Senotherapeutic peptide treatment reduces biological age and senescence burden in human skin models

Abstract

Cellular senescence is known to play a role in age-related skin function deterioration which potentially influences longevity. Here, a two-step phenotypic screening was performed to identify senotherapeutic peptides, leading to the identification of Peptide (Pep) 14. Pep 14 effectively decreased human dermal fibroblast senescence burden induced by Hutchinson-Gilford Progeria Syndrome (HGPS), chronological aging, ultraviolet-B radiation (UVB), and etoposide treatment, without inducing significant toxicity. Pep 14 functions via modulation of PP2A, an understudied holoenzyme that promotes genomic stability and is involved in DNA repair and senescence pathways. At the single-cell level, Pep 14 modulates genes that prevent senescence progression by arresting the cell cycle and enhancing DNA repair, which consequently reduce the number of cells progressing to late senescence. When applied on aged ex vivo skin, Pep 14 promoted a healthy skin phenotype with structural and molecular resemblance to young ex vivo skin, decreased the expression of senescence markers, including SASP, and reduced the DNA methylation age. In summary, this work shows the safe reduction of the biological age of ex vivo human skins by a senomorphic peptide.

Double‐blind, vehicle‐controlled clinical investigation of peptide OS‐01 for skin rejuvenation

“…As such, the effects of OS‐01 results in improved skin barrier and hydration, as measured both quantitatively as well as qualitatively, may have health implications beyond the appearance of the skin. Most likely, the positive results obtained in vivo regarding skin hydration and skin barrier are a reflection of the data obtained from 3D skin equivalents and skin biopsies tested with OS‐01 peptide in vitro, which presents an increase in the epidermal thickness following peptide treatment, as well as increased mRNA expression of Hyaluronan Synthase 2, an enzyme that synthesizes hyaluronic acid in the skin, promoting water retention 21 . The improvement in the skin barrier function was not observed in the vehicle formula, suggesting that it is directly associated with the presence of the peptide.…”

“…In cell cultures, 3D skin equivalents, and organotypic ex vivo skin cultures, the OS‐01 peptide reduced cellular senescence levels and inflammation while boosting cellular renewal, and the expression of Collagen and Hyaluronan Synthase 2 21 . Furthermore, the peptide promoted better skin structural profiles, as well as rejuvenated mRNA and DNA methylation profiles, characterizing a lower biological age of treated samples and a decreased senescence burden.…”

“…Cellular senescence has been highlighted as a key pathway in a host of diseases, in particular age‐related diseases, such as cancer, 22 as well as playing a role in skin aging and the associated effects 23 . OS‐01 is a unique senotherapeutic peptide, shown to be safe 24 and to reduce cellular senescence burden and, consequently, reduce the skin biological age in vitro and ex vivo 21 . While the importance of these previous studies demonstrates the peptide's safety, efficacy, and underlying mechanisms as an active ingredient used in topical formulations, it is important to assess the effects of the peptide formulation in vivo.…”

“…The improvement in the skin barrier function was not observed in the vehicle formula, suggesting that it is directly associated with the presence of the peptide. Based on our previously published investigations into the mechanisms of OS‐01, we posit that the improved skin barrier is due to OS‐01 targeting and reducing senescent cells, as well as promoting cellular proliferation, as assessed by Ki67 staining in vitro 21 . The results presented here suggest that such mechanisms were effective in enhancing the health of the skin, measured by assessing the impact of a formulation containing the OS‐01 peptide on improving the skin barrier function, compared to the vehicle formulation only.…”

“…Peptide 14) is the main ingredient of the first topical product developed by a longevity company, focusing on promoting skin health and preventing the accumulation of senescent cells in the skin 20 . Recently, our group has shown that the OS‐01 peptide reduces cellular senescence burden both in 3D human skin equivalents and ex vivo skin samples, promoting health markers and, importantly, reducing the skin's biological age 21 . Besides the OS‐01 peptide, this formula contains other ingredients known to be moisturizing, anti‐inflammatory, and have antioxidant properties such as Pracaxi Oil, Andiroba Oil, Oleic Pau Mulato Extract, Niacinamide, Allantoin, and Hyaluronic Acid.…”