-related air pollution contributes to development of facial lentigines: further epidemiological evidence from Caucasians and Asians.J Invest Dermatol. 2016; 136: 1053-1056Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar report lentigines in sun-exposed anatomic sites only. The additional role of NO2 appears to be that of increasing the number of lentigines. Because geometric means were reported by Hüls et al., 2016Hüls A. Vierkötter A. Gao W. Krämer U. Yang Y. Ding A. et al.Traffic-related air pollution contributes to development of facial lentigines: further epidemiological evidence from Caucasians and Asians.J Invest Dermatol. 2016; 136: 1053-1056Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, likely because of nonnormal distributions of lentigo counts, perhaps a subset of the populations studied are susceptible to increased numbers of lentigines. This possibility, although not explored in the Hüls et al., 2016Hüls A. Vierkötter A. Gao W. Krämer U. Yang Y. Ding A. et al.Traffic-related air pollution contributes to development of facial lentigines: further epidemiological evidence from Caucasians and Asians.J Invest Dermatol. 2016; 136: 1053-1056Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar study, would include genetic predisposition (suggested by uncommon genodermatoses with increased lentigo formation such as Peutz-Jeghers syndrome, although not necessarily at play in the study by Hüls et al., 2016Hüls A. Vierkötter A. Gao W. Krämer U. Yang Y. Ding A. et al.Traffic-related air pollution contributes to development of facial lentigines: further epidemiological evidence from Caucasians and Asians.J Invest Dermatol. 2016; 136: 1053-1056Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar), comorbidities, and/or exposure to other pollutants in addition to NO2. Because the increase in geometric mean numbers of cheek lentigines per unit of increase in NO2 was fairly small, prospective studies are needed to confirm the findings reported by Hüls et al., 2016Hüls A. Vierkötter A. Gao W. Krämer U. Yang Y. Ding A. et al.Traffic-related air pollution contributes to development of facial lentigines: further epidemiological evidence from Caucasians and Asians.J Invest Dermatol. 2016; 136: 1053-1056Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar. Ideally, these studies would use more individualized measurements of environmental exposures including NO2, ultraviolet radiation dosimetry, clinical histories, and genotype, although these types of studies would require significant resources over long periods of time. A second study in this issue, by Bowman and Birch-Machin, 2016Bowman A. Birch-Machin M.A. The age-dependent decrease of mitochondrial complex II activity in human skin and fibroblasts.J Invest Dermatol. 2016; 136: 912-919Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar, is an in vitro study that shows decreasing mitochondrial complex II activity in foreskin fibroblasts with increasing chronological age. Using foreskin (presumably a sun-protected anatomic location) from 27 individuals whose ages spanned eight decades, Bowman and Birch-Machin, 2016Bowman A. Birch-Machin M.A. The age-dependent decrease of mitochondrial complex II activity in human skin and fibroblasts.J Invest Dermatol. 2016; 136: 912-919Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar found that the rate of complex II activity per unit of mitochondria was decreased in cultured fibroblasts, but not in keratinocytes, with increasing chronological age. These observations were supported by parallel declines in complex II subunit transcript and protein levels. The results of this study are consistent with known decreases in mitochondrial complex II activity in numerous animal models, including the skin of naturally aged mice (Velarde et al., 2012Velarde M.C. Flynn J.M. Day N.U. Melov S. Campisi J. Mitochondrial oxidative stress caused by Sod2 deficiency promotes cellular senescence and aging phenotypes in the skin.Aging (Albany NY). 2012; 4: 3-12Crossref PubMed Scopus (186) Google Scholar), although in mice the effects were seen primarily in keratinocytes, not fibroblasts. In addition, decreased mitochondrial complex activity was associated with shortened lifespan in the nematode (Pfeiffer et al., 2011Pfeiffer M. Kayzer E.B. Yang X. Abramson E. Kenaston M.A. Lago C.U. et al.Caenorhabditis elegans UCP4 protein controls complex II-mediated oxidative phosphorylation through succinate transport.J Biol Chem. 2011; 286: 37712-37720Crossref PubMed Scopus (32) Google Scholar) and fruitfly (Tsuda et al., 2007Tsuda M. Sugiara T. Ishii T. Ishii N. Aigaki T. A mev-1-like dominant negative Sdhc increases oxidative stress and reduces lifespan in Drosophila.Biochem Biophys Res Commun. 2007; 363: 342-346Crossref PubMed Scopus (20) Google Scholar), indicating the pro-aging effect of mitochondrial dysfunction. The mechanism by which mitochondrial dysfunction promotes aging is thought to be via oxidative stress. Oxidative stress is known to lead to epidermal skin thinning in SOD-deficient mice (Velarde et al., 2012Velarde M.C. Flynn J.M. Day N.U. Melov S. Campisi J. Mitochondrial oxidative stress caused by Sod2 deficiency promotes cellular senescence and aging phenotypes in the skin.Aging (Albany NY). 2012; 4: 3-12Crossref PubMed Scopus (186) Google Scholar). More recently, oxidative stress has been observed to increase in human dermal fibroblasts if complex II function is abrogated (Anderson et al., 2014Anderson A. Bowman A. Boulton S.J. Manning P. Birch-Machin M.A. A role for human mitochondrial complex II in the production of reactive oxygen species in human skin.Redox Biol. 2014; 2: 1016-1022Crossref PubMed Scopus (47) Google Scholar). Oxidative stress has been reported to lead to mitochondrial DNA damage in human dermal fibroblasts (Quan et al., 2015Quan C. Cho M.K. Perry D. Quan T. Age-associated reduction of cell spreading induces mitochondrial DNA common deletion by oxidative stress in human skin dermal fibroblasts: implication for human skin connective tissue aging.J Biomed Sci. 2015; 22: 62Crossref PubMed Scopus (50) Google Scholar), potentially leading to a vicious cycle of increased oxidative stress (Rinnerthaler et al., 2015Rinnerthaler M. Bischof J. Streubel M.K. Trost A. Richter K. Breitenbach M. Oxidative stress in aging human skin.Biomolecules. 2015; 5: 545-589Crossref PubMed Scopus (478) Google Scholar). The main limitation of the Bowman and Birch-Machin, 2016Bowman A. Birch-Machin M.A. The age-dependent decrease of mitochondrial complex II activity in human skin and fibroblasts.J Invest Dermatol. 2016; 136: 912-919Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar study is the lack of clinical histories of the 27 participants. For instance, there may be confounding effects on the skin fibroblasts from older individuals with significant smoking histories or who may have lived in areas with air pollution for long periods of time, both of which may promote oxidative stress. Future studies will need to address these potential confounders. Another question arising from Bowman and Birch-Machin, 2016Bowman A. Birch-Machin M.A. The age-dependent decrease of mitochondrial complex II activity in human skin and fibroblasts.J Invest Dermatol. 2016; 136: 912-919Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar study is how mitochondrial complex II activity is decreased although complex IV activity is not. Loss of autophagy with age can lead to accumulation of dysfunctional mitochondria and increased levels of oxidative stress (Green et al., 2011Green D.R. Galuzzi L. Kroemer G. Mitochondria and the autophagy-inflammation-cell death axis in organismal aging.Science. 2011; 333: 1109-1112Crossref PubMed Scopus (840) Google Scholar, Lopez-Armada et al., 2013Lopez-Armada M.I. Riveiro-Naveira R.R. Vaamonde-Garcia C. Valcarcel-Ares M.N. Mitochondrial dysfunction and the inflammatory response.Mitochondrion. 2013; 13: 106-118Crossref PubMed Scopus (298) Google Scholar). It could be hypothesized that with age, abnormal mitophagy could result in the sparing of mitochondria with complex II dysfunction. This hypothesis remains to be explored. Mitochondrial complex II mutations in humans lead to variable clinical phenotypes (Rivner et al., 1989Rivner M.D. Shamsnia M. Swift T.R. Trefz J. Roesel R.A. Carter A.L. et al.Kearns-Sayre syndrome and complex II deficiency.Neurology. 1989; 39: 693-696Crossref PubMed Google Scholar). Although cutaneous lentigines are not reported as one of the clinical signs, pigmentary alterations in the retina have been observed (Rivner et al., 1989Rivner M.D. Shamsnia M. Swift T.R. Trefz J. Roesel R.A. Carter A.L. et al.Kearns-Sayre syndrome and complex II deficiency.Neurology. 1989; 39: 693-696Crossref PubMed Google Scholar). The Bowman and Birch-Machin, 2016Bowman A. Birch-Machin M.A. The age-dependent decrease of mitochondrial complex II activity in human skin and fibroblasts.J Invest Dermatol. 2016; 136: 912-919Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar study describes decreased mitochondrial complex II activity with increasing chronological age, and future studies of sun-exposed skin sites, with clear clinical histories, will likely clarify whether this phenomenon is exacerbated by external insults. Interestingly, the aryl hydrocarbon receptor has been reported to play a role in protecting the skin from carcinogen-mediated oxidative stress (Melchini et al., 2011Melchini A. Catania S. Stancanelli R. Tommasini S. Costa C. Interaction of a functionalized complex of the flavonoid hesperetin with the AhR pathway and CYP1A1 expression: involvement in its protective effects against benzo[a]pyrene-induced oxidative stress in human skin.Cell Biol Toxicol. 2011; 27: 371-379Crossref Scopus (11) Google Scholar), although some studies indicate that the aryl hydrocarbon receptor may also promote inflammation (Stockinger et al., 2014Stockinger B. Di Meglio P. Gialitakis M. Duarte J.H. The aryl hydrocarbon receptor: multitasking in the immune system.Ann Rev Immunol. 2014; 32: 403-432Crossref PubMed Scopus (555) Google Scholar). Although it is known that ultrafine particulate pollutants induce oxidative stress and mitochondrial damage (Li et al., 2003Li N. Sloutas C. Cho A. Schmitz D. Misra C. Sempf J. et al.Ultrafine particulate pollutants induce oxidative stress and mitochondrial damage.Environ Health Perspect. 2003; 111: 455-460Crossref PubMed Scopus (1681) Google Scholar), NO2 has not been shown specifically to induce oxidative stress in vivo. If NO2 is capable of increasing oxidative stress in vivo, pathways such as the aryl hydrocarbon receptor pathway may respond in a manner that protects the skin from environmentally induced oxidative stress, and this response may include lentigo formation. This possibility remains to be examined (Figure 1). Airborne environmental pollution is a growing worldwide health problem, and understanding how various components of pollutants, particularly as they may interact with ultraviolet radiation to cause cellular damage, is of critical importance in therapeutic efforts to maintain healthy skin into advanced age and to repair or reverse cutaneous damage. The author states no conflict of interest. Age-Dependent Decrease of Mitochondrial Complex II Activity in Human Skin FibroblastsJournal of Investigative DermatologyVol. 136Issue 5PreviewThe mitochondrial theory of aging remains one of the most widely accepted aging theories and implicates mitochondrial electron transport chain dysfunction with subsequent increasing free radical generation. Recently, complex II of the electron transport chain appears to be more important than previously thought in this process, suggested predominantly by nonhuman studies. We investigated the relationship between complex II and aging using human skin as a model tissue. The rate of complex II activity per unit of mitochondria was determined in fibroblasts and keratinocytes cultured from skin covering a wide age range. Full-Text PDF Open ArchiveTraffic-Related Air Pollution Contributes to Development of Facial Lentigines: Further Epidemiological Evidence from Caucasians and AsiansJournal of Investigative DermatologyVol. 136Issue 5PreviewSkin integrity is compromised by air pollution (Krutmann et al., 2014). Chronic exposure to traffic-related particulate matter (PM) was previously linked to development of facial lentigines in 400 Caucasian women from the Study on the Influence of Air Pollution on Lung Function, Inflammation and Aging (SALIA) cohort study. In addition to PM, traffic-related air pollution is characterized by increased concentrations of nitrogen dioxide (NO2). NO2 exposure is known to be associated with low lung function and lung cancer (Adam et al., 2015; Hamra et al., 2015). Full-Text PDF Open Archive
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