J Invest Dermatol. 2017 Apr 6. pii: S0022-202X(17)31408-2. doi: 10.1016/j.jid.2017.04.002. [Epub ahead of print]

Lifestyle and physiological factors associated with facial wrinkling in men and women.


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 north-western 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 (IQR):2.9-6.3]) than in women (3.6%, [IQR: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, while 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.



The MC1R Gene and Youthful Looks.

Curr Biol. 2016 May 9;26(9):1213-20. doi: 10.1016/j.cub.2016.03.008. Epub 2016 Apr 28.

Liu F1Hamer MA2Deelen J3Lall JS4Jacobs L2van Heemst D5Murray PG4Wollstein A6de Craen AJ5Uh HW7Zeng C8Hofman A9Uitterlinden AG10,Houwing-Duistermaat JJ11Pardo LM2Beekman M3Slagboom PE3Nijsten T2Kayser M12Gunn DA13.


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.



Validation of image analysis techniques to measure skin aging features from facial photographs.

Skin Res Technol. 2015 Nov;21(4):392-402. doi: 10.1111/srt.12205. Epub 2015 Jan 20.

Hamer MA1,2Jacobs LC1,2Lall JS3Wollstein A4Hollestein LM1Rae AR5Gossage KW6Hofman A7Liu F8Kayser M8Nijsten T1,2Gunn DA3.



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.


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.


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).


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.


Digital; Grading scale; Photonumeric; Pigmented spots; Skin aging; Telangiectasia; Wrinkles



A Genome-Wide Association Study Identifies the Skin Color Genes IRF4, MC1R, ASIP, and BNC2 Influencing Facial Pigmented Spots.

J Invest Dermatol. 2015 Jul;135(7):1735-42. doi: 10.1038/jid.2015.62. Epub 2015 Feb 23.

Jacobs LC1Hamer MA1Gunn DA2Deelen J3Lall JS2van Heemst D4Uh HW5Hofman A6Uitterlinden AG7Griffiths CE8Beekman M3Slagboom PE3,Kayser M9Liu F9Nijsten T1.


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.



Intrinsic and extrinsic risk factors for sagging eyelids.

JAMA Dermatol. 2014 Aug;150(8):836-43. doi: 10.1001/jamadermatol.2014.27.

Jacobs LC1Liu F2Bleyen I3Gunn DA4Hofman A5Klaver CC6Uitterlinden AG7Neumann HA1Bataille V8Spector TD9Kayser M2Nijsten T1.



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.


To study nongenetic and genetic risk factors for sagging eyelids.


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.


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.


Sagging eyelid severity levels, ranging from 1 (normal control) to 4 (severe sagging).


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.


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.




Jacobs, L.C. (2015, September 11). Genetic Determinants of Skin Color, Aging, and Cancer. Erasmus University Rotterdam.

Retrieved from http://hdl.handle.net/1765/78544