RESUMO
Keratinocytes produce lipids that are critical for the skin barrier, however, little is known about the impact of age on fatty acid (FA) biosynthesis in these cells. We have examined the relationship between keratinocyte FA composition, lipid biosynthetic gene expression, gene promoter methylation and age. Expression of elongase (ELOVL6 and 7) and desaturase (FADS1 and 2) genes was lower in adult versus neonatal keratinocytes, and was associated with lower concentrations of n-7, n-9 and n-10 polyunsaturated FA in adult cells. Consistent with these findings, transient FADS2 knockdown in neonatal keratinocytes mimicked the adult keratinocyte FA profile in neonatal cells. Interrogation of methylation levels across the FADS2 locus (53 genomic sites) revealed differential methylation of 15 sites in neonatal versus adult keratinocytes, of which three hypermethylated sites in adult keratinocytes overlapped with a SMARCA4 protein binding site in the FADS2 promoter.
Assuntos
Metilação de DNA , Dessaturase de Ácido Graxo Delta-5 , Ácidos Graxos Dessaturases , Ácidos Graxos Insaturados , Queratinócitos , Adulto , DNA Helicases/metabolismo , Ácidos Graxos Dessaturases/genética , Ácidos Graxos Dessaturases/metabolismo , Ácidos Graxos Insaturados/metabolismo , Humanos , Recém-Nascido , Queratinócitos/metabolismo , Proteínas Nucleares/metabolismo , Regiões Promotoras Genéticas , Fatores de Transcrição/metabolismoRESUMO
BACKGROUND: The severity of facial telangiectasia or red veins is associated with many lifestyle factors. However, the genetic predisposition remains unclear. OBJECTIVES: We performed a genome-wide association study (GWAS) on facial telangiectasia in the Rotterdam Study (RS) and tested for replication in two independent cohorts. Additionally, a candidate gene approach with known pigmentation genes was performed. METHODS: Facial telangiectasia were extracted from standardized facial photographs (collected from 2010-2013) of 2842 northwestern European participants (median age 66.9, 56.8% female) from the RS. Our GWAS top hits (P-value <10-6 ) were tested for replication in 460 elderly women of the SALIA cohort and in 576 additional men and women of the RS. Associations of top single nucleotide polymorphisms (SNPs) with expression quantitative trait loci (eQTL) in various tissues were reviewed (GTEx database) alongside phenotype associations in the UK biobank database. SNP-based associations between known pigmentation genes and facial telangiectasia were tested. Conditional analysis on skin colour was additionally performed. RESULTS: Our most significant GWAS signal was rs4417318 (P-value 5.38*10-7 ), an intergenic SNP on chromosome 12 mapping to the SLC16A7 gene. Other suggestive SNPs tagged genes ZNF211, ZSCAN4, ICOS and KCNN3; SNP eQTLs and phenotype associations tagged links to the vascular system. However, the top signals did not pass significance in the two replication cohorts. The pigmentation genes KIAA0930, SLCA45A2 and MC1R, were significantly associated with telangiectasia in a candidate gene approach but not independently of skin colour. CONCLUSION: In this GWAS on telangiectasia in a northwestern European population, no genome-wide significant SNPs were found, although suggestive signals indicate genes involved in the vascular system might be involved in telangiectasia. Significantly associated pigmentation genes underline the link between skin colour and telangiectasia.
Assuntos
Estudo de Associação Genômica Ampla , Telangiectasia , Idoso , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Telangiectasia/genéticaRESUMO
BACKGROUND: The underlying phenotypic correlations between wrinkles, pigmented spots (PS), telangiectasia and other related facial-ageing subphenotypes are not well understood. OBJECTIVES: To analyse the underlying phenotypic correlation structure between seven features for facial ageing: global wrinkling, perceived age (PA), Griffiths photodamage grading, PS, telangiectasia, actinic keratosis (AK) and keratinocyte cancer (KC). METHODS: This was a cross-sectional study. Facial photographs and a full-body skin examination were used. We used principal component analysis (PCA) to derive principal components (PCs) of common variation between the features. We performed multivariable linear regressions between age, sex, body mass index, smoking and ultraviolet radiation exposure and the PC scores derived from PCA. We also tested the association between the main PC scores and 140 single-nucleotide polymorphisms (SNPs) previously associated with skin-ageing phenotypes. RESULTS: We analysed data from 1790 individuals with complete data on seven features of skin ageing. Three main PCs explained 73% of the total variance of the ageing phenotypes: a hypertrophic/wrinkling component (PC1: global wrinkling, PA and Griffiths grading), an atrophic/skin colour component (PC2: PS and telangiectasia) and a cancerous component (PC3: AK and KC). The associations between lifestyle and host factors differed per PC. The strength of SNP associations also differed per component with the most SNP associations found with the atrophic component [e.g. the IRF4 SNP (rs12203592); P-value = 1·84 × 10-22 ]. CONCLUSIONS: Using a hypothesis-free approach, we identified three major underlying phenotypes associated with extrinsic ageing. Associations between determinants for skin ageing differed in magnitude and direction per component. What's already known about this topic? Facial ageing is a complex phenotype consisting of different features including wrinkles, pigmented changes, telangiectasia and cancerous-related growths; it is not clear how these phenotypes are related to each other and to other phenotypes. A few studies have described two main clinical phenotypes for photoageing, namely hypertrophic ageing and atrophic ageing, which have been based solely on the clinical assessment of photoageing characteristics. What does this study add? We are the first to use epidemiology data to identify three main components associated with photoageing, namely a hypertrophic component (global wrinkling; perceived age; Griffiths grading) and atrophic component (pigmented spots; telangiectasia) and a cancer component (actinic keratosis; keratinocyte cancer). Association analysis showed different effects and direction of environmental determinants and genetic associations with the three components, with the most significant gene variants associations found for the atrophic component.
Assuntos
Envelhecimento da Pele , Estudos Transversais , Humanos , Análise de Componente Principal , Envelhecimento da Pele/genética , Pigmentação da Pele/genética , Raios Ultravioleta/efeitos adversosRESUMO
BACKGROUND: Onset of basal cell carcinoma (BCC) is connected to skin ageing, but it is unclear whether higher BCC genetic susceptibility drives skin ageing. OBJECTIVES: To investigate whether loci increasing genetic susceptibility to BCC also drive multiple features of skin ageing, independently of confounding factors, using Mendelian randomization. METHODS: A Mendelian randomization study was conducted in older adults from the Leiden Longevity Study (N = 604). A total of 25 BCC loci, selected based on a published genome-wide association study on BCC (P-value < 5 × 10-8 ), were used as genetic instruments for the calculation of a standardized (mean = 0, SD = 1) weighted BCC genetic risk score. Based on facial photographs, we determined perceived age, and skin wrinkling and pigmented spot grading. RESULTS: A higher BCC genetic risk score was associated with a higher perceived age (adjusted for chronological age and sex) of 0.88 years (95% CI: 0.44, 1.31; P-value = 7.1e-5 ), greater wrinkling by 0.14 grades (95% CI: 0.05, 0.23; P-value = 2.3e-3 ), and greater pigmented spots by 0.17 grades (95% CI: 0.08, 0.25; P-value = 1.1e-4 ). These findings were weakened but still present after exclusion of gene variants in MC1R and IRF4 which have potential pleiotropic effects. CONCLUSIONS: Mechanisms influenced by genetic loci increasing susceptibility to BCC also drive skin ageing suggesting shared biology and shared targets for interventions.
Assuntos
Carcinoma Basocelular/genética , Predisposição Genética para Doença/genética , Envelhecimento da Pele/genética , Neoplasias Cutâneas/genética , Idoso , Carcinoma Basocelular/patologia , Estudos de Coortes , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Envelhecimento da Pele/patologia , Neoplasias Cutâneas/patologiaRESUMO
BACKGROUND: Telangiectasia or red veins are one of the prominent features of facial skin ageing. To date, there are few studies investigating the determinants of telangiectasia. OBJECTIVES: We investigated lifestyle and physiological factors associated with facial telangiectasia in a large prospective Dutch cohort study. METHODS: Telangiectasia was quantified digitally from standardized facial photographs of 2842 North European participants (56.8% female, median age 66.9) from the Rotterdam Study, collected in 2010-2013. Effect estimates from multivariable linear regressions are presented as the percentage difference in the mean value of telangiectasia area per unit increase of a determinant (%Δ) with corresponding 95% CI. RESULTS: Significant determinants were older age [1.7%Δ per year (95% CI 1.4, 2.0)], female sex [18.3%Δ (95% CI 13.2, 23.6)], smoking [current versus never 38.4%Δ (95% CI 30.3, 47.0); former versus never 11.6%Δ (95% CI 6.6, 16.9)], a high susceptibility to sunburn [10.2%Δ (95% CI 5.4, 15.3)] and light skin colour [pale versus white-to-olive 31.4%Δ (95% CI 19.7, 44.1]; white vs. white-to-olive 9.2%Δ (95% CI 2.8, 16.0)]. CONCLUSIONS: In this large cohort study, we confirmed known and described new determinants of facial telangiectasia.
Assuntos
Face/irrigação sanguínea , Telangiectasia/epidemiologia , Telangiectasia/etiologia , Fatores Etários , Idoso , Estudos Transversais , Feminino , Humanos , Estilo de Vida , Masculino , Países Baixos/epidemiologia , Estudos Prospectivos , Fatores de Risco , Fatores SexuaisRESUMO
In addition to measures already used in clinical practice, molecular measures have been proposed to assess health status, but these have not yet been introduced into clinical practice. We aimed to test the association of functional capacity measures used in current practice and molecular measures with age and health status. The cohort consisted of 178 middle-aged to old participants of the Leiden Longevity Study (range 42-82years). We tested associations between functional capacity measures (physical tests: grip strength, 4-meter walk, chair stand test; cognitive tests: Stroop test, digit symbol substitution test and 15-picture learning test) with age and with cardiovascular or metabolic disease as a measure of the health status. These associations with age and health status were also tested for molecular measures (C reactive protein (CRP), numbers of senescent p16INK4a positive cells in the epidermis and dermis and putative immunosenescence (presence of CD57+ T cells)). All functional capacity measures were associated with age. CRP and epidermal p16INK4a positivity were also associated with age, but with smaller estimates. Grip strength and the Stroop test were associated with cardiovascular or metabolic disease, as was epidermal p16INK4a positivity. All associations with cardiovascular or metabolic disease attenuated when adjusting for age. In conclusion, in middle-aged to old persons, the molecular measures tested here were more weakly associated with age and health status than functional capacity measures. Whether these molecular measures associate more closely with health status in the elderly or in specific groups of patients needs to be explored further.
Assuntos
Avaliação Geriátrica/métodos , Nível de Saúde , Longevidade/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/análise , Proteína C-Reativa/análise , Feminino , Força da Mão/fisiologia , Humanos , Imunossenescência , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Teste de Stroop , Proteína Supressora de Tumor p14ARF/análise , Teste de CaminhadaRESUMO
BACKGROUND: Multiple biomarkers have been associated with hair loss in women, but studies have shown inconsistent results. OBJECTIVES: We investigated the associations between markers of cardiovascular disease risk (e.g. serum lipid levels and hypertension) and ageing [e.g. 25-hydroxyvitamin D and insulin-like growth factor (IGF)] with hair loss in a population of middle-aged women. METHODS: In a random subgroup of 323 middle-aged women (mean age 61·5 years) from the Leiden Longevity Study, hair loss was graded by three assessors using the Sinclair scale; women with a mean score > 1·5 were classified as cases with hair loss. RESULTS: Every 1 SD increase in high-density lipoprotein (HDL) cholesterol was associated with a 0·65-times lower risk [95% confidence interval (CI) 0·46-0·91] of hair loss. For IGF-1 the risk was 0·68 times lower (95% CI 0·48-0·97) per 1 SD increase, independently of the other studied variables. Women with both IGF-1 and HDL cholesterol levels below the medians of the study population had a 3·47-times higher risk (95% CI 1·30-9·25) of having hair loss. CONCLUSIONS: Low HDL cholesterol and IGF-1 were associated with a higher risk of hair loss in women. However, further studies are required to infer causal relationships.
Assuntos
Alopecia/etiologia , HDL-Colesterol/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Alopecia/sangue , Alopecia/fisiopatologia , Biomarcadores/metabolismo , Glicemia/metabolismo , Pressão Sanguínea/fisiologia , Estudos Transversais , Feminino , Humanos , Insulina/metabolismo , Masculino , Pessoa de Meia-Idade , Fatores de RiscoAssuntos
Biomarcadores/metabolismo , Nível de Saúde , Lentigo/epidemiologia , Estudos Transversais , Diabetes Mellitus/epidemiologia , Feminino , Humanos , Hipertensão/epidemiologia , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Transtornos de Fotossensibilidade/epidemiologia , Fatores de Risco , Luz Solar/efeitos adversos , Vitamina D/análogos & derivados , Vitamina D/metabolismo , Deficiência de Vitamina D/epidemiologiaRESUMO
BACKGROUND: Lifestyle has been proven to have a dramatic effect on the risk of age-related diseases. The association of lifestyle and facial ageing has been less well studied. OBJECTIVES: To identify lifestyle factors that associate with perceived facial age in white north European men and women. METHODS: Lifestyle, facial wrinkling and perceived facial age were studied in two cross-sectional studies consisting of 318 Dutch men and 329 women aged 45-75 years who were part of the Leiden Longevity Study, and 162 English women aged 45-75 years who were nonsmokers. RESULTS: In Dutch men, smoking, having skin that went red in the sun, being outside in the sun most of the summer, sunbed use, wearing false teeth and not flossing teeth were all significantly associated (P < 0·05) with a total 9·3-year higher perceived facial age in a multivariate model adjusting for chronological age. In Dutch women, smoking, sunbathing, sunbed use, few remaining teeth and a low body mass index (BMI) were associated with a total 10·9-year higher perceived facial age. In English women, cleaning teeth only once a day, wearing false teeth, irregular skin moisturization and having skin that went red in the sun were associated with a total 9·1-year higher perceived facial age. Smoking and sunbed use were associated more strongly with wrinkling in women than in men. BMI, sun exposure and skincare were associated predominantly with perceived facial age via wrinkling, whereas oral care was associated via other facial features. CONCLUSIONS: Although associative in nature, these results support the notion that lifestyle factors can have long-term beneficial effects on youthful looks.
Assuntos
Imagem Corporal/psicologia , Face , Estilo de Vida , Envelhecimento da Pele/etnologia , Idoso , Estudos Transversais , Inglaterra/etnologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos/etnologia , Percepção , Caracteres Sexuais , População Branca/etnologiaRESUMO
BACKGROUND: Accurate measurement of the extent skin has aged is crucial for skin aging research. Image analysis offers a quick and consistent approach for quantifying skin aging features from photographs, but is prone to technical bias and requires proper validation. METHODS: Facial photographs of 75 male and 75 female North-European participants, randomly selected from the Rotterdam Study, were graded by two physicians using photonumeric scales for wrinkles (full face, forehead, crow's feet, nasolabial fold and upper lip), pigmented spots and telangiectasia. Image analysis measurements of the same features were optimized using photonumeric grades from 50 participants, then compared to photonumeric grading in the 100 remaining participants stratified by sex. RESULTS: The inter-rater reliability of the photonumeric grades was good to excellent (intraclass correlation coefficients 0.65-0.93). Correlations between the digital measures and the photonumeric grading were moderate to excellent for all the wrinkle comparisons (Spearman's rho ρ = 0.52-0.89) bar the upper lip wrinkles in the men (fair, ρ = 0.30). Correlations were moderate to good for pigmented spots and telangiectasia (ρ = 0.60-0.75). CONCLUSION: These comparisons demonstrate that all the image analysis measures, bar the upper lip measure in the men, are suitable for use in skin aging research and highlight areas of improvement for future refinements of the techniques.
Assuntos
Face/anatomia & histologia , Interpretação de Imagem Assistida por Computador/métodos , Reconhecimento Automatizado de Padrão/métodos , Fotografação/métodos , Envelhecimento da Pele/patologia , Feminino , Humanos , Aumento da Imagem/métodos , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Insulin-like growth factor (IGF)-1 is a growth factor that can influence fibroblast functioning, with effects including the inhibition of collagenases and the induction of collagen expression. OBJECTIVES: To assess whether serum IGF-1, IGF-binding protein (IGFBP)3 and the ratio between IGF-1 and IGFBP3, as a measure of IGF-1 bioavailability, are associated with facial ageing and skin wrinkling. METHODS: From a random sample comprising 617 subjects from the Leiden Longevity Study, perceived age and skin wrinkling were assessed from facial photographs, and IGF-1 and IGFBP3 were measured in serum. The associations were assessed using linear regression models, adjusted for chronological age, sex, body mass index, smoking and sun exposure. RESULTS: Across tertiles of the ratio of IGF-1 to IGFBP3, and after adjusting for all potential confounding factors, the mean perceived age decreased from 60·6 years in the lowest tertile to 59·5 years in the highest (P = 0·045). Similarly, the mean skin wrinkling grade decreased from 4·8 in the lowest tertile to 4·5 in the highest (P = 0·011). Adding skin wrinkling as a covariate in the analysis between IGF-1 and perceived age diminished this association. CONCLUSIONS: This study demonstrates that a higher ratio of IGF-1 to IGFBP3 associates with a lower perceived age, via its association with reduced skin wrinkling. Whether high IGF-1 levels actually delay the accumulation of skin wrinkling now needs investigating.
Assuntos
Face/fisiologia , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Envelhecimento da Pele/fisiologia , Estudos Transversais , Exposição Ambiental/análise , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Luz SolarRESUMO
BACKGROUND: Perceived age is important to women and is a primary driver for topical product use and facial cosmetic surgery. Changes in facial features and biophysical skin parameters with chronological age and their associations with perceived age have not been described in Asian populations. OBJECTIVE: To investigate the relationship between biophysical properties of the skin, visual features of skin ageing and perceived facial age in Chinese women. METHODS: Facial photographs were collected of 250 Chinese women, aged 25-70 years in Shanghai, China. The perceived facial age was determined and related to the chronological age for each participant and to a range of visual assessments of skin appearance and objective biophysical measurements of the skin. The profile of changes in these parameters with age was investigated together with the differences in those parameters for women judged to look younger than their chronological age and those judged to look older than their chronological age. RESULTS: Large discrepancies in perceived age (up to 29 years) were found in women of the same chronological age. Each objective skin measure and visual assessment parameter had a stronger correlation with perceived age than with chronological age. The strongest relationships to perceived age were for wrinkles and hyperpigmentation. Skin colour, hydration and trans-epidermal water loss (TEWL) had weaker associations with perceived age. Women judged to look older than their chronological age had significantly higher scores than those judged to look younger for coarse wrinkles and hyperpigmentation across all age groups. The appearance differences between these groups were evident in composite facial images of the same average chronological age. CONCLUSIONS: We have identified the skin attributes which differ with perceived age in Chinese women. Perceived age is a better measure of the biological age of facial skin than is chronological age in this population.