Reversing skin aging through senescence modulation

How to turn back our biological clock?

Approaches to slowing or reversing aging have gained momentum in recent years, but the field is still in its infancy, with hurdles to overcome, as illustrated by efforts to develop therapies that eliminate senescent cells. Delaying aging, restoring youth, regenerative medicine… whatever the term used, research aimed at targeting the fundamental mechanisms of aging to increase hope and quality of life has flourished in recent years.

Among efforts to hit these milestones with potential therapies, those focused on cellular senescence have been at the forefront of industry activity, with more than 20 companies established in the last decade. In this article, we highlight some of the advances and challenges for a selection of these companies.

Over time, processes such as DNA damage, infection, and oxidative stress can cause cells to not function properly, but also not die as they should and instead remain in a zombie-like state. It is thought that these damaged cells, known as senescent cells, enter this state as a way of not becoming cancerous, but this also has a downside. Senescent cells can accumulate in various tissues and organs, and they are not just a passive disorder – they secrete pro-inflammatory molecules such as cytokines, growth factors and proteases. The phenomenon is known as senescence-associated secretory phenotype (SASP) and leads to an inflammatory environment that can result in chronic tissue damage and contributes to a number of diseases, including liver and lung fibrosis, atherosclerotic diabetes, and osteoarthritis (Nat. Rev. Nephrol . 18, 611–627; Consequently, these cells have become targets for the development of anti-aging therapies. Companies exploring this approach are developing senolytic drugs that directly target senescent cells, while others are manipulating mechanisms that modulate senescent cells.

Featured news published by Raveena Bhambra on Nature Biopharm Dealmakers on 12/01/2023 provides a summary of the senescence mechanism that occurs in the human body (Fig. 1), and provides a list of leading companies in the market targeting senescent cells as a treatment for aging, treating aging as an intrinsic disease of the organism human.

https://www.nature.com/biopharmdeal

Increasing evidence suggests that senescent cells accumulate in chronologically aged skin, as well as prematurely aged skin, and may contribute to age-related skin changes and pathologies. The accumulation of senescent keratinocytes and fibroblasts in the skin produces cytokines, extracellular matrix-modifying enzymes and other molecules that can act remotely and therefore exert far-reaching effects on the microenvironment of neighboring cells. Intrinsic and extrinsic factors can induce permanent senescence in skin cells, resulting from telomere shortening, mitochondrial impairment and upregulation of DNA damage response signaling, ultimately leading to cell cycle arrest. Consequently, it has been suggested that the presence of senescent keratinocytes and fibroblasts contributes to the decline in skin integrity and function. Melanocytes were also found to exhibit the markers of senescence, including elevated p16INK4A, reduced HMGBI (high-mobility group box 1), and dysfunctional telomeres, and affect basal keratinocyte proliferation through the activation of reactive oxygen species (ROS). ) mitochondrial function dependent on the chymosin receptor CXC 3, thus contributing to epidermal atrophy.

Furthermore, proliferative arrest of cultured skin cells due to replicative or stress-induced senescence also represents a useful model for studying aging-related processes in the skin. Consequently, it was demonstrated, using models in vitro, that skin cell types exposed to UVB (fibroblasts, keratinocytes) exhibit DNA damage and cell cycle pause and express biomarkers of senescence, such as increased senescence-associated β-galactosidase (SA-β-Gal), p16INK4A, p21Waf-1, p53 activation and lamin B1 downregulation.

Natural compounds have been used in dermatology as oral dietary supplements or topical formulations for a long time. Polyphenols are the most abundant natural biochemicals found in fruits, vegetable seeds and spices, as well as in red wine, coffee and cocoa. Many beneficial effects of polyphenols have been demonstrated, including antioxidant and free radical scavenging activity, antitumor and anti-inflammatory properties, and antithrombotic and antimicrobial activity. Additionally, there is growing evidence that polyphenols may slow or prevent aging-related deterioration in skin appearance and function. The anti-inflammatory effect of the flavonoids apigenin, quercetin, kaempferol, naringenin and wogonin was tested on bleomycin-induced senescence in human foreskin fibroblasts. In this study, all flavonoids except naringenin significantly inhibited the secretion of SASP markers IL-6, IL-8 and IL-1β. Hydroxytyrosol also showed protective potential against cellular aging induced by UVA in human dermal fibroblasts, as it reduced the expression of the inflammatory cytokines IL-1β, IL-6 and IL-8, MMP-1 and -3 gene and SA-β- marker. Gal in a dose-dependent manner. HaCaT keratinocytes cultured in the presence of bergamot polyphenolic fraction (BPF) after UVB treatment resulted in recovery of cell viability through modulation of the pro-inflammatory cytokine IL-1β.

Marine natural products provide a rich source of chemical diversity that can be used to develop promising new anti-aging agents for skin care. Extracts from three species of seaweed Alariaceae, Eisenia bicyclis, Ecklonia cava It is Ecklonia stolonifera, showed a strong inhibition of NF-κB and AP-1 activity, which were well correlated with their abilities to inhibit MMP-1 expression in human dermal fibroblasts. However, it is important to mention that the beneficial effect of polyphenols does not only mean preventing or delaying the outcome of the senescent phenotype, but also consists of eliminating cells that are already senescent. The elimination of senescent cells is called senolysis, and many polyphenols, as potential senolytic drugs, also in the context of age-associated skin deterioration, are under investigation.

References:

BULBIANKOVA D.; DÍAZ-PUERTAS R.; ÁLVAREZ-MARTÍNEZ FJ; HERRANZ-LÓPEZ M.; BARRAJÓN-CATALÁN E.; MICOL V. (2023). Hallmarks and Biomarkers of Skin Senescence: In Updated Review of Skin Senotherapeutics. Review. Antioxidants; 12: 444. https://doi.org/10.3390/antiox12020444.

HUANG W.; HICKSON LT. J.; EIRIN A.; KIRKLAND JL; LERMAN LO (2022). Cellular senescence: the good, the bad and the unknown. Nature Reviews/Nephrology; 18: 611. https://doi.org/10.1038/s41581-022-00601-z.

ERIKA C. & RACKOVÁ L. (2021). Skin Aging, Cellular Senescence and Natural Polyphenols. International Journal of Molecular Sciences. Review; 22: 12641. https://doi.org/10.3390/ijms222312641.

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