Ryeim ansaf
Aging scientists have been exploring a cell growth arrest phenomenon, cellular senescence, as a possible cause of biological aging. Senotherapeutic treatments have been discovered to reduce biological aging through the clearance of these growth-arrested “senescent” cells, resulting in mechanisms to increase biological age longevity. Could senotherapeutics be the path to human lifespan expansion?
Senescent cells were first discovered in 1961 through serially sub-cultured human fibroblasts, which lost their replicative properties while remaining viable. A few sources describe these cells as “zombie” stability growth arrested cells that typically arise with aging. Some of the morphological and metabolic changes of these cells include an elongated cell shape, altered gene expression, and the secretion of a pro-inflammatory phenotype commonly referred to as the senescence-associated secretory phenotype. Reducing the number of these cells is essential to healthy aging through the reduction of the biological age of tissues. As the human lifespan increases, eliminating senescence has become essential to maintain healthy biological function.
OneSkin Inc., a longevity company focusing on skin senescence, is developing products for the extension of skin and body health. In their recent study, “Senotherapeutic peptide treatment reduces biological age and senescence burden in human skin models”, published in the journal Regenerative Medicine, they have discovered the Peptide 14 serotherapeutic treatment. Using a two-step phenotypic screening, the Peptide 14 treatment was identified as a senotherapeutic. Similar to senolytics, senotherapeutics eliminate senescence; however, senotherapeutics eliminate senescent cells in a selective manner. Furthermore, senomorphics, a specific subset of senotherapeutics, modulate the function and morphology of senescent cells. Peptide 14, the discovered senotherapeutic, decreases senescence burden induced by a Hutchinson-Gilford Progeria Syndrome model (a syndrome that accelerates aging), ultraviolet-B radiation, and even chronological aging. The mechanism of Peptide 14 has been explored to function through the modulation of PP2A, a holoenzyme that promotes genomic stability. In addition to cellular senescence, this holoenzyme is also involved in DNA repair. Peptide 14 carries out its role as a senotherapeutic through modulating the genes driving senescence progression, thus arresting the cell cycle and enhancing DNA repair. Through this, less cells progress to a late senescence stage. The emphasis of the role of this treatment on skin is correlated with cellular senescence’s deterioration of skin functions and structure with aging. Examples of these changes include a thinning top epidermal layer of skin, decreased sensation, and the onset of wrinkles.
Upon this discovery, the researchers also explored the effects of Peptide 14 on healthy skin prototypes with structural and molecular resemblance to young ex vivo skin. Peptide 14 reinforced its senotherapeutic properties by reducing senescence markers and DNA methylation-associated age. These findings are important as they support the idea that the biological age of skin can be reduced with peptide 14 as a senotherapeutic. Clinically, this can have many benefits, such as healthier appearing skin, more skin elasticity, and better skin function.
Although this discovery is significant in the field of aging, age reversal of tissue remains to be a challenging task. One of the challenges behind this is limitations in the detection of senescent cells. Until now, a biomarker that exclusively marks senescent cells has not been discovered. Hence, there is a lot of off-target clearance that affects healthy cells in the body. Additionally, since the study was limited to ex vivo human skin cell equivalents and involved many different concentrations of the peptide, the exact dose is yet to be optimized.
Despite these challenges in cellular senescence research, Peptide 14 is a significant addition to the field of dermatology and is the first treatment of its kind. Additionally, although this paper was specifically focused on skin, it will open avenues for new research in therapeutic peptides as potential senotherapeutic for various organs. The work has emphasized that safe reduction of the biological age of ex vivo human skin is possible through peptide 14, and, someday, this technology could be applied to human skin helping millions of humans living with age-related skin disease. With healthier aging, humans entering their 8th and 9th decade of life will have a better quality of life, less phenotypic aging, and most importantly, lower loss of organ functionality.
References:
Schneider EL. Aging and cultured human skin fibroblasts. J Invest Dermatol. 1979 Jul;73(1):15-8. doi: 10.1111/1523-1747.ep12532753. PMID: 448173.
WHO methods and data sources for life tables 1990-2019 (Global Health Estimates Technical Paper WHO/DDI/DNA/GHE/2020.1)
Zonari, A., Brace, L.E., Al-Katib, K. et al. Senotherapeutic peptide treatment reduces biological age and senescence burden in human skin models. npj Aging 9, 10 (2023). https://doi.org/10.1038/s41514-023-00109-1
Chaib, S., Tchkonia, T. & Kirkland, J.L. Cellular senescence and senolytics: the path to the clinic. Nat Med 28, 1556–1568 (2022). https://doi.org/10.1038/s41591-022-01923-y.