Cellular senescence, skin aging, and cosmeceuticals

I just completed the third edition of my Cosmetic Dermatology textbook (McGraw Hill), which will come out later this year. Although writing it is a huge effort, I really enjoy all the basic science. While I was working on the book, I was most surprised by the findings on cellular senescence and autophagy, and I would like to share what I learned. These will be buzz words in the skin care field in the future.

Dr. Leslie S. Baumann

Right now, it is too early, and we don’t know enough yet, to have cosmeceuticals that affect cellular senescence and autophagy. But, it’s not too early to learn about this research, to avoid falling prey to any pseudoscience that invariably ends up affecting cosmeceuticals on the market. The following is a brief primer on cellular senescence, skin aging, and cosmeceuticals; it represents what we currently know.

Cell phases

Keratinocytes and fibroblasts go through five different phases: stem, proliferation, differentiation, senescence, and apoptosis. The difference between apoptotic cells and senescent cells is that apoptotic cells are not viable and are eliminated, while senescent cells, even though they have gone into cell cycle arrest, remain functional and are not eliminated from the skin.

What are senescent cells?

Senescent cells have lost the ability to proliferate but have not undergone apoptosis. Senescent human skin fibroblasts in cell culture lose the youthful spindlelike shape and become enlarged and flattened.¹ Their lysosomes and mitochondria lose functionality.² The presence of senescent cells is associated with increased aging and seems to speed aging.

^{"Cosmetic Dermatology," 3rd ed. (New York: McGraw Hill, 2021, in press)}

Senescent cells and skin aging

Senescent cells are increased in the age-related phenotype³ because of an age-related decline of senescent cell removal systems, such as the immune system⁴ and the autophagy-lysosomal pathway.⁵ Senescent cells are deleterious because they develop into a senescence-associated secretory phenotype (SASP), which is believed to be one of the major causes of aging. SASP cells communicate with nearby cells using proinflammatory cytokines, which include catabolic modulators such as Matrix metalloproteinases. They are known to release growth factors, cytokines, chemokines, matrix-modeling enzymes, lipids, and extracellular vesicles. The last are lipid bilayer-lined vesicles that can transport functional RNA and microRNA and facilitate other modes of communication between cells.⁶

The SASP is likely a natural tumor suppressive mode employed by cells to prevent cells with cancerous mutations from undergoing replication;⁷ however, when it comes to aging, the deleterious effects of SASP outweigh the beneficial effects. For example, SASP contributes to a prolonged state of inflammation, known as “inflammaging,”⁸ which is detrimental to the skin’s appearance. Human fibroblasts that have assumed the SASP secrete proinflammatory cytokines and MMPs and release reactive oxygen species,^9,10 resulting in degradation of the surrounding extracellular matrix (ECM). Loss of the ECM leads to fibroblast compaction and reduced DNA synthesis, all caused by SASPs.⁹

What causes cellular senescence?

Activation of the nuclear factor-erythroid 2-related transcription factor 2 (NRF2) induces cellular senescence via direct targeting of certain ECM genes. NRF2 is a key regulator of the skin’s antioxidant defense system, which controls the transcription of genes encoding reactive oxygen species–detoxifying enzymes and various other antioxidant proteins.¹¹ Loss of mitochondrial autophagy also induces senescence, as do activation of the TP53 gene, inactivity of SIRT-1, and short telomeres.