New Concepts in Antiaging Dermatology

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What is cellular aging?

Antiaging dermatology has the basic goal of slowing or reversing changes known as cellular senescence, which is cell damage that results in an irreversible cell cycle arrest. This means the senescent cells cannot proliferate and experience mitotic arrest due to cellular stress causing cellular damage. There are no specific cell markers that code for senescence, but increases in cell cycle inhibitors (p21C1P1, p16INK4A) and a proinflammatory secretome are indicators. A proinflammatory secretome, known as the senescence-associated secretory phenotype, consists of cytokines, chemokines, metalloproteases (collagenase, elastase), and growth factors. You may ask why the body developed cellular senescence, but it is very important in tumor suppression, as oncogene-induced senescence prevents premalignant cells from reproducing and becoming cancerous. Thus, our endogenous mechanisms to prevent cancer also end up producing the signs and symptoms of aging as the senescent cells accumulate in the body.

How does cellular aging affect skin cellular components, including keratinocytes?

Intrinsic and extrinsic aging both contribute to cellular senescence. Intrinsic aging is characterized by oxidative stress from bodily functions and telomere shortening. Extrinsic aging, driven primarily by UV and pollution exposure, affects all skin cell types. Keratinocytes are less subject to senescence due to their rapid turnover; however, senescent keratinocytes have reduced extracellular matrix production and decreased cell adhesion. This could explain, in part, why the skin barrier is less robust and more permeable with advancing age.

How do fibroblasts respond to cellular senescence?

Dermal fibroblasts experience cellular senescence, which leads to fibroblast death. This means the shape of the fibroblast must become extended to compensate for the reduced fibroblast density. UV exposure induces the senescent phenotype, as mentioned previously, of cell cycle inhibitors (p21C1P1, p16INK4A) and a proinflammatory secretome. These senescent fibroblasts induce apoptosis or cell death in surrounding fibroblasts leading to further loss. Senescence also affects the secretory capabilities of fibroblasts. Senescent fibroblasts secrete less insulinlike growth factor-1 due to mitochondrial dysfunction, resulting in decreased collagen production.

However, fibroblast senescence plays a very important role in wound healing. Senescent fibroblasts limit collagen deposition that leads to fibrosis, thus preventing hypertrophic scars and keloids.

Are melanocytes affected by cellular senescence?

Melanocytes are indeed greatly affected by cellular senescence as manifested by the universal graying of hair with aging. The melanocyte count decreases with age. Decreased laminin B1 and increased p16INK4A are senescent-associated melanocyte markers, which can be used to track the clearance of senescent melanocytes with various experimental treatments. It is interesting to note that senescent cells of one cell type can influence other cell types. For example, senescent melanocyte spent media can induce telomere dysfunction in fibroblasts, indicating that paracrine mechanisms can be used to promote senescence.

What are senotherapeutics?

The new concept of cellular senescence in dermatology has led to the search for senotherapeutics, which are small molecules designed to target senescent cells. Senotherapeutics can be divided into senolytics or senomorphics. Senolytics are designed to clear senescent cells through senolysis. Senomorphics are intended to decrease the secretion of proinflammatory substances by affecting the spread of paracrine senescence. Senotherapeutics is a new concept in antiaging dermatology. 

Zoe Diana Draelos, MD, is a consulting professor of dermatology at Duke University School of Medicine in Durham, North Carolina, and Dermatology Times’ editor in chief emeritus.