New research highlights that senotherapeutic peptides are capable of reducing biological age in human skin models.

The skin is the largest organ of the body, comprising several compartments and about 20 different cell types that are involved in various skin functions – complexity that is more than skin deep! [1] Skin aging is a multifactorial process that is impacted by several intrinsic and extrinsic factors. Constant exposure of the human skin to such stimuli impacts its function and accelerates aging resulting in dry skin, wrinkling, thinning of the epidermis, and reduced barrier integrity. While we notice most of those changes by looking in a mirror – something the cosmetics industry has leveraged to multi-billion dollar effect – older skin is more at risk of injury, less able to sense touch, heat and cold, slower to heal and more prone to cellulitis and other skin infections.

Aging is a complex and gradual process characterized by a reduction in function and reproducibility along with an increase in the incidence of degenerative diseases. Skin aging has been reported to be associated with the presence and accumulation of senescent cells. “A number of diseases that increase in older people may have a unifying underlying mechanism having to do with senescence,” says Ruth Montgomery, PhD, professor of medicine and epidemiology (microbial diseases) at Yale School of Medicine [2].

Senescent cells are those that have lost their proliferative capacity, are resistant to apoptosis, and secrete factors that can cause tissue deterioration and inflammation [3]. These factors are termed senescence-associated secretory phenotype (SASP) and can lead to extracellular matrix (ECM) deposition, impact epidermal stem cell renewal and worsen melanin synthesis.

Longevity.Technology: Suppression or selective elimination of the senescent cell population can prevent their adverse outcomes on the skin. Although such a strategy has been tested in animal models, clearing these cells has led to certain unwanted outcomes such as defective wound healing. Researchers have indicated compounds that reverse or modulate the phenotypes of senescent cells (senomorphics) might serve as effective alternatives. However, to date, only one study has reported senotherapeutic strategies to be effective in promoting the rejuvenation of skin through the application of topical rapamycin on the skin [4].

In a new study published in npj Aging, Alessandra Zonari, PhD, Co-founder and Chief Scientific Officer at OneSkin, and her team screened and analyzed the role of Peptide 14 in the reduction of levels of cellular senescence in a Hutchinson-Gilford Progeria Syndrome (HGPS) model of cellular aging [5].

Peptide 14 (Pep 14) was reported to reduce cellular senescence levels and was also observed to be a safe molecule with no carcinogenesis, toxicity, or chromosomal instability. Peptide 14 was observed to reduce the production of SASP and block the induction of the senescence marker senescence-associated beta-galactosidase staining (SA-BGal). “Pep 14 was capable of protecting dermal cells from multiple forms of extrinsic stressors that contribute to senescence and aging,” said Zonari [5].

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Pep 14 was observed to modulate 20 genes that were associated with important aging-related pathways such as longevity, cellular senescence, FoxO signaling, and others. Moreover, treatment with Pep 14 was observed to promote a younger gene expression signature. Pep 14 was found to be not highly similar to any known proteins and exerted its role as a senotherapeutic molecule via the protein phosphatase 2 (PP2A) signaling, which is a holoenzyme that promotes genomic stability. Pep 14 was also reported to modulate PP2A and CDKN2AP1 in early-stage senescent cells thereby promoting DNA repair and preventing these cells from becoming late senescent cells.

The study also indicated Pep 14 increases the epidermal thickness of the skin, reduces the biological age of the skin, and improves several markers of cellular senescence and skin health, as compared with rapamycin. Pep 14 was observed to promote a younger skin profile as well as reduced expression of senescent cells.

“Our data demonstrate that Pep 14 is a senotherapeutic compound that supports DNA repair, prevents SASP by preventing cells from progressing to late stages of cellular senescence, therefore improving skin health, and significantly reducing the skin biological age,” said Zonari.

This suggests that senomorphic peptides can be used as therapeutic approaches for the safe reduction of the biological age of skin – approaches that will contribute to healthier outcomes, as well as younger outward appearances.

[1] https://www.sciencedirect.com/science/article/pii/S004763742100097X
[2] https://medicine.yale.edu/profile/ruth-montgomery/
[3] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8657738/
[4] https://link.springer.com/article/10.1007/s11357-019-00113-y
[5] https://www.nature.com/articles/s41514-023-00109-1