The skin has many roles which are backed by the highly controlled interactions among various cells of epithelial, mesenchymal, neuronal and immunological origin, which are ingrained in a complex extracellular matrix (ECM) structure and are responsible for the biomechanical features of the skin.

Keratinocytes (KCs) are constantly replenished by stem cells (SCs). Epidermal homeostasis relies on cellular differentiation that implicates the regulation of integrins and shows the movement of the differentiated cells to the upper layers of the epidermis from where they are shed.

Skin also includes structures like hair follicles (HFs); sebaceous, apocrine and eccrine glands; and a complex network of immunocompetent cells. The basement membrane connects the epidermis to the underlying dermis and subcutis where fibroblasts and vessel-forming cells resided in a dense ECM containing numerous collagenous and noncollagenous proteins and proteoglycans, which help in creating the skin matrisome.

Fibroblasts regulate the functions of the KCs, the melanocytes, the Langerhans cells and SC reservoirs in the bulge regions of HFs and the interfollicular epidermis.

Currently, fibroblast subsets involved in specific activities are being investigated promptly to establish their role in distinct disease entities. 

These cellular and extracellular constituents witness changes in their biophysical and biological activities by intrinsic aging that causes a decrease in elastin fibers and collagen and losses the tensile strength of the skin. 

Ultraviolet (UV) irradiation and other external environmental factors provoke extrinsic aging by inducing metalloproteases, releasing VEGF and alterating elastic fibers and the corresponding microfibrillar network. 

The skin model is best for studying the principal mechanisms of aging pertaining to its complex tissue composition featuring distinct types of cells and its exposure to the environment, along with easy accessibility.

Key processes involved in aging are DNA damage, defective repair processes, protein aggregates accumulation, mitochondria functions alterations and cell membrane defects. These may trigger metabolic changes, compel chronic inflammation, and harm the functioning of the immune system. Additionally, they are involved in skin diseases in the elderly, like epithelial cancer and autoimmunological diseases, and also in alterations in the barrier function. 

This understanding has led to the identification of specific target circuits and structures to allow therapeutic modulation.

Source: Schumacher B, Krieg TM. The aging skin: from basic mechanisms to clinical applications. J Investig Dermatol. 2021;141(4):949-50.