Clock Regulation of Skin Regeneration in Stem Cell Aging

Periodically oscillating biological processes, such as circadian rhythms, are carefully concerted events that are only beginning to be understood in the context of tissue pathology and organismal health, as well as the molecular mechanisms underlying these interactions. Recent reports indicate that light can independently entrain peripheral circadian clocks, challenging the currently prevalent hierarchical model. Despite the recent progress that has been made, a comprehensive overview of these periodic processes in skin is lacking in the literature. In this review, molecular circadian clock machinery and the factors that govern it have been highlighted. Circadian rhythm is closely linked to immunological processes and skin homeostasis, and its desynchrony can be linked to the perturbation of the skin. The interplay between circadian rhythm and annual, seasonal oscillations, as well as the impact of these periodic events on the skin, is described. Finally, the changes that occur in the skin over a lifespan are presented. This work encourages further research into the oscillating biological processes occurring in the skin and lays the foundation for future strategies to combat the adverse effects of desynchrony, which would likely have implications in other tissues influenced by periodic oscillatory processes.

Preclinical human skin ageing research has been limited by the paucity of instructive and clinically relevant models. In this pilot study, we report that healthy human skin of different age groups undergoes extremely accelerated ageing within only 3 days, if organ‐cultured in a defined serum‐free medium. Quantitative (immuno‐)histomorphometry documented this unexpected ex vivo phenotype on the basis of ageing‐associated biomarkers: the epidermis showed significantly reduced rete ridges and keratinocyte proliferation, sirtuin‐1, MTCO1 and collagen 17a1 protein levels; this contrasted with significantly increased expression of the DNA‐damage marker, γH2A.X. In the dermis, collagen 1 and 3 and hyaluronic acid content were significantly reduced compared to Day 0 skin. qRT‐PCR of whole skin RNA extracts also showed up‐regulated mRNA levels of several (inflamm‐) ageing biomarkers (MMP‐1, ‐2, ‐3, ‐9; IL6, IL8, CXCL10 and CDKN1). Caffeine, a methylxanthine with recognized anti‐ageing properties, counteracted the dermal collagen 1 and 3 reduction, the epidermal accumulation of γH2A.X, and the up‐regulation of CXCL10, IL6, IL8, MMP2 and CDKN1. Finally, we present novel anti‐ageing effects of topical 2,5‐dimethylpyrazine, a natural pheromone TRPM5 ion channel activator. Thus, this instructive, clinically relevant “speed‐ageing” assay provides a simple, but powerful new research tool for dissecting skin ageing and rejuvenation, and is well‐suited to identify novel anti‐ageing actives directly in the human target organ.

First described in the early 20 th century, diurnal oscillations in stem cell proliferation exist in multiple internal epithelia, including in the gastrointestinal track, and in the epidermis. In the mouse epidermis, 3- to 4-fold more stem cells are in S-phase during the night than during the day. Work that is more recent showed that an intact circadian clock intrinsic to keratinocytes is required for these oscillations in epidermal stem cell proliferation. The circadian clock also regulates DNA excision repair and DNA-damage in epidermal stem cells in response to ultraviolet B radiation. During skin inflammation, epidermal stem cell proliferation is increased and diurnal oscillations are suspended. Here we discuss possible reasons for the evolution of this stem cell phenomenon. We argue that the circadian clock coordinates intermediary metabolism and the cell cycle in epidermal stem cells to minimize accumulation of DNA damage from metabolism-generated reactive oxygen species. Circadian disruption, common in modern society, leads to asynchrony between metabolism and the cell cycle, and we speculate this will lead to oxidative DNA damage, dysfunction of epidermal stem cells, and skin aging.