Unveiling the molecular determinants of mammalian skin ageing: A proteomic and transcriptomic approach

Abstract

As the limits of human lifespan continue to expand, ageing biologists must address the decline in the integrity of bodily tissues with time. Our skin is drastically impacted by both intrinsic and extrinsic ageing processes, driven by gradual accumulation of cellular damage and environmental insults like ultra-violet irradiation.
Together intrinsic and extrinsic skin ageing give rise to clinical issues such as xerosis, pruritus and neoplasms. Cosmetic issues, such as unsightly wrinkling, thinning and sagging of the skin also impact human psychological and social wellbeing. Given these issues, studying the molecular mechanisms of intrinsic and extrinsic skin ageing processes is an important element of biological research, as a better understanding of how these processes contribute to reduced tissue integrity will allow us to develop therapies to attenuate the ageing process.
Using tissues taken from C57BL/6 male mice and female humans as our models, we analysed skin at early, middle and late stages within both the murine and human lifespans to assess the impact of ageing on changes in the epidermis, dermis and at the basement membrane. By considering tissue taken from photo-protected and photo-exposed sites of humans, we additionally studied the differential changes occurring during intrinsic and extrinsic skin ageing (photo-ageing).
Our studies showed that several morphometric changes occur to the epidermis with age in mouse skin, where we observed thinning and cellular loss. Cell proliferation and lamin B1 levels declined, which was coupled with decreased expression of dermal and basement membrane collagens. Many of these observations were ubiquitous in intrinsically aged human skin, where we additionally show unique transcriptional changes at the basement membrane. One little studied pathway in skin ageing is the Hippo pathway, which has crucial roles in epidermal development through its control of epidermal cell proliferation. We identify a novel modulation of the Hippo pathway effector YAP1 in aged mouse and human skin, where we show that nuclear localisation of YAP1 increases during epidermal ageing.
Together this body of work demonstrates that C57BL/6 mouse skin ageing shares common mechanisms of intrinsic human skin ageing. Additionally, we show that YAP1 localisation is altered during epidermal ageing, which suggests that the Hippo pathway is sensitive to both changes in the extra-cellular matrix content, and cell-proliferation properties of skin over time.