Two new epigenetic skin clocks separately measure solar and intrinsic aging from a single sample and reveal a collagen gene more active in the chronically sun-exposed skin of older adults
Two new epigenetic skin clocks separately measure solar and intrinsic aging from a single sample and reveal a collagen gene more active in the chronically sun-exposed skin of older adults
A team from King's College London, Erasmus MC in Rotterdam, and Unilever published both methods on 11 September and validated them on hand, abdomen, and facial skin from hundreds of people. One finding was unexpected: collagen gene RNA levels rose together with the solar aging score of the skin, even though photoaged skin physically contains less collagen protein.
Skin ages along two paths: from within, through metabolism and hormones, and from outside, when ultraviolet light penetrates the stratum corneum. Sun-exposed sites carry a higher risk of skin cancer, including melanoma. Until now there was no way to separate the two processes in a single sample. Earlier epigenetic skin clocks, methods that estimate the biological age of a tissue from DNA methylation marks, were trained to predict the donor's chronological age using a mixture of sun-exposed and sun-protected skin. Intrinsic aging is shared across all body sites, so such models latch on to the common marks and treat the solar signature as noise.
In a paper in Clinical Epigenetics, the team of Christopher Shore and David Gunn trained two clocks on distinct sets of DNA methylation sites: the "solar" clock on sites that change with age only in sun-exposed skin, and the "intrinsic" clock on sites that change only in sun-protected skin. On hand skin the design worked as intended: the solar clock showed a markedly older age for the exposed side compared with the protected side of the same person, while the intrinsic clock and other previously published skin clocks saw no difference, confirming they are equally blind to sun damage.
The clocks were then tested against actual sun-exposure history. Among 242 of 414 twins from the British TwinsUK cohort who completed a questionnaire on years spent in hot countries, solar clock acceleration correlated with that measure: weakly, but significantly. A non-invasive version was also tried: on 44 facial swabs the same clocks agreed with clinical photoaging grades assigned by physicians, suggesting the method could be offered to a living patient from a simple swab.
The specificity shows at the gene level. Across the skin of 364 individuals, expression of 202 genes was significantly associated with solar clock acceleration, while neither the intrinsic clock nor earlier skin clocks showed a significant association with any gene in the same samples. The solar clock captures a single process, photodamage, whereas the other two are spread across many weak contributors to aging such as diet and smoking, each too small for statistical detection. The effect for 134 of these genes was confirmed in 24 RNA profiles from hand skin of 12 donors. The pathway picture is consistent: the protective EIF2 signaling pathway weakens, while the tumor microenvironment pathway grows, in the same tissue where sun exposure raises skin cancer risk.
Among the confirmed genes is COL1A1, the gene for type I collagen, the main structural protein of skin. Its expression in sun-exposed skin turned out to be higher, even though photoaged skin contains less collagen protein, as shown separately in earlier work by other groups. The explanation lies in the trajectory of this gene over a lifetime: in sun-protected skin, expression declines slowly but continuously throughout life, whereas in sun-exposed skin it drops rapidly in youth and then levels off at a plateau. By old age the continuous decline in protected skin falls below that early plateau, and the collagen gene ends up more active precisely in skin that spent decades in the sun.
The study was supported by Unilever: the patent on both methods belongs to the company, and three of the thirteen authors are its employees. For a cosmetics company, this tool shows whether a given product acts on the solar process or the intrinsic one.