Cellular Senescence in Skin as an Early Sign of Aging

While no-one likes to be reminded of it, there are clear, albeit minor signs of aging that arise in as young a stage of life as the late 20s and early 30s. These early manifestations of aging are very poorly understood; perhaps understandably, near all research into mechanisms of aging is focused on late life pathology and its causes. Thus we are left with a very unsatisfactory understanding of what exactly is going in early adult life that makes a mid-30s adult physiologically different from an immediately post-development teenager.

In today's open access commentary, researchers report on evidence implicating senescent cells in these differences, at least in skin, and this is quite interesting. Present understanding holds that the accumulation of senescent cells in later life is most likely driven by immune dysfunction that impairs the timely clearance of newly created senescent cells. A similar immune-driven slowdown in clearance in the 20s and 30s, as described here, is unexpected.

Immune dysfunction over the course of life is thought to proceed along much the same lines as cancer risk, because of the role of the immune system in suppressing precancerous lesions. Risk of cancer doesn't start to meaningfully increase until the 50s and on. Still, it is also clear that the gut microbiome begins to change in the 30s as well, and there also the immune system is implicated, as immune cells are responsible for gardening the gut microbiome, destroying problematic microbes. We might speculate that these recent discoveries are setting the stage for the realization that early immune aging both exists and is a driver of the comparatively small changes in physiology that take place in the 20s and 30s.

Changes of senescent cell accumulation and removal in skin tissue with ageing

Senescent cells are known to secrete various inflammatory cytokines (known as the senescence-associated secretory phenotype factors: SASP factors) and adversely affect surrounding tissues. Senolytic drugs that selectively induce the death of senescent cells are under development. We reported that skin inherently possesses mechanisms to remove senescent cells. In the epidermis, this is achieved by the binding of JAG1, a Notch ligand expressed on adjacent non-senescent keratinocytes, to Notch1 receptors expressed by senescent keratinocytes, which promotes the exclusion of senescent cells from the basal layer by inducing differentiation. Meanwhile, in the dermis, senescent cells are phagocytosed by macrophages through recognition by the phosphatidyl serine (PS) receptor STAB1. However, since ageing is associated with the accumulation of senescent cells in skin tissue, it is hypothesized that this accumulation is preceded by a decline in the ability to remove them.

Here, we tested this hypothesis by analysing in detail the changes in the number of senescent cells and the ability of them to be removed from the skin with ageing. Marginal skin tissues at the time of surgery were collected from patients who had provided informed consent. Paraffin-embedded sections prepared from the unexposed skin tissue were subjected to immunostaining with the major senescent cell marker p16INK4A to analyse the number of senescent cells. To characterize the ability for senescent cells to be removed from the skin, the expression of JAG1 in the epidermal keratinocytes and STAB1 in macrophages was analysed. The results confirmed that senescent cell accumulation was increased with age in both epidermis and dermis. We also found that the ability to remove senescent cells decreased with age.

In addition, it was observed that while the accumulation of senescent cells was detected after 30s, the removal capacity began to decrease at 20s. Although there was a delay of the age at which senescent cell accumulation starts after the onset of declining of senescent cell removal ability, there appears to be a correlation across all ages between the removal ability and the accumulation of senescent cells. The reason of the decline in the senescent cell removal function in the 20s, before senescent cells accumulate, is still a mystery. We believe that environmental factors such UV radiation, reactive oxygen species, and exposure to SASP factors released by transiently senescent cells in young age may have an impact on the function of senescent cell removal. Future plans for this research include a closer look at these factors and the techniques for enhancing the efficiency of senescent cell removal.