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Gewei Zhu,1 Sophie Cassidy,2 Hugo Hiden,3 Simon Woodman,3 Michael Trenell,4 David A Gunn,5 Michael Catt,6 Mark Birch-Machin,1,6 Kirstie N Anderson7 1Faculty of Medical Sciences, Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, UK; 2Central Clinical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia; 3National Innovation Centre for Data, School of Computing, The Catalyst, Newcastle Helix, Newcastle Upon Tyne, UK; 4NIHR Innovation Observatory, The Catalyst, Newcastle Helix, Newcastle upon Tyne, UK; 5Colworth Science Park, Sharnbrook, Bedfordshire, UK; 6National Innovation Centre for Ageing, The Catalyst, Newcastle Helix, Newcastle upon Tyne, UK; 7Department of Neurology, Royal Victoria Infirmary, Newcastle upon Tyne, UKCorrespondence: Kirstie N AndersonDepartment of Neurology, Royal Victoria Infirmary, Newcastle upon Tyne, UKTel +44 01912823833Email kirstieanderson@nhs.netPurpose: Short and long sleep durations have adverse effects on physical and mental health. However, most studies are based on self-reported sleep duration and health status. Therefore, this longitudinal study aims to investigate objectively measured sleep duration and subsequent primary health care records in older adults to investigate the impact of sleep duration and fragmentation on physical and mental health.Methods: Data on objective sleep duration were measured using accelerometry. Primary care health records were then obtained from the UK Biobank (n=84,404). Participants (mean age, 62.4 years) were divided into five groups according to their sleep duration derived from the accelerometry data: < 5 hours, 5– 6 hours, 6– 7 hours, 7– 8 hours and > 8 hours. ICD-10 codes were used for the analysis of primary care data. Wake after sleep onset, activity level during the least active 5 hours and episodes of movement during sleep were analysed as an indication for sleep fragmentation. Binary regression models were adjusted for age, gender and Townsend deprivation score.Results: A “U-shaped” relationship was found between sleep duration and diseases including diabetes, hypertension and heart disease and depression. Short and long sleep durations and fragmented sleep were associated with increased odds of disease.Conclusion: Six to eight hours of sleep, as well as less fragmented sleep, predicted better long-term metabolic and mental health.Keywords: sleep, health, UK Biobank, primary care

Effective management of railway infrastructure is becoming increasingly reliant upon remote condition monitoring of geotechnical asset condition. Current monitoring approaches focus on confirmation of the morphological effects caused by subsurface processes driving deterioration. However, geophysical imaging offers new opportunities for ‘predict and prevent’ practices, providing access to monitoring internal property change patterns preceding these morphological responses. Geophysical methods utilize disturbances that propagate through and holistically sample earthworks and are especially suited to imaging the unique heterogeneity of aged embankments. In this case study, surface wave seismic surveys are interpreted to construct a stiffness ground model consistent with a heterogeneous embankment comprising local borrow materials. Time-lapse electrical resistivity imaging was also used to investigate and visualise ground water ingress and movement within this ground model. Ground water movement was shown to be highly dynamic, responding very quickly to local storm events with infiltration into the embankment within hours. Subsequent wetting and drying cycles throughout the embankment's lifespan have caused the dissolution, mobilisation and re-precipitation of soluble minerals within the fill materials. This process has driven the deterioration of the fill fabric, which is evidenced in thin sections by voids and localised rupture about in situ mineral growths. Finally, we provide a framework showing how geophysical methods could support more risk-based asset management practices of the future.

A significant portion of the UK's transportation system relies on a network of geotechnical earthworks (cuttings and embankments) that were constructed more than 100 years ago, whose stability is affected by the change in precipitation patterns experienced over the past few decades. The vulnerability of these structures requires a reliable, cost- and time-effective monitoring of their geomechanical condition. We have assessed the potential application of P-wave refraction for tracking the seasonal variations of seismic properties within an aged clay-filled railway embankment, located in southwest England. Seismic data were acquired repeatedly along the crest of the earthwork at regular time intervals, for a total period of 16 months. P-wave first-break times were picked from all available recorded traces, to obtain a set of hodocrones referenced to the same spatial locations, for various dates along the surveyed period of time. Traveltimes extracted from each acquisition were then compared to track the pattern of their temporal variability. The relevance of such variations over time was compared with the data experimental uncertainty. The multiple set of hodocrones was subsequently inverted using a tomographic approach, to retrieve a time-lapse model of VP for the embankment structure. To directly compare the reconstructed VP sections, identical initial models and spatial regularization were used for the inversion of all available data sets. A consistent temporal trend for P-wave traveltimes, and consequently for the reconstructed VP models, was identified. This pattern could be related to the seasonal distribution of precipitation and soil-water content measured on site.

The UK's transportation network is supported by critical geotechnical assets (cuttings/embankments/dams) that require sustainable, cost-effective management, while maintaining an appropriate service level to meet social, economic, and environmental needs. Recent effects of extreme weather on these geotechnical assets have highlighted their vulnerability to climate variations. We have assessed the potential of surface wave data to portray the climate-related variations in mechanical properties of a clay-filled railway embankment. Seismic data were acquired bimonthly from July 2013 to November 2014 along the crest of a heritage railway embankment in southwest England. For each acquisition, the collected data were first processed to obtain a set of Rayleigh-wave dispersion and attenuation curves, referenced to the same spatial locations. These data were then analyzed to identify a coherent trend in their spatial and temporal variability. The relevance of the observed temporal variations was also verified with respect to the experimental data uncertainties. Finally, the surface wave dispersion data sets were inverted to reconstruct a time-lapse model of S-wave velocity for the embankment structure, using a least-squares laterally constrained inversion scheme. A key point of the inversion process was constituted by the estimation of a suitable initialmodel and the selection of adequate levels of spatial regularization. The initial model and the strength of spatial smoothing were then kept constant throughout the processing of all available data sets to ensure homogeneity of the procedure and comparability among the obtained VSsections. A continuous and coherent temporal pattern of surface wave data, and consequently of the reconstructed VSmodels, was identified. This pattern is related to the seasonal distribution of precipitation and soil water content measured on site.

Measurement sensors permanently installed on landslides will inevitably change their position over time due to mass movements. To interpret and correct the recorded data, these movements have to be determined. This is especially important in the case of geoelectrical monitoring, where incorrect sensor positions produce strong artefacts in the resulting resistivity models. They may obscure real changes, which could indicate triggering mechanisms for landslide failure or reactivation. In this paper we introduce a methodology to interpolate movements from a small set of sparsely distributed reference points to a larger set of electrode locations. Within this methodology we compare three interpolation techniques, i.e., a piecewise planar, bi-linear spline, and a kriging based interpolation scheme. The performance of these techniques is tested on a synthetic and a real-data example, showing a recovery rate of true movements to about 1% and 10% of the electrode spacing, respectively. The significance for applying the proposed methodology is demonstrated by inverse modelling of 4D electrical resistivity tomography data, where it is shown that by correcting for sensor movements corresponding artefacts can virtually be removed and true resistivity changes be imaged.

BACKGROUND: As facial appearance can be readily quantified and skin tissue easily accessed, they could be valuable tools for determining how biological mechanisms influence tissue degeneration with age and, consequently, human health and lifespan. It is unknown, however, whether appearance reflects disease risk or lifespan independently of factors already known to associate with both health and appearance. METHODS: In a cross-sectional study, we compared the amount of skin wrinkling on a sun-protected site (upper inner arm) and the facial appearance of 261 offspring (mean age 63.2 y) of nonagenarian siblings with 253 age-matched controls (mean age 62.7 y), all with no reported disease history. We next examined whether any appearance features that significantly associated with familial longevity also associated with the Framingham cardiovascular disease (CVD) risk score. All analyses were adjusted for chronological age, smoking, photodamage, and body mass index. RESULTS: Female and male offspring had reduced upper inner arm skin wrinkling (p = .03 and p < .001, respectively), and the male offspring looked 1.4 y younger than the controls (p = .002). There were no significant associations between CVD risk and upper inner arm skin wrinkling. Women in the lowest quartile of CVD risk looked more than 2 y younger for their age than those in higher risk quartiles (p = .002). Systolic blood pressure was the most significant (p = .004) CVD risk factor that was associated with perceived age in women. CONCLUSIONS: Facial appearance and skin wrinkling at a sun-protected site reflect the propensity to reach an extreme old age, and facial appearance reflects the risk of succumbing to CVD independently of chronological age, smoking, photodamage, and BMI. [ABSTRACT FROM AUTHOR]

Geotechnical asset owners need to know which parts of their asset network are vulnerable to climate change induced failure in order to optimise future investment. Protecting these vulnerable slopes requires monitoring systems capable of identifying and alerting to asset operators changes in the internal conditions that precede failure. Current monitoring systems are heavily reliant on point sensors which can be difficult to interpret across slope scale. This paper presents challenges to producing such a system and research being carried out to address some of these using electrical resistance tomography (ERT). Experimental results show that whilst it is possible to measure soil water content indirectly via resistivity the relationship between resistivity and water content will change over time for a given slope. If geotechnical parameters such as pore water pressure are to be estimated using this method then ERT systems will require integrating with more conventional geotechnical instrumentation to ensure correct representative information is provided. The paper also presents examples of how such data can be processed and communicated to asset owners for the purposes of asset management.

Background: Perceived age (PA) has been associated with mortality, genetic variants linked to ageing and several age-related morbidities. However, estimating PA in large datasets is laborious and costly to generate, limiting its practical applicability., Objectives: To determine if estimating PA using deep learning-based algorithms results in the same associations with morbidities and genetic variants as human-estimated perceived age., Methods: Self-supervised learning (SSL) and deep feature transfer (DFT) deep learning (DL) approaches were trained and tested on human-estimated PAs and their corresponding frontal face images of middle-aged to elderly Dutch participants (n = 2679) from a population-based study in the Netherlands. We compared the DL-estimated PAs with morbidities previously associated with human-estimated PA as well as genetic variants in the gene MC1R; we additionally tested the PA associations with MC1R in a new validation cohort (n = 1158)., Results: The DL approaches predicted PA in this population with a mean absolute error of 2.84 years (DFT) and 2.39 years (SSL). In the training-test dataset, we found the same significant (p < 0.05) associations for DL PA with osteoporosis, ARHL, cognition, COPD and cataracts and MC1R, as with human PA. We also found a similar but less significant association for SSL and DFT PAs (0.69 and 0.71 years per allele, p = 0.008 and 0.011, respectively) with MC1R variants in the validation dataset as that found with human, SSL and DFT PAs in the training-test dataset (0.79, 0.78 and 0.71 years per allele respectively; all p < 0.0001)., Conclusions: Deep learning methods can automatically estimate PA from facial images with enough accuracy to replicate known links between human-estimated perceived age and several age-related morbidities. Furthermore, DL predicted perceived age associated with MC1R gene variants in a validation cohort. Hence, such DL PA techniques may be used instead of human estimations in perceived age studies thereby reducing time and costs., (© 2024 The Author(s). Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Whole-skin DNA methylation variation has been implicated in several diseases, including melanoma, but its genetic basis has not yet been fully characterized. Using bulk skin tissue samples from 414 healthy female UK twins, we performed twin-based heritability and methylation quantitative trait loci (meQTL) analyses for >400,000 DNA methylation sites. We find that the human skin DNA methylome is on average less heritable than previously estimated in blood and other tissues (mean heritability: 10.02%). meQTL analysis identified local genetic effects influencing DNA methylation at 18.8% (76,442) of tested CpG sites, as well as 1,775 CpG sites associated with at least one distal genetic variant. As a functional follow-up, we performed skin expression QTL (eQTL) analyses in a partially overlapping sample of 604 female twins. Colocalization analysis identified over 3,500 shared genetic effects affecting thousands of CpG sites (10,067) and genes (4,475). Mediation analysis of putative colocalized gene-CpG pairs identified 114 genes with evidence for eQTL effects being mediated by DNA methylation in skin, including in genes implicating skin disease such as ALOX12 and CSPG4. We further explored the relevance of skin meQTLs to skin disease and found that skin meQTLs and CpGs under genetic influence were enriched for multiple skin-related genome-wide and epigenome-wide association signals, including for melanoma and psoriasis. Our findings give insights into the regulatory landscape of epigenomic variation in skin., Competing Interests: Declaration of interests DG is an employee of Unilever., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Itch, common in dermatological conditions, is often accompanied by psychological distress and reduced quality of life. However, research on the prevalence and associated factors of itch with skin conditions in general populations is limited., Objectives: This cross-sectional study aimed to determine the lifetime prevalence of itch with skin conditions and to identify its associated factors in individuals aged > 50 years., Methods: Participants from the Rotterdam Study, a population-based cohort, were interviewed to assess whether they had ever had an itchy skin condition, defining lifetime itch with skin conditions. Over 20 demographic, lifestyle, dermatological and nondermatological factors were recorded. Multivariable logistic regression analysis explored associations between these factors and itch with skin conditions, reported as odds ratios (ORs) with 95% confidence intervals (CIs)., Results: In total, 5246 eligible participants were included (age range 51-100 years, median age 67; 56.0% women). The results revealed a -lifetime prevalence of 33.7% for itch with skin conditions. Factors significantly associated with itch were female sex (OR 1.26, 95% CI 1.11-1.43), body mass index (1.02, 1.01-1.03), self-reported atopic dermatitis (4.29, 3.74-4.92), presence of atopic dermatitis (1.97, 1.60-2.43), self--reported psoriasis (2.31, 1.77-3.01), presence of psoriasis (2.11, 1.55-2.87), self-reported dry skin (1.95, 1.73-2.20), self-reported asthma (1.40, 1.08-1.83), renal impairment (1.45, 1.17-1.79), and clinically relevant depressive (1.85, 1.52-2.25) and anxiety symptoms (1.36, 1.11-1.66)., Conclusions: This study reveals a substantial one-third lifetime prevalence of itch with skin conditions in individuals aged > 50 years. Significant associations with diverse lifestyle, demographic, dermatological and, intriguingly, nondermatological factors, including renal impairment, imply additional contributors to induction or persistence of itch in individuals with skin conditions., Competing Interests: Conflicts of interest No products produced by Unilever were tested in this study. However, it is possible that this study could be used to promote products and services in the future, leading to financial gain. L.M.P. has received consulting fees from Centogene. L.C. has received flash glucose sensors for research ­purposes. Other authors declare no conflict of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Objectives: Scalp hair has the greatest number of hairs (typically 1-5) per follicular unit but is also the most susceptible body site to hair loss with age. Hence, we set-out to determine the degree to which scalp hair parameters change with age in women and men, any sex differences thereof and whether hair loss is random across follicular units., Methods: A retrospective cross-sectional study of 200 Chinese men and 200 Chinese women (30-69 years). Image analysis and manual counting methods were used to measure occipital located hair parameters from 6 × 8 mm shaved scalp photographs and plucked hair microscopy images., Results: Of the five hair parameters, the number of hairs per follicular unit had the greatest (negative) correlation with age in both men and women. Men had a greater number of hairs and follicular units than women on average but had a greater decrease in the number of hairs per follicular unit with age, particularly for the loss of multi-hair (3+) follicular units. The loss of hairs with age was significantly different to that expected by a random loss of hairs across follicular units and better described by a model of increased hair loss risk the greater number of hairs per follicular unit., Conclusions: We have found evidence of hair loss preferentially occurring in multi-hair follicular units, which was more pronounced in men. These data suggest that part of the reason scalp hair is more susceptible to hair loss than on other body sites is due to the greater presence of multi-hair follicular units on the scalp., (© 2023 Society of Cosmetic Scientists and Societe Francaise de Cosmetologie.)

Background: Looking older for one's chronological age is associated with a higher mortality rate. Yet it remains unclear how perceived facial age relates to morbidity and the degree to which facial ageing reflects systemic ageing of the human body., Objectives: To investigate the association between ΔPA and age-related morbidities of different organ systems, where ΔPA represents the difference between perceived age (PA) and chronological age., Methods: We performed a cross-sectional analysis on data from the Rotterdam Study, a population-based cohort study in the Netherlands. High-resolution facial photographs of 2679 men and women aged 51.5-87.8 years of European descent were used to assess PA. PA was estimated and scored in 5-year categories using these photographs by a panel of men and women who were blinded for chronological age and medical history. A linear mixed model was used to generate the mean PAs. The difference between the mean PA and chronological age was calculated (ΔPA), where a higher (positive) ΔPA means that the person looks younger for their age and a lower (negative) ΔPA that the person looks older. ΔPA was tested as a continuous variable for association with ageing-related morbidities including cardiovascular, pulmonary, ophthalmological, neurocognitive, renal, skeletal and auditory morbidities in separate regression analyses, adjusted for age and sex (model 1) and additionally for body mass index, smoking and sun exposure (model 2)., Results: We observed 5-year higher ΔPA (i.e. looking younger by 5 years for one's age) to be associated with less osteoporosis [odds ratio (OR) 0.76, 95% confidence interval (CI) 0.62-0.93], less chronic obstructive pulmonary disease (OR 0.85, 95% CI 0.77-0.95), less age-related hearing loss (model 2; B = -0.76, 95% CI -1.35 to -0.17) and fewer cataracts (OR 0.84, 95% CI 0.73-0.97), but with better global cognitive functioning (g-factor; model 2; B = 0.07, 95% CI 0.04-0.10)., Conclusions: PA is associated with multiple morbidities and better cognitive function, suggesting that systemic ageing and cognitive ageing are, to an extent, externally visible in the human face., Competing Interests: Conflicts of interest D.A.G. is a Unilever employee and as an author had an influence on the analyses and interpretation of the results. Although no products were tested, these results could be used more generally to promote antiageing products and services that lead to financial gain for Unilever., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., Competing Interests: Declaration of competing interest Messenger D.J.(2), Barrett K.E.(2), Hyliands D.(2), Talbot D.(2), Fowler M.I.(2), Kawatra T.(2), Gunn D.A.(2), Lim FL.(2), Wainwright L.J.(2), Jenkins G.(2), are employed by Unilever R&D. Griffiths H.R.(1,3) received part funding from Unilever R&D and BBSRC to undertake this study., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (© 2020 European Academy of Dermatology and Venereology.)

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., (© 2019 British Association of Dermatologists.)

Aim: UVA radiation drives skin photoaging in the dermis, plausibly via persistent changes to DNA methylation in dermal fibroblasts. Methods: Genome-wide DNA methylation changes after five repeated daily UVA doses were determined at 48 h (transitionary) and 1 week (recovery) post final irradiation. Results: Differential methylation was found at the transitionary time point in active chromatin states near genes that are highly expressed in fibroblasts and are involved in cellular defensive mechanisms; the majority of these methylation differences were restored to control levels after 7 day recovery. At the recovery time point, new differential methylation occurred at repressed regions near developmental genes, normally weakly expressed in fibroblasts. Conclusion: UVA irradiation induces transitionary and recovery-associated DNA methylation responses in fibroblasts with contrasting functional characteristics.

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., (© 2019 European Academy of Dermatology and Venereology.)

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., (© 2019 European Academy of Dermatology and Venereology.)

Cellular senescence has been shown to contribute to skin ageing. However, the role of melanocytes in the process is understudied. Our data show that melanocytes are the only epidermal cell type to express the senescence marker p16 INK4A during human skin ageing. Aged melanocytes also display additional markers of senescence such as reduced HMGB1 and dysfunctional telomeres, without detectable telomere shortening. Additionally, senescent melanocyte SASP induces telomere dysfunction in paracrine manner and limits proliferation of surrounding cells via activation of CXCR3-dependent mitochondrial ROS. Finally, senescent melanocytes impair basal keratinocyte proliferation and contribute to epidermal atrophy in vitro using 3D human epidermal equivalents. Crucially, clearance of senescent melanocytes using the senolytic drug ABT737 or treatment with mitochondria-targeted antioxidant MitoQ suppressed this effect. In conclusion, our study provides proof-of-concept evidence that senescent melanocytes affect keratinocyte function and act as drivers of human skin ageing., (© 2019 The Authors.)

Background: Determinants and the extent of dry skin in healthy middle-aged and elderly populations have not been well established., Objective: We aimed to identify the prevalence and determinants for generalized dry skin (GDS) and localized dry skin (LDS) within a large prospective population-based cohort of middle-aged and elderly individuals of the Rotterdam Study., Methods: Dry skin was physician-graded as none, localized, or generalized. For GDS and LDS, separate multivariable logistic regression analyses were performed to search for association with participant characteristics, lifestyle factors, environmental factors, several comorbidities, and drug exposure., Results: Among the 5547 eligible participants, 60% had dry skin, of whom a fifth had GDS. Age, female sex, skin color, body mass index, outside temperature, eczema, and chemotherapy in the past were significant determinants for both GDS and LDS. Smoking, the use of statins and diuretics, poorer self-perceived health, and several dermatologic conditions increased the likelihood of having GDS only. Daily cream use was associated with less LDS., Limitations: Interobserver variability and residual confounding could have influenced our results. Because of our cross-sectional design, we could not infer causality., Conclusion: We identified factors significantly associated with dry skin in a general middle-aged and elderly population, with health parameters more strongly associated with GDS., (Copyright © 2019 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

With advancing age, many organs exhibit functional deterioration. The age-associated accumulation of senescent cells is believed to represent one factor contributing to this phenomenon. While senescent cells are found in several different organ systems, it is not known whether they arise independently in each organ system or whether their prevalence within an individual reflects that individual's intrinsic aging process. To address this question, we studied senescence in two different organ systems in humans, namely skin and T cells in 80 middle-aged and older individuals from the Leiden Longevity Study. Epidermal p16INK4a positivity was associated with neither CD4 + nor CD8 + T-cell immunosenescence phenotype composites (i.e., end-stage differentiated/senescent T cells, including CD45RA + CCR7 - CD28 - CD27 - CD57 + KLRG1 + T cells). Dermal p16INK4a positivity was significantly associated with the CD4 + , but not with the CD8 + immunosenescence composite. We therefore conclude that there is limited evidence for a link between skin senescence and immunosenescence within individuals., (© 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Background: Little is known about the effects of different dietary patterns on facial wrinkling., Objective: We aimed to investigate the association between diet and facial wrinkles in a population-based cohort of 2753 elderly participants of the Rotterdam study., Methods: Wrinkles were measured in facial photographs by digitally quantifying the area wrinkles occupied as a percentage of total skin area. Diet was assessed by the Food Frequency Questionnaire. Adherence to the Dutch Healthy Diet Index (DHDI) was calculated. In addition, we used principal component analysis (PCA) to extract relevant food patterns in men and women separately. All food patterns and the DHDI were analyzed for an association with wrinkle severity using multivariable linear regression., Results: Better adherence to the Dutch guidelines was significantly associated with less wrinkles among women but not in men. In women, a red meat and snack-dominant PCA pattern was associated with more facial wrinkles, whereas a fruit-dominant PCA pattern was associated with fewer wrinkles., Limitations: Due to the cross-sectional design of our study, causation could not be proven. Other health-conscious behaviors of study participants could have influenced the results., Conclusion: Dietary habits are associated with facial wrinkling in women. Global disease prevention strategies might benefit from emphasizing that a healthy diet is also linked to less facial wrinkling., (Copyright © 2018 American Academy of Dermatology, Inc. All rights reserved.)

Little is known on how well senescence markers in vitro and in situ correlate within individual donors. We studied correlations between the same and different in vitro markers. Furthermore, we tested correlations between in vitro markers with in situ p16INK4a positivity.From 100 donors (20-91 years), cultured dermal fibroblasts were assessed for reactive oxygen species (ROS), telomere-associated foci (TAF), p16INK4a and senescence-associated β-gal (SAβ-gal), with/ without 0.6 µM rotenone for 3 days (short-term). In fibroblasts from 40 donors, telomere shortening, ROS and SAβ-gal were additionally assessed, with/ without 20 nM rotenone for 7 weeks (long-term). In skin from 52 donors, the number of p16INK4a positive dermal cells was assessed in situ .More than half of the correlations of the same senescence markers in vitro between duplicate experiments and between short-term versus long-term experiments were significant. Half of the different senescence marker correlations were significant within the short-term and within the long-term experiments. The different senescence markers in vitro were not significantly correlated intra-individually with in situ p16INK4a positivity.
In conclusion, the same and different senescence markers are frequently correlated significantly within and between in vitro experiments, but in vitro senescence markers are not correlated with p16INK4a positivity in situ .

Data from in vitro experiments suggest that vitamin D reduces the rate of skin aging, whereas population studies suggest the opposite, most likely due to confounding by UV exposure. We investigated whether there are causal associations between 25-hydroxyvitamin D concentrations and features of skin aging in a bidirectional Mendelian randomization study. In the Rotterdam Study (N = 3,831; 58.2% women, median age 66.5 years) and Leiden Longevity Study (N = 661; 50.5% women, median age 63.1 years), facial skin aging features (perceived age, wrinkling, pigmented spots) were assessed either manually or digitally. Associations between 25-hydroxyvitamin D and skin aging features were tested by multivariable linear regression. Mendelian randomization analyses were performed using single nucleotide polymorphisms identified from previous genome-wide association studies. After meta-analysis of the two cohorts, we observed that higher serum 25-hydroxyvitamin D was associated with a higher perceived age (P-value = 3.6 × 10 -7 ), more skin wrinkling (P-value = 2.6 × 10 -16 ), but not with more pigmented spots (P-value = 0.30). In contrast, a genetically determined 25-hydroxyvitamin D concentration was not associated with any skin aging feature (P-values > 0.05). Furthermore, a genetically determined higher degree of pigmented spots was not associated with higher 25-hydroxyvitamin D (P-values > 0.05). Our study did not indicate that associations between 25-hydroxyvitamin D and features of skin aging are causal., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Facial wrinkling is one of the most notable signs of skin aging. Men and women show different wrinkling patterns yet the lifestyle and physiological factors underlying these sex-specific patterns are relatively unknown. Here, we investigated sex-specific determinants for facial wrinkles. Wrinkle area was quantified digitally using facial photographs of 3,831 northwestern Europeans (51-98 years, 58% female). Effect estimates from multivariable linear regressions are presented as the percentage difference in the mean value of wrinkle area per unit increase of a determinant (%Δ). Wrinkle area was higher in men (median 4.5%, interquartile range: 2.9-6.3) than in women (3.6%, interquartile range: 2.2-5.6). Age was the strongest determinant, and current smoking (men: 15.5%Δ; women: 30.9%Δ) and lower body mass index (men: 1.7%Δ; women: 1.8%Δ) were also statistically significantly associated with increased wrinkling. Pale skin color showed a protective effect (men: -21.0%Δ; women: -28.5%Δ) and, in men, sunburn tendency was associated with less wrinkling. In women, low educational levels and alcohol use were associated with more wrinkling, whereas female pattern hair loss and a higher free androgen index were associated with less wrinkling. In summary, we validated known and identified additional determinants for wrinkling. Skin aging-reducing strategies should incorporate the sex differences found in this study., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.)

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., (© 2016 British Association of Dermatologists.)

Senescent cells are more prevalent in aged human skin compared to young, but evidence that senescent cells are linked to other biomarkers of aging is scarce. We counted cells positive for the tumor suppressor and senescence associated protein p16INK4a in sun-protected upper-inner arm skin biopsies from 178 participants (aged 45-81 years) of the Leiden Longevity Study. Local elastic fiber morphology, facial wrinkles, and perceived facial age were compared to tertiles of p16INK4a counts, while adjusting for chronological age and other potential confounders.The numbers of epidermal and dermal p16INK4a positive cells were significantly associated with age-associated elastic fiber morphologic characteristics, such as longer and a greater number of elastic fibers. The p16INK4a positive epidermal cells (identified as primarily melanocytes) were also significantly associated with more facial wrinkles and a higher perceived age. Participants in the lowest tertile of epidermal p16INK4a counts looked 3 years younger than those in the highest tertile, independently of chronological age and elastic fiber morphology.In conclusion, p16INK4a positive cell numbers in sun-protected human arm skin are indicative of both local elastic fiber morphology and the extent of aging visible in the face., (© The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Looking young for one's age has been a desire since time immemorial. This desire is attributable to the belief that appearance reflects health and fecundity. Indeed, perceived age predicts survival [1] and associates with molecular markers of aging such as telomere length [2]. Understanding the underlying molecular biology of perceived age is vital for identifying new aging therapies among other purposes, but studies are lacking thus far. As a first attempt, we performed genome-wide association studies (GWASs) of perceived facial age and wrinkling estimated from digital facial images by analyzing over eight million SNPs in 2,693 elderly Dutch Europeans from the Rotterdam Study. The strongest genetic associations with perceived facial age were found for multiple SNPs in the MC1R gene (p < 1 × 10(-7)). This effect was enhanced for a compound heterozygosity marker constructed from four pre-selected functional MC1R SNPs (p = 2.69 × 10(-12)), which was replicated in 599 Dutch Europeans from the Leiden Longevity Study (p = 0.042) and in 1,173 Europeans of the TwinsUK Study (p = 3 × 10(-3)). Individuals carrying the homozygote MC1R risk haplotype looked on average up to 2 years older than non-carriers. This association was independent of age, sex, skin color, and sun damage (wrinkling, pigmented spots) and persisted through different sun-exposure levels. Hence, a role for MC1R in youthful looks independent of its known melanin synthesis function is suggested. Our study uncovers the first genetic evidence explaining why some people look older for their age and provides new leads for further investigating the biological basis of how old or young people look., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: It is unknown whether facial or surrounding (eg, hair and clothing) cues have the strongest influence on the perceived age of subjects in photographic images, and which drives links between perceived age and survival., Methods: In 2001, 187 Danish twin pairs (n = 374) aged 70+ years were photographed generating passport-type images. The faces of the twins in these images were swapped creating two new images per twin pair (748 images in total). Ten nurses rated the perceived age of the twin from the original and swapped facial images. The survival of the twins was determined through to the end of 2013., Results: Changing the face or its surrounding significantly changed the perceived age of the images, with only a marginal difference between their effect sizes (difference of 0.5 years, 95% confidence interval CI -0.1 to 1.1). Perceived age, adjusting for chronological age, and sex, was a predictor of survival up to 7 years (hazard ratio 1.17, 95% CI 1.10-1.25) and also 7-12 years (hazard ratio 1.06, 95% CI 1.00-1.12) after the photographs were taken. Where the older looking twin died first they had a significantly older looking face (1.4 years older, 95% CI 0.3-2.6) but not surrounding (0.3 years older, 95% CI -0.8 to 1.4) compared to where the older looking twin died second., Conclusions: Facial visual cues but not hair or clothing cues drive the link between perceived age and survival., (© The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons.)

Facial pigmented spots are a common skin aging feature, but genetic predisposition has yet to be thoroughly investigated. We conducted a genome-wide association study for pigmented spots in 2,844 Dutch Europeans from the Rotterdam Study (mean age: 66.9±8.0 years; 47% male). Using semi-automated image analysis of high-resolution digital facial photographs, facial pigmented spots were quantified as the percentage of affected skin area (mean women: 2.0% ±0.9, men: 0.9% ±0.6). We identified genome-wide significant association with pigmented spots at three genetic loci: IRF4 (rs12203592, P=1.8 × 10(-27)), MC1R (compound heterozygosity score, P=2.3 × 10(-24)), and RALY/ASIP (rs6059655, P=1.9 × 10(-9)). In addition, after adjustment for the other three top-associated loci the BNC2 locus demonstrated significant association (rs62543565, P=2.3 × 10(-8)). The association signals observed at all four loci were successfully replicated (P<0.05) in an independent Dutch cohort (Leiden Longevity Study n=599). Although the four genes have previously been associated with skin color variation and skin cancer risk, all association signals remained highly significant (P<2 × 10(-8)) when conditioning the association analyses on skin color. We conclude that genetic variations in IRF4, MC1R, RALY/ASIP, and BNC2 contribute to the acquired amount of facial pigmented spots during aging, through pathways independent of the basal melanin production.

Circulatory levels of insulin-like growth factor (IGF-1), glucose, and cortisol have been previously associated with facial aging. However, as these serum measures are related, it is unclear whether their associations with skin aging occur independently from each other. We aimed to investigate whether the associations between serum IGF-1, glucose, and cortisol levels and perceived age/wrinkle grade occur independently of each other and whether these are mediated via skin wrinkling or via other skin aging features. Perceived age and skin wrinkling grade were assessed in a random sample from the Leiden Longevity Study with non-fasted (N = 579) and fasted blood sampling (N = 219). In our study population, a higher non-fasted IGF-1 level was associated with a lower skin wrinkling grade (p value = 0.014) and tended to associate with a lower perceived age (p value = 0.067), which was mediated for approximately 100 % by skin wrinkling. A higher non-fasted glucose level was associated with a higher perceived age (p value = 0.017), which was mediated for 51 % by skin wrinkling grade (p value = 0.112). A higher fasted cortisol level tended to associate with a higher perceived age (p value = 0.116), which was mediated for 29 % by skin wrinkling. Results remained similar when the serum measures were statistically adjusted for each other. Thus, the previously reported serum measures associate independently from each other with skin aging. IGF-1 is predominantly associated with perceived age by skin wrinkling, whereas cortisol and glucose also by other skin aging features.

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., (© 2015 British Association of Dermatologists.)

Skeletal muscle is the key site of peripheral insulin resistance in type 2 diabetes. Insulin-stimulated glucose uptake is decreased in differentiated diabetic cultured myotubes, which is in keeping with a retained genetic/epigenetic defect of insulin action. We investigated differences in gene expression during differentiation between diabetic and control muscle cell cultures. Microarray analysis was performed using skeletal muscle cell cultures established from type 2 diabetic patients with a family history of type 2 diabetes and clinical evidence of marked insulin resistance and nondiabetic control subjects with no family history of diabetes. Genes and pathways upregulated with differentiation in the diabetic cultures, compared with controls, were identified using Gene Spring and Gene Set Enrichment Analysis. Gene sets upregulated in diabetic myotubes were associated predominantly with inflammation. p38 MAPK was identified as a key regulator of the expression of these proinflammatory gene sets, and p38 MAPK activation was found to be increased in the diabetic vs. control myotubes. Although inhibition of p38 MAPK activity decreased cytokine gene expression from the cultured diabetic myotubes significantly, it did not improve insulin-stimulated glucose uptake. Increased cytokine expression driven by increased p38 MAPK activation is a key feature of cultured myotubes derived from insulin-resistant type 2 diabetic patients. p38 MAPK inhibition decreased cytokine expression but did not affect the retained defect of impaired insulin action in the diabetic muscle cells., (Copyright © 2015 the American Physiological Society.)

Type 2 diabetes is characterised by an age-related decline in insulin secretion. We previously identified a 50% age-related decline in mitochondrial DNA (mtDNA) copy number in isolated human islets. The purpose of this study was to mimic this degree of mtDNA depletion in MIN6 cells to determine whether there is a direct impact on insulin secretion. Transcriptional silencing of mitochondrial transcription factor A, TFAM, decreased mtDNA levels by 40% in MIN6 cells. This level of mtDNA depletion significantly decreased mtDNA gene transcription and translation, resulting in reduced mitochondrial respiratory capacity and ATP production. Glucose-stimulated insulin secretion was impaired following partial mtDNA depletion, but was normalised following treatment with glibenclamide. This confirms that the deficit in the insulin secretory pathway precedes K+ channel closure, indicating that the impact of mtDNA depletion is at the level of mitochondrial respiration. In conclusion, partial mtDNA depletion to a degree comparable to that seen in aged human islets impaired mitochondrial function and directly decreased insulin secretion. Using our model of partial mtDNA depletion following targeted gene silencing of TFAM, we have managed to mimic the degree of mtDNA depletion observed in aged human islets, and have shown how this correlates with impaired insulin secretion. We therefore predict that the age-related mtDNA depletion in human islets is not simply a biomarker of the aging process, but will contribute to the age-related risk of type 2 diabetes.

Importance: Sagging eyelids, or dermatochalasis, are a frequent concern in older adults. It is considered a feature of skin aging, but risk factors other than aging are largely unknown., Objective: To study nongenetic and genetic risk factors for sagging eyelids., Design: Upper eyelid sagging was graded in 4 categories of severity using digital photographs. Dermatochalasis was defined as the eyelid hanging over the eyelashes. Age, sex, skin color, tanning ability, hormonal status in women, current smoking, body mass index, and sun protection behavior were analyzed in a multivariable multinomial logistic regression model. Genetic predisposition was assessed using heritability analysis and a genome-wide association study., Setting and Participants: The study was performed in 2 independent population-based cohorts. The Rotterdam Study included older adults from one district in Rotterdam, the Netherlands, and the UK Adult Twin Registry (TwinsUK) included twins from all over the United Kingdom. Participants were 5578 unrelated Dutch Europeans (mean age, 67.1 years; 44.0% male) from the Rotterdam Study and 2186 twins (mean age, 53.1 years; 10.4% male) from the TwinsUK., Main Outcomes and Measures: Sagging eyelid severity levels, ranging from 1 (normal control) to 4 (severe sagging)., Results: Among 5578 individuals from the Rotterdam Study, 17.8% showed dermatochalasis (moderate and severe sagging eyelids). Significant and independent risk factors for sagging eyelids included age, male sex, lighter skin color, and higher body mass index. In addition, current smoking was borderline significantly associated. Heritability of sagging eyelids was estimated to be 61% among 1052 twin pairs from the TwinsUK (15.6% showed dermatochalasis). A meta-analysis of genome-wide association study results from 5578 Rotterdam Study and 1053 TwinsUK participants showed a genome-wide significant recessive protective effect of the C allele of rs11876749 (P = 1.7 × 10(-8)). This variant is located close to TGIF1 (an inducer of transforming growth factor β), which is a known gene associated with skin aging., Conclusions and Relevance: This is the first observational study to date demonstrating that other risk factors (male sex, genetic variants, lighter skin color, high body mass index, and possibly current smoking) in addition to aging are involved in the origin of sagging eyelids.

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., (© 2012 The Authors. BJD © 2012 British Association of Dermatologists.)

mTOR signalling is implicated in the development of disease and in lifespan extension in model organisms. This pathway has been associated with human diseases such as diabetes and cancer, but has not been investigated for its impact on longevity per se. Here, we investigated whether transcriptional variation within the mTOR pathway is associated with human longevity using whole-blood samples from the Leiden Longevity Study. This is a unique cohort of Dutch families with extended survival across generations, decreased morbidity and beneficial metabolic profiles in middle-age. By comparing mRNA levels of nonagenarians and middle-aged controls, the mTOR signalling gene set was found to associate with old age (P = 4.6 × 10(-7)). Single gene analysis showed that seven of 40 mTOR pathway genes had a significant differential expression of at least 5%. Of these, the RPTOR (Raptor) gene was found to be differentially expressed also when the offspring of nonagenarians was compared with their spouses, indicating association with familial longevity in middle-age. This association was not explained by variation between the groups in the prevalence of type 2 diabetes and cancer or glucose levels. Thus, the mTOR pathway not only plays a role in the regulation of disease and aging in animal models, but also in human health and longevity., (© 2012 The Authors Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.)