Test anti-senescence interventions to postpone or reverse skin ageing

Abstract

While the role of cell senescence is well-established as a main driver of ageing in various tissues, the impact in human skin ageing remains unclear. Many studies predominantly focused on specific skin compartments or cell types foregoing the importance of cellular crosstalk. This makes cross-model comparisons challenging due to variation in the causes and effects of senescence. Consequently, the existing data do not conclusively establish whether senescence of skin cells is the primary contributor to skin ageing. This study aims to evaluate the role of senescence in skin ageing by assessing changes in morphology during skin ageing in various mammalian models, including human skin biopsies from donors of different ages, mice, therapy-induced premature-ageing mice, and senolytic/senostatic treated mice. We also tested a range of natural compounds and compared their senolytic efficacy against skin fibroblasts with published data. As there was no consensus on which senescent marker best distinguishes senescent cells in the skin, this study was designed to validate as many senescence markers as possible in both in vitro dermal fibroblasts and keratinocytes and in vivo ageing human skin. We also created 3D bioengineered skin equivalents to study the crosstalk between skin layers by incorporating different frequencies of senescent fibroblasts in the dermis. This study showed that senolytic or senostatic did not improve extrinsic skin ageing characteristic in therapy-induced premature -ageing mice. Natural compounds with reported ‘anti-ageing’ activity showed no senolytic efficacy against skin fibroblasts. Senescence markers were well detected in vitro, but they were not as sensitive in in vivo skin samples. Some senescence markers were found to be cell-type specific and could vary over the course of senescence development. However, the enlargement of cell size has shown reliability as a senescence marker in both in vitro and 3D model, potentially in vivo if we have better quality samples. In comparison to published results, 3D skin models revealed effects of senescent dermal fibroblasts onto the epidermis are largely matrix dependent.