In a new systematic review published in Scientific Reports, multiple genes driving skin aging were identified .
The authors start by explaining the intrinsic (genetic and chronological) and extrinsic (environmental) factors that drive skin aging. While the environmental factors that affect the rate of skin aging, such as sun exposure and smoking, can be controlled, the intrinsic factors are not yet amenable to manipulation. Therefore, the researchers focus their review on these intrinsic drivers of skin aging.
Genetics are hard to beat
Studies show that skin ages differently in different genders and ethnicities. For example, Korean men have a smaller risk of developing wrinkles than Korean women, while the reverse is true for Japanese people up to the age of 65. Overall, Asians have deeper wrinkles on the forehead and in the crow’s feet area compared to Caucasians. However, the latter develop more wrinkles under the eyes, and their skin sags more than other races. In addition, a lower level of melanin in Caucasian skin makes it less protected from sun-driven photoaging. Meanwhile, both Asians and people with black skin are more prone to abnormal pigmentation.
Interestingly, different ethnicities demonstrate a different pace of skin aging. It was shown that French women develop wrinkles in a linear fashion from 20 to 60 years of age, while Chinese women become wrinkled rapidly at the age of 40-50. This may explain why Europeans find it hard to accurately judge the age of Asians.
All these examples point to the importance of genetics dictating different skin aging phenotypes. Previous studies have already identified single-nucleotide polymorphisms (one “letter” differences at a specific genomic position in different people) associated with skin aging phenotypes. This review sought to explore the genetics of skin aging and uncover some of the biological processes underlying skin aging by employing bioinformatics techniques.
Skin aging phenotypes
Often, systematic reviews have to combine results from studies that differ greatly in terms of methodology. This review is not an exception: entirely different features (wrinkles, pigmentation, etc.) and assessment measures (image analysis, visual assessment by a dermatologist, etc.) are used in different studies that describe skin aging. Therefore, the authors first examine what skin aging phenotypes have already been described and use them as a proxy of overall skin aging.
Surprisingly, there is no complete list of skin aging phenotypes. Thus, the researchers mined various studies, databases, and two medical books to compile a comprehensive list of skin aging phenotypes. As a result, 56 phenotypes were identified with “eyebags”, “sagging of jawline”, “global facial photoaging” among others. All the phenotypes can be grouped into 4 categories: skin cancer-related, skin color-related, wrinkling and sagging-related, skin global impression. Skin aging can then be treated as a result of skin changes in these four aspects.
Skin aging: is it just about single “letters”?
Next, the authors looked into the connection between skin aging phenotypes and single-nucleotide polymorphisms. They included 44 observational studies conducted in 16 countries with participants of different ages, genders, and nationalities. They only analyzed single-nucleotide polymorphisms that had been reported in association with a skin aging phenotype in at least two independent studies.
Although thousands of single-nucleotide polymorphisms were reported to be associated with skin aging phenotypes, only 19 of them were significant in several studies. For example, single-nucleotide polymorphisms in genes PRDM16 and TANC2 are associated with the wrinkling phenotype category. This might indicate that instead of individual single-nucleotide polymorphisms, many of them in the same genomic region are involved in driving a skin aging phenotype
A few genes define your skin color and aging
After assembling a comprehensive list of genes associated with skin aging, the researchers were able to determine which genes are most responsible for it. They identified a specific region on chromosome 16, band 16q24.3, as hosting a particularly high number of pleiotropic genes, which are associated with two or more morphologically different skin aging phenotypes (different phenotype categories).
Many of the identified pleiotropic genes are known to be related to skin color, such as MC1R, which suggests that in addition to their pigmentation role, these genes are responsible for setting the pace of skin aging. On the other hand, some genes on chromosome 16 that are not known to be skin color genes are associated with skin color-related phenotypes.
Gene enrichment analysis confirmed the results: a handful of 44 pleiotropic genes, which belong to chromosomal band 16q24.3 or are related to skin color, encode highly interconnected proteins driving skin aging phenotypes.
In order to get more insight into the biology of skin aging, the researchers extracted and analyzed expression data of the 44 pleiotropic skin aging genes and 32 skin color genes (some of which are also pleiotropic genes) in young and aged skin. Among the pleiotropic genes, SPIRE2, BNC2, SHC4, SLC24A5, and TYR were found to be downregulated with aging. Meanwhile, aging is accompanied by the upregulation of several skin color genes, such as AGR3, DSTYK, and TPCN2.
Importantly, there are some genes, such as DBNDD1, that are pleiotropic genes, but their expression is affected by environmental factors (UV exposure) rather than chronological age. This is an important reminder that protecting skin from sun exposure is still the best method of keeping it as young as possible, as there are no interventions that directly manipulate skin aging genes.
Skin ageing is the result of intrinsic genetic and extrinsic lifestyle factors. However, there is no consensus on skin ageing phenotypes and ways to quantify them. In this systematic review, we first carefully identified 56 skin ageing phenotypes from multiple literature sources and sought the best photo-numeric grading scales to evaluate them. Next, we conducted a systematic review on all 44 Genome-wide Association Studies (GWAS) on skin ageing published to date and identified genetic risk factors (2349 SNPs and 366 genes) associated with skin ageing. We identified 19 promising SNPs found to be significantly (p-Value < 1E−05) associated with skin ageing phenotypes in two or more independent studies. Here we show, using enrichment analyses strategies and gene expression data, that (1) pleiotropy is a recurring theme among skin ageing genes, (2) SNPs associated with skin ageing phenotypes are mostly located in a small handful of 44 pleiotropic and hub genes (mostly on the chromosome band 16q24.3) and 32 skin colour genes. Since numerous genes on the chromosome band 16q24.3 and skin colour genes show pleiotropy, we propose that (1) genes traditionally identified to contribute to skin colour have more than just skin pigmentation roles, and (2) further progress towards understand the development of skin pigmentation requires understanding the contributions of genes on the chromosomal band 16q24.3. We anticipate our systematic review to serve as a hub to locate primary literature sources pertaining to the genetics of skin ageing and to be a starting point for more sophisticated work examining pleiotropic genes, hub genes, and skin ageing phenotypes.
This comprehensive systematic review addressed several challenging issues: defining skin aging, compiling a list of skin aging phenotypes and skin aging genes, and identifying the pleiotropic genes that drive several skin aging phenotypes. Although skin aging seems to be manifested in several distinct phenotypes, the genes associated with them are interconnected, and most are involved in defining skin color. The results of this review could serve as a platform to explore skin aging genes in detail in order to develop effective skin rejuvenation approaches.
 Ng, J. Y. & Chew, F. T. A systematic review of skin ageing genes: gene pleiotropy and genes on the chromosomal band 16q24.3 may drive skin ageing. Sci. Rep. 12, 13099 (2022).