Two quite interesting findings are presented in this open access paper. Firstly, the pigmented areas of skin called age spots are in large part generated by the presence of senescent cells and their detrimental effects on mechanisms of skin pigmentation. Secondly, one the skin treatments that has for years been touted as rejuvenating by vendors in the more dubious, unscientific end of the medical community in fact destroys a fair number of senescent cells and therefore might actually be a legitimate rejuvenation therapy, albeit limited to the skin. This is certainly a novelty, but I suppose that the research community might find more such cases as the understanding of senescent cells in aging continues to grow in detail and sophistication. There will be a certain amount of up-ending of expectations on all sides as rejuvenation therapies and their associated research communities make progress in the years to come.
A caveat on this research is that the portion using human data involves results obtained from only a few individuals, while much of the mechanistic examination in cells and tissues largely uses senescence induced in non-physiological conditions. Based on other research, cells made senescent in various non-physiological ways can differ in state significantly from those that arise naturally in the body. They are more or less vulnerable to different senolytics, for example. Still, this work is intriguing, a good start, and plausible when taken as a whole. I wouldn't be overly surprised to find it validated when a more extensive study is undertaken. One possible approach to independent confirmation is for the groups working on human trials of senolytic drugs to start paying attention to the age spots of their patients. This could be accomplished without excessive additional cost: a photographic record of hands and forearms, for example.
Pigmentation is an outcome of the interplay between melanocytes and neighbouring cells, such as keratinocytes and fibroblasts. Cutaneous ageing is an important extrinsic process that modifies the pigmentary system. Senile lentigo, also known as age spots, is one of the major changes associated with laxity and wrinkling during the ageing of skin. It is characterized by the presence of hyperpigmented spots in the elderly.
Cellular senescence is a fundamental ageing mechanism. Senescent cells and those with the related senescence-associated secretory phenotype (SASP) are known to be the main drivers of the age-related phenotype. During intrinsic and extrinsic skin ageing, the skin can contain senescent cells in epidermal and dermal compartments. Cellular senescence has been studied in dermal fibroblasts, which secrete factors that contribute to skin wrinkling. For example, the chronic secretion of matrix metalloproteinases by senescent cells is an important contributor to the degradation of collagen and other extracellular matrix components in dermal tissue. A decrease in the expression of transforming growth factor type II receptor appeared to be a critical event in age-related skin thinning. However, despite the important role exerted by neighbouring cells on the regulation of melanocyte biology, few studies have examined how senescent cells are involved in skin pigmentation, and it remains unclear whether senescent cells affect nearby epidermal melanocytes and influence ageing pigmentation.
In this study, we reveal what we believe is a novel mechanism whereby aged fibroblasts contribute to the local regulation of melanogenesis. We show that as an individual ages, pigmented skin contains an increasing proportion of senescent fibroblasts. Phenotype switching in these cells results in the loss of SDF1, and SDF1 deficiency appears to be a potent stimulus for the melanogenic processes that contribute to uneven pigmentation. These changes might be epigenetic. For example, the level of hypermethylation of the SDF1 promoter was remarkably different between hyperpigmented and perilesional skin.
The human skin, unlike other organs, undergoes photo-ageing in addition to natural ageing processes, and photo-ageing has been attributed to ageing pigmentation. Both processes are cumulative, and the most noticeable age-related changes therefore occur in the superficial layer of the skin. In the present study, we show that cellular senescence is especially likely to occur in fibroblasts located in the upper dermis of pigmented skin. Senescent fibroblasts are expected to influence melanocytes via cross-talk that can readily occur through a damaged basement membrane. We showed that senescent fibroblasts play a stimulatory role in pigmentation by upregulating the expression of the melanogenesis regulators MITF and tyrosinase in melanocytes.
Moreover, the impact of senescent fibroblasts on skin pigmentation was directly demonstrated when eliminating senescent cells with an intervention that reduced pigmentation. Microneedle fractional radiofrequency (RF) is a cosmetic therapy that induces skin rejuvenation via electromagnetic thermal injury. The microneedle RF device was chosen to manipulate only dermal cells, in which the microneedles generate thermal coagulation columns in the dermis, not in the epidermis. It was previously demonstrated that fractional laser treatment decreases the occurrence of senescent fibroblasts in aged dermis. Ten volunteers with senile lentigo were treated with RF, and skin samples were collected from 4 participants who agreed to undergo a skin biopsy before and at 6 weeks after treatment. Following RF treatment, the number of senescent fibroblasts was significantly reduced. The elimination of these cells was thought to be caused by RF-induced cell death. The elimination of senescent fibroblasts from senile lentigo was accompanied by skin lightening.