Skin Aging and Cellular Senescence

Much attention has been focused on the ability of aged senescent cells to encourage senescence in surrounding cells. In other words, the more you age, the more accelerated your aging becomes. This has led antiaging researchers to wonder whether the skin, a very accessible organ for observation and biopsy, can be predictive of total body aging or the aging of other individual organs.

Q: What is skin cellular aging?

Skin cellular aging is characterized by the accumulation of senescent cells in the skin throughout an individual’s lifetime. A senescent cell is in cell cycle arrest triggered by some oxidative, mechanical, or genotoxic event that results in DNA damage. This DNA damage accumulates over time, leading to genomic instability. This genomic instability leads to defective skin DNA repair, which leads to more skin DNA damage and cumulative cellular decline. DNA damage can also lead to mitochondrial dysfunction, resulting in the production of excess reactive oxygen species. Thus, while the damaged skin cell remains metabolically active, it is unresponsive to apoptotic cell death signals, resulting in the accumulation of senescent cells.

Q: What are the cellular signs of aging?

We see the appearance-related visual signs of aging on a daily basis, consisting of wrinkles, fine lines, dyspigmentation, etc. What about the signs of aging on a cellular level? Do these cellular signs of senescence correlate with appearance changes? The answer is yes. For example, melanocyte telomere damage is positively correlated with flattening of the epidermal-dermal junction and skin wrinkling. Further, reduced skin wrinkling in sun-protected areas is positively correlated with longevity and a perceived younger age and less cardiovascular disease risk in women. The relative absence of skin aging on a cellular level can be associated with longevity and overall enhanced appearance.

Q: Does skin aging affect aging in other body organs?

Apparently, senescent skin cells influence aging in other body organs by promoting dysfunction through senescence-associated secretory phenotype, known as SASP, which is composed of growth factors, chemokines, cytokines, proteases, and extracellular matrix components. This induces aging in other cells through a process called paracrine senescence. The presence of senescent skin cells leads to a decrease in macrophage function, which leads to further accumulation of senescent cells.

However, cellular senescence is necessary for human life. It is important in human limb development during embryogenesis for tissue remodeling. The presence of senescent cells also upregulates tissue repair and healing, making them crucial in wound healing and organ repair. It is postulated that healing would be greatly slowed in the absence of senescent cells. Senescent cells are also an indicator of disease, as they are found in increased amounts in inflammatory bowel disease and osteoarthritis. It is unclear whether the disease causes the senescent cells or whether the senescent cells cause the disease. There are no data indicating that removing senescent cells would lead to long-term disease benefits.

Q: What are the markers of skin senescence?

A variety of classic markers of skin cell senescence have been identified. These include expression of SA-β-galactosidase, deletion of 4977 base pairs in mitochondrial DNA (caused by UV radiation exposure), and loss of lamin B1 expression. You may think it would be interesting to develop a panel of these markers and track patients who are undergoing dermatologic antiaging therapy. However, SA-β-galactosidase is lost in tissue fixation, and deletion of 4977 base pairs is also seen in sun-protected skin.

Senescent cells can also be identified by their cellular products. For example, senescent fibroblasts secrete decreased IGF-1, resulting in decreased collagen expression. They also secrete increased IL-6 and IL-8, resulting in increased inflammation. The hope is that targeting cellular senescence in the skin will open up the next frontier in cosmeceutical technology.

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