Effects of Age and Sex on the Expression of Core Circadian Clock Genes in Human Skin Epidermis

Many aspects of skin biochemistry and physiology, including wound healing, immune defense, and responses to stress exhibit circadian rhythmicity. Much of our understanding of circadian rhythms in the skin has been derived from studies in nocturnal mice ( Mohawk et al., 2012 Mohawk J.A. Green C.B. Takahashi J.S. Central and peripheral circadian clocks in mammals. Annu Rev Neurosci. 2012; 35: 445-462 Crossref PubMed Scopus (1506) Google Scholar ), and thus work with diurnal human subjects is important to extend and validate this knowledge to humans. Though two previous studies confirmed the rhythmic expression of core clock genes in the epidermis ( Spörl et al., 2012 Spörl F. Korge S. Jürchott K. Wunderskirchner M. Schellenberg K. Heins S. et al. Krüppel-like factor 9 is a circadian transcription factor in human epidermis that controls proliferation of keratinocytes. Proc Natl Acad Sci U S A. 2012; 109: 10903-10908 Crossref PubMed Scopus (110) Google Scholar ; Wu et al., 2018 Wu G. Ruben M.D. Schmidt R.E. Francey L.J. Smith D.F. Anafi R.C. et al. Population-level rhythms in human skin with implications for circadian medicine. Proc Natl Acad Sci U S A. 2018; 115: 12313-12318 Crossref PubMed Scopus (65) Google Scholar ), this work was limited to younger adults and primarily to males. Because both age and sex may affect clock-controlled processes, it is important to examine how these factors affect circadian gene expression in human subjects. Furthermore, though other studies have analyzed global gene expression in the skin of human subjects from a range of ages from males and/or females ( Chang et al., 2013 Chang A.L.S. Bitter P.H. Qu K. Lin M. Rapicavoli N.A. Chang H.Y. Rejuvenation of gene expression pattern of aged human skin by broadband light treatment: A pilot study. Journal of Investigative Dermatology. 2013; 133 Abstract Full Text Full Text PDF Scopus (33) Google Scholar ; Glass et al., 2013 Glass D. Vinuela A. Davies M.N. Ramasamy A. Parts L. Knowles D. et al. Gene expression changes with age in skin, adipose tissue, blood and brain. Genome Biol. 2013; 14: R75-r75 Crossref PubMed Scopus (196) Google Scholar ; Haustead et al., 2016 Haustead D.J. Stevenson A. Saxena V. Marriage F. Firth M. Silla R. et al. Transcriptome analysis of human ageing in male skin shows mid-life period of variability and central role of NF-kappaB. Sci Rep. 2016; 626846 Crossref PubMed Scopus (37) Google Scholar ; Kimball et al., 2018 Kimball A.B. Alora-Palli M.B. Tamura M. Mullins L.A. Soh C. Binder R.L. et al. Age-induced and photoinduced changes in gene expression profiles in facial skin of Caucasian females across 6 decades of age. J Am Acad Dermatol. United States. 2018; 78: 29-39.e7 Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar ), the time of day of biopsy collection was not recorded and epidermis was not always separated from the dermis. Circadian gene expression in the epidermis has been reported to be more robust and variable than the dermis ( Del Olmo et al., 2022 Del Olmo M. Spörl F. Korge S. Jürchott K. Felten M. Grudziecki A. et al. Inter-layer and inter-subject variability of diurnal gene expression in human skin. NAR Genom Bioinform. 2022; 4: lqac097 Crossref PubMed Scopus (1) Google Scholar ; Wu et al., 2020 Wu G. Ruben M.D. Francey L.J. Smith D.F. Sherrill J.D. Oblong J.E. et al. A population-based gene expression signature of molecular clock phase from a single epidermal sample. Genome Med. 2020; 12: 73 Crossref PubMed Scopus (20) Google Scholar ), and thus focusing on epidermis may provide new insights into the role of the clock in epidermal function and pathophysiology.